Photodynamic Therapy for the Treatment of Early Esophageal Cancer: a Systematic Review and Economic Evaluation

Health Technology & Policy Series; 2009:2

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation

FINAL REPORT August 2009

Submitted to: Submitted by: The Alberta Health Technologies Decision Process Health Technology & Policy Unit Health Technologies and Services Policy Unit School of Public Health Clinical Advisory and Research Branch Department of Public Health Sciences Health Policy and Service Standards Division University of Alberta Alberta Health and Wellness Edmonton, AB Edmonton, AB Canada Canada

Production of this document has been made possible by a financial contribution from Alberta Health and Wellness and under the auspices of the Alberta Health Technologies Decision Process initiative: the Alberta model for health technology assessment and policy analysis. The views expressed herein do not necessarily represent the official policy of Alberta Health and Wellness.

Project team: Health Technology & Policy Unit School of Public Health, University of Alberta 3021 Research Transition Facility (RTF Building) 8308‐114 St Edmonton, AB Canada T6G 2V2 Telephone: 780‐492‐9070 / Fax: 780‐248‐1546 / E‐mail: [email protected]

With special thanks for their advice and support throughout the project:

Dr. Caroline Davis, Health Technologies and Services Policy Unit, Alberta Health and Wellness Dr. Christopher McCabe, Academic Unit of Health Economics, University of Leeds Dr. Clarence Wong, Department of Gastroenterology, Royal Alexandra Hospital, University of Alberta (Dr. Wong was also a member of the Expert Advisory Committee for this project)

We also thank the members of the Expert Advisory Committee for their review and comments on the draft report:

Dr Raymond Howard, Medical Consultant, Alberta Health and Wellness Ms. Andrea Nagle, Pharmaceutical Policy Consultant, Alberta Health and Wellness Dr. Marc Kerba, Radiation Oncologist, Tom Baker Cancer Centre; Clinical Assistant Professor, University of Calgary Dr. Eric Bedard, Division of Thoracic Surgery, Department of Surgery, University of Alberta Ms. Marg Semel, Director, Surgical Inpatients and Trauma, (Calgary Health Region), Alberta Health Services Ms. Shelley Johannsson, Project Consultant, Royal Alexandra Hospital Mr. Darryl Diletzoy, Director, Finance, (Alberta Cancer Board), Alberta Health Services

This assessment has been requested by Alberta Health and Wellness as part of its process for considering photodynamic therapy (PDT) as a publicly funded treatment for early esophageal cancer.

Early esophageal cancer refers to cancer that has not spread beyond the mucosal lining of the esophagus or to the lymph nodes. Using the American Joint Committee on Cancer classification system, early esophageal cancer is limited to T1 to T2 (tumour stage 1 and 2), N0 (lymph node negative) cancers, which have not metastasized (spread) beyond the esophagus.

Photodynamic therapy (PDT) is one of several endoscopic techniques used to treat early stage esophageal cancer. It uses a photosensitizing drug that is activated by light to ablate abnormal tissue.

This assessment examines the safety and effectiveness of PDT for early stage esophageal cancer, compared to surgery (esophagectomy), chemotherapy, radiotherapy, combined chemoradiotherapy, and a number of more recently introduced endoscopic techniques (endoscopic mucosal resection, radiofrequency ablation, argon plasma coagulation and cryoablation). (Photodynamic therapy is also used as a palliative treatment in advanced esophageal cancer, but its role in advanced cancer treatment is not included in this review.)

This report also assesses the social and economic considerations associated with PDT compared to other therapies, and the implications of its use in Alberta.

A companion review assesses the evidence on photodynamic therapy and other treatments for Barrett’s esophagus with high grade dysplasia that are used to prevent the development of esophageal cancer.

Questions & answers for policy makers

1. What is the potential role of photodynamic therapy (PDT) in the management of early esophageal cancer in adults?

Like other endoscopic treatments, PDT offers a less invasive alternative to esophagectomy (surgical removal of the esophagus). It also offers a treatment option for patients with other health conditions who cannot undergo esophagectomy. In addition, PDT may be useful in combination with other endoscopic treatments, as part of a multi‐treatment strategy. [See pages 30‐32.]

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta 2. In comparison with alternate treatments (chemotherapy, radiotherapy, and combined chemoradiotherapy), recently introduced endoscopic treatments (endoscopic mucosal resection, radiofrequency ablation, argon plasma coagulation, and cryoablation), and to surgery (esophagectomy), what is the safety of PDT for early esophageal cancer?

There was one treatment‐related death (due to perforation) in the studies of photodynamic therapy for early esophageal cancer. Adverse effects varied depending on the photosensitizer used. Stricture (which was resolved endoscopically with dilation) was the most common adverse event reported in studies of PDT with the photosensitizer porfimer sodium (occurring in about 13% of patients), No strictures were reported in studies of PDT with the photosensitizer ALA. Photosensitivity was reported in about 3% of patients who received PDT with porfimer sodium. Other adverse events with PDT using porfimer sodium included bleeding and perforation, but these occurred in less than 1% of patients.

Many of the studies of other endoscopic techniques did not report information on adverse events. However, in those that did, strictures occurred less frequently than with PDT.

Treatment‐related deaths occurred in about 3% of the patients who underwent radiotherapy, and 1% of patients who received chemoradiotherapy. Only one esophagectomy study reported adverse events in patients with early esophageal cancer. In this study, 2% of patients died from surgical complications. Moreover, strictures occurred in 16% of esophagectomy patients, and infections and anastomotic leaks occurred in 8% of patients. Other adverse events associated with esophagectomy included cardiovascular and respiratory complications, and delayed gastric emptying in 3% to 5% of patients.

Although the available information on adverse events is limited, the safety profile of PDT and other endoscopic treatments appears promising relative to that of esophagectomy. [See pages 42‐43.]

3. In comparison with alternate treatments, what is the effectiveness or efficacy of PDT for early esophageal cancer?

These results should be interpreted with caution given the poor quality of the studies and because many patients received additional treatments after the study treatment. The main outcome measures reported were response to treatment, recurrence of cancer, cause‐specific and overall survival, but few of the studies reported information on all outcomes.

Response to treatment: In the PDT studies, 50% of patients with adenocarcinoma and 70% of patients with squamous cell carcinoma experienced a complete response after 1 to 3 treatment sessions. The complete response rates achieved with PDT were lower than those of other endoscopic treatments, but this may be because the PDT studies appeared to include more patients with an advanced stage of early cancer (Stage 2).

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta None of the studies of chemotherapy reported complete response rates, but several of the studies that used chemoradiotherapy (chemotherapy in combination with radiotherapy) did. Pooled results from the 4 studies of patients with squamous cell cell carcinoma show a complete response rate of 86%, while the single study of patients that included squamous cell and adenocarcinoma reported a complete response rate of 77%. These results were similar to those achieved with PDT for cancers of the same cell type. As with the PDT studies, the response rate decreased as the tumour stage increased.

Pooled results from the radiotherapy studies (most of the patients had squamous cell carcinoma) showed a complete complete response rate was achieved in 81% of patients.

Only one of the esophagectomy studies, which compared endoscopic mucosal resection and PDT to esophagectomy, reported complete response rates. It found no statistically significant difference in complete response rates (83% with the combined endoscopic treatments versus 100% with esophagectomy), which suggests the combination of endoscopic therapies may offer comparable effectiveness in eradicating cancerous tissue.

Recurrence of cancer:

In patients who had squamous cell cancer treated with PDT (using ALA), 19% experienced a recurrence (after an average follow‐up period of 18 months). Only 3% of PDT‐treated adenocarcinoma patients had disease recurrence, despite a longer follow‐up.

Differences in disease recurrence between cancers of different cell types (squamous versus adenocarcinoma) were also found. These findings were comparable to those for the other endoscopic techniques. In the small studies of argon plasma coagulation, cancer recurrence rates in patients with squamous cell cancer were 25%, but no recurrence was reported in the study of 3 patients with adenocarcinoma. Many of the studies of non‐endoscopic treatments did not report recurrence rates, or did so without stating the length of follow‐up. In the studies of esophagectomy, only one small case series reported recurrence rates; during the four‐year follow‐up cancer recurred in 33% of patients.

Survival:

Only 2 of the 26 PDT studies reported 5‐year cause‐specific survival rates. In these 2 studies, 90% of patients had not died from esophageal cancer after 5 years. However, patients who had a recurrence of cancer received other additional treatments. Therefore, it is not possible to determine the survival benefit due to PDT alone. None of the other studies of endoscopic ablative treatments reported long‐term cause‐specific or overall survival information.

In the 3 studies of endoscopic mucosal resection that reported long‐term survival, rates were similar to those for PDT, and patients whose cancer recurred also received other treatments, making it difficult to separate out the survival benefit due to specific treatments.

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta In the chemotherapy studies that reported survival rates, overall survival was similar to that achieved with esophagectomy alone, suggesting that the addition of chemotherapy did not offer an advantage. [See pages 43‐48.]

4. What are the patient factors related to outcomes?

Most of the published studies did not provide outcomes information for patient sub‐groups based on early and advanced cancer.

Several studies (using various treatments) found lower rates of cancer recurrence and higher survival rates in patients who had esophageal adenocarcinoma, in comparison to those with squamous cell esophageal cancer. [See pages 43‐48.]

5. What are the known challenges to using PDT for early esophageal cancer?

None of the studies assessed the effect of physician experience (the “learning curve”) with PDT on patient outcomes. Although training is required, the administration of PDT is not technically difficult. More of an issue is the training of nursing staff to ensure the photosensitivity procedures are in place and that patients are well informed about photosensitivity restrictions. Photosensitivity restrictions, which apply for about 30 days with the photosensitizer porfimer sodium, may also be a burden for some patients and their families. [See pages 43, 49, 68.]

6. Is PDT for early esophageal cancer less costly than standard procedures, and, if not, do the benefits of using PDT outweigh its cost?

Although it is the most costly of the endoscopic therapies, compared to esophagectomy, PDT is less costly, has a lower mortality rate, and causes fewer major adverse events. As with other endoscopic treatments, multiple treatment sessions, and a combination of different endoscopic techniques may be used. Given the small number of patients in Alberta with esophageal cancer, and the need for multiple endoscopic treatments, a change in practice from esophagectomy to endoscopic therapies may not result in significant cost savings. [See pages 50‐67.]

Executive summary

Introduction:

Esophageal cancer is a relatively rare type of cancer, but it is particularly deadly if not treated at an early stage. The two main types of esophageal cancer are squamous cell carcinoma and adenocarcinoma.

A benign condition, called Barrett’s esophagus, often precedes esophageal adenocarcinoma. Precancerous cells (dysplasia) may form in the abnormal Barrett’s tissue. Consequently, individuals with Barrett’s esophagus have an increased risk for developing esophageal adenocarcinoma.

Interventions, such as surgical and ablative techniques, to remove the dysplasia may prevent the development of esophageal cancer. Many of the treatments used to remove dysplasia are also used to treat patients with early esophageal cancer. It is not yet clear which treatments have the best outcomes in terms of reducing the risk of esophageal cancer progression, preventing recurrence, or increasing survival.

Photodynamic therapy (PDT) is one of the endoscopic, ablative techniques used to treat Barrett’s esophagus and early esophageal cancer. It uses a photosensitizing drug that is activated by a laser to ablate (remove) abnormal tissue. Porfimer sodium (Photofrin®) is the only photosensitizing drug approved for use by Health Canada for photodynamic treatment of Barrett’s esophagus with dysplasia and esophageal cancer.

This report reviews the safety and effectiveness of PDT for early stage esophageal cancer, compared to surgery (esophagectomy), chemotherapy, radiotherapy, combined chemoradiotherapy, and several more recently introduced endoscopic techniques (endoscopic mucosal resection, radiofrequency ablation, argon plasma coagulation and cryoablation). The report also examines the cost of PDT compared to the other treatments, and the potential social and financial implications of its use in Alberta.

Methods:

Two literature searches were undertaken for this assessment, in conjunction with a companion review on photodynamic therapy and other treatments for Barrett’s esophagus. The main project search focused on studies of photodynamic therapy, and the second search focused on studies of alternative treatments (i.e., esophagectomy, endoscopic and ablative treatments, chemotherapy, and radiation therapy).

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta This assessment includes a comprehensive economic decision model. The model used cost and treatment information from the published literature, industry sources, Alberta Health and Wellness, the Alberta Cancer Board, and from consultation with clinical experts.

Safety and effectiveness:

Seventy‐five studies were included in this review. Most of these were non‐comparative studies with limited follow‐up. The three main outcomes reported were treatment response (eradication or shrinkage of the tumour), recurrence and survival.

About half of the studies of PDT reported on adverse events. The type and frequency of adverse events varied depending on the photosensitizing agent used. The most commonly reported adverse event was the development of strictures (in about 13% of patients – all of which were resolved with endoscopic dilation). Photosensitivity occurred in about 3% of patients who received PDT with porfimer sodium. Other adverse events associated with photodynamic therapy (e.g., bleeding and perforation) occurred in less than 1% of patients. Most of the studies of other ablative treatments did not report on adverse events in patients with early esophageal cancer.

Economic considerations:

The literature search did not identify any economic evaluations of treatments for early esophageal cancer.

A comprehensive economic decision model was developed. In this model, a patient with early cancer of the esophagus (Stages 0 to IIA) begins treatment with one of the set of possible technologies included in the review of clinical effectiveness. Depending on a number of factors (e.g., outcome with this treatment, limits to repeat treatments, etc.), the patient may subsequently be treated with one or more of the other therapies, reflecting local clinical practice.

Based on this model, incremental cost‐effectiveness ratios (ICERs) were produced for each of the technologies, with esophagectomy as the “gold standard”. Photodynamic therapy had the highest cost per QALY of all the endoscopic therapies. Nevertheless, all of the endoscopic therapies were more cost‐effective than esophagectomy.

Contents

Purpose of the report ...... 3 Questions & answers for policy makers ...... 3 Executive summary...... 7 Contents...... 9 List of figures ...... 10 List of tables...... 10 Abbreviations...... 13 Glossary...... 15 Part I: Introduction & background...... 18 Development of esophageal cancer...... 18 Risk factors for esophageal cancer...... 20 Diagnosis of esophageal cancer ...... 21 Staging esophageal cancer...... 22 Incidence and prevalence of esophageal cancer ...... 26 Burden of esophageal cancer...... 26 Management of early esophageal cancer...... 28 Esophagectomy ...... 28 Chemotherapy...... 29 Radiation therapy (radiotherapy)...... 29 Endoscopic treatments for early esophageal cancer ...... 30 Endoscopic mucosal resection ...... 30 Argon plasma coagulation...... 30 Cryoablation ...... 30 Photodynamic therapy ...... 31 Radiofrequency ablation ...... 31 Status of photodynamic therapy & other treatments for early esophageal cancer in Canada 32 Market status...... 32 Diffusion of photodynamic therapy ...... 33 Part II: Safety & efficacy of photodynamic therapy for early esophageal cancer in comparison to other management strategies ...... 34 Research questions ...... 34 Methods ...... 34 Literature search...... 34 Selection of relevant studies ...... 35 Synthesis & critical appraisal of selected studies ...... 36 Data analysis...... 37 Results ...... 38 Description of included studies ...... 39 Quality of included studies...... 41

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Safety...... 42 Efficacy / effectiveness...... 43 Response...... 43 Recurrence...... 45 Survival ...... 46 Summary of other assessments of photodynamic therapy for early esophageal cancer ...... 47 Other assessments in progress...... 48 Part III: Social & ethical implications of photodynamic therapy for early esophageal cancer..... 49 Part IV: Economic and fiscal considerations...... 50 Research question...... 50 Methods ...... 50 Literature search...... 50 Selection of relevant studies ...... 50 Results ...... 50 Development of the economic model...... 50 Results ...... 57 Economic model ...... 57 Probabilistic sensitivity analysis ...... 58 Budget impact analysis...... 65 Part V: Policy considerations ...... 66 Part VI: Conclusions ...... 68 Appendices...... 69 Appendix A ‐ Literature searches ...... 70 Appendix B ‐ Evidence tables: included studies...... 79 Appendix C ‐ Evidence tables: excluded studies ...... 136 Appendix D ‐ Safety (adverse events) ...... 142 Appendix E ‐ Efficacy / effectiveness tables...... 156 Appendix F ‐ Evidence tables: survival...... 172 Appendix G ‐ Levels of Evidence & Grades of Recommendation ...... 191 References ...... 192

List of figures Figure 1. The digestive system...... 18 Figure 2. The esophageal wall...... 19 Figure 3. Esophageal cancer staging...... 23 Figure 4. Literature search results, study selection process and results...... 1 Figure 5. Probabilistic sensitivity analysis for treatments of esophageal cancer...... 64

List of tables Table 1. AJCC TNM staging system for esophageal cancer ...... 25 Table 2. Photodynamic therapy centres in Canada...... 33 Table 3. Criteria for including studies in this review ...... 36 Table 4. Summary of elements comprising the data abstraction form...... 37 Table 5. Key characteristics & overall description of included studies ...... 41 10

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Table 6. Summary of variables included in the economic model...... 52 Table 7. Estimated per procedure costs of treatment alternatives ...... 55 Table 8. Summary of ICERs for treatment options included ...... 58 Table 9. Probabilistic sensitivity analysis ‐ Costs ...... 60 Table 10. Probabilistic sensitivity analysis ‐ Probabilities, rates and treatment effects ...... 61 Table 11. Probabilistic sensitivity analysis ‐ Utilities...... 62 Table 12. Probabilistic sensitivity analysis ‐ Average costs, effectiveness & ICERS...... 63 Table 13. Estimated treatment costs...... 65

Table B 1. Studies of photodynamic therapy (PDT) for esophageal cancer ...... 80 Table B 2. Studies of argon plasma coagulation (APC) for esophageal cancer ...... 98 Table B 3. Studies of cryoablation for esophageal cancer...... 100 Table B 4. Studies of radiofrequency ablation (RFA) for esophageal cancer ...... 101 Table B 5. Studies of endoscopic mucosal resection (EMR) for esophageal cancer ...... 102 Table B 6. Studies of chemotherapy (CT) for esophageal cancer...... 110 Table B 7. Studies of external beam radiotherapy (EBRT) or intraluminal brachytherapy for esophageal cancer ...... 112 Table B 8. Studies of chemoradiotherapy (CRT) for esophageal cancer ...... 117 Table B 9. Studies of chemoradiotherapy (CRT) and surgery (esophagectomy) for esophageal cancer...... 122 Table B 10. Studies of surgery (esophagectomy) for esophageal cancer...... 124

Table C 1. Excluded studies...... 137

Table D 1. Adverse events/complications reported in studies of photodynamic therapy (PDT) for esophageal cancer ...... 143 Table D 2. Adverse events/complications reported in studies of argon plasma coagulation (APC) for esophageal cancer...... 145 Table D 3. Adverse events/complications reported in studies of cryoablation for esophageal cancer...... 146 Table D 4. Adverse events/complications reported in studies of radiofrequency ablation (RFA) for esophageal cancer...... 147 Table D 5. Adverse events/complications reported in studies of endoscopic mucosal resection (EMR) for esophageal cancer...... 148 Table D 6. Adverse events/complications reported in studies of chemotherapy for esophageal cancer...... 149 Table D 7. Adverse events/complications reported in studies of external beam radiotherapy (EBRT) and/or brachytherapy (BT) for esophageal cancer...... 150 Table D 8. Adverse events/complications reported in studies of chemoradiotherapy (CRT) for esophageal cancer ...... 151

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Table D 9. Adverse events/complications reported in studies of chemoradiotherapy (CRT) and surgery (esophagectomy) for esophageal cancer...... 152 Table D 10. Adverse events/complications reported in studies of surgery (esophagectomy) for esophageal cancer ...... 153

Table E 1. Treatment response and tumour recurrence in patients receiving photodynamic therapy (PDT) for esophageal cancer ...... 157 Table E 2. Treatment response and tumour recurrence in patients who received argon plasma coagulation (APC) for esophageal cancer...... 160 Table E 3. Treatment response and tumour recurrence in patients who received cryoablation for esophageal cancer...... 161 Table E 4. Treatment response and tumour recurrence in patients who received radiofrequency ablation (RFA) for esophageal cancer...... 162 Table E 5. Treatment response and tumour recurrence in patients receiving endoscopic mucosal resection (EMR) for esophageal cancer...... 163 Table E 6. Treatment response and tumour recurrence in patients who received chemotherapy (CT) for esophageal cancer ...... 165 Table E 7. Treatment response and tumour recurrence in patients receiving external beam radiotherapy (EBRT) or brachytherapy (BT) for esophageal cancer...... 166 Table E 8. Treatment response and tumour recurrence in patients receiving chemoradiotherapy (CRT) for esophageal cancer ...... 167 Table E 9. Treatment response and tumour recurrence in patients receiving chemoradiotherapy (CRT) and surgery (esophagectomy) for esophageal cancer...... 168 Table E 10. Treatment response and tumour recurrence in patients who underwent surgery (esophagectomy) for esophageal cancer...... 169

Table F 1. Survival rates in studies of photodynamic therapy (PDT) for esophageal cancer ..... 173 Table F 2. Survival rates in studies of argon plasma coagulation (APC) for esophageal cancer 176 Table F 3. Survival rates in studies of cryoablation for esophageal cancer...... 177 Table F 4. Survival rates in studies of radiofrequency ablation (RFA) for esophageal cancer ... 178 Table F 5. Survival rates in studies of endoscopic mucosal resection (EMR) for esophageal cancer...... 179 Table F 6. Survival rates in studies of chemotherapy (CT) for esophageal cancer...... 181 Table F 7. Survival rates in studies of external beam radiotherapy (EBRT) and/or intraluminal brachytherapy (BT) for esophageal cancer...... 182 Table F 8. Survival rates in studies of chemoradiotherapy (CRT) for esophageal cancer ...... 184 Table F 9. Survival rates in studies of chemoradiotherapy (CRT) and surgery (esophagectomy) for esophageal cancer...... 185 Table F 10. Survival rates in studies of surgery (esophagectomy) for esophageal cancer...... 186

AH&W Alberta Health & Wellness AJCC American Joint Committee on Cancer ALA aminolevulinic acid APC argon plasma coagulation ARDS acute respiratory distress syndrome ARS anti‐reflux surgery BE Barrett’s esophagus BMI body mass index BT brachytherapy CIM cardia intestinal metaplasia CR complete response CRT chemoradiotherapy CT chemotherapy DVT deep vein thrombosis EAC esophageal adenocarcinoma EBRT external beam radiotherapy EMR endoscopic mucosal resection ERCP endoscopic retrograde cholangiopancreatography ESD endoscopic submucosal dissection ESO esophagectomy EUS endoscopic ultrasound FNA fine needle aspiration GERD gastroesophageal reflux disease GI gastrointestinal HGD high grade dysplasia HpD hematoporphyrin derivative HPV human papillomavirus HRQL health‐related quality of life ICER incremental cost‐effectiveness ratio IM intestinal metaplasia IMC intramucosal carcinoma IV intravenous KTP potassium titanyl phosphate laser LGD low grade dysplasia mTHPC meta‐tetrahydroxyphenylchlorin Nd:YAG neodymium doped yttrium aluminum garnet laser NR no‐response PDT photodynamic therapy PET positron emission tomography PR partial response QALY quality–adjusted life year

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta RCT randomized controlled trial RFA radiofrequency ablation RT radiotherapy SCC squamous cell carcinoma TNM tumour node metastases TTE Transthoracic esophagectomy

Ablation: removal (e.g., of tissue). Adjuvant therapy: therapy given as a supplementary treatment to the main treatment, such as chemotherapy after surgical resection of a tumour. Aminolevulinic acid: a photosensitizing drug used in photodynamic therapy. Anastomosis: a surgical connection, usually between two tubular or hollow (e.g., blood vessels, intestines, stomach, esophagus) parts of the body. Argon plasma coagulation: use of argon gas and a monoplar electrical current to coagulate tissue. Barrett’s esophagus (also called Barrett esophagus or oesophagus, Barrett syndrome, Barrett’s epithelium, Barrett’s metaplasia): abnormal tissue (intestinal metaplasia) that replaces the normal lining of the esophagus as a result of gastroesophageal reflux disease. Biopsy: removal of tissue samples for pathological examination to determine the presence or extent of disease. Brachytherapy: a type of radiotherapy where the radiation source is inserted within the body at the site of the tumour. Budget impact analysis: the estimated costs to a particular health care budget of adopting and using a new technology. Cardia: the lower esophageal sphincter; the junction of the esophagus and stomach. Chemoradiotherapy: the combined use of chemotherapy and radiation therapy. Cryoablation (also called cryotherapy or cryosurgery): the use of liquid nitrogen or carbon dioxide gas to freeze and destroy tissue. Dysphagia: difficulty in swallowing. Dysplasia (also known as intraepithelial neoplasia): precancerous, abnormal cells. Early esophageal cancer: cancer that has not spread beyond the mucosal lining of the esophagus or to the lymph nodes (i.e., cancer that is up to and including Stage IIa in the American Joint Committee on Cancer TNM staging classification – see Table 1) Endoscope: a flexible, lit tube with a tiny camera that transmits images to a screen. In upper gastrointestinal endoscopy the endoscope is inserted through the mouth and down the esophagus to allow visualization of the esophagus, stomach and the upper part of the small intestine (duodenum). Endoscopic mucosal resection: the surgical resection of abnormal tissue through an endoscope; typically used to remove lesions <2 cm, or for removal of larger lesions piece by piece. Endoscopic submucosal dissection: typically used for the removal of larger (>2cm) lesions in the gastrointestinal tract. Endoscopic ultrasound: the use of an ultrasound transducer and an endoscope to obtain more detailed images of the gastrointestinal tract; used for diagnosis, staging and tissue sampling. Endoscopy: the use of an endoscope to see inside the body; endoscopy is also used to perform endoscopic procedures, such as biopsy or endoscopic mucosal resection; upper endoscopy, also called esophagoscopy, is endoscopy of the upper part of the gastrointestinal tract. Epithelium: layers of cells covering external body surfaces or lining internal organs.

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Esophageal adenocarcinoma: a type of esophageal cancer that originates in the abnormal glandular cells that have replaced the normal lining at the lower end of the esophagus. Esophagectomy: Surgical removal of all or part of the esophagus. Esophagitis: inflammation of the esophagus, usually caused by gastroesophageal reflux disease. Esophagoscopy: endoscopy of the upper part of the gastrointestinal tract. Esophagus (also known as the gullet): part of the digestive system connecting the mouth to the stomach. Fine needle aspiration: a biopsy technique that uses a hollow needle to aspirate fluid or cells. Gastroesophageal junction: where the esophagus joins the stomach. Gastroesophageal reflux disease (GERD, also known as gastro‐oesophageal reflux disease or GORD): frequent, chronic regurgitation of the stomach contents that damages the lining of the esophagus and may cause symptoms that affect quality of life. Human papillomavirus: a family of viruses that have been associated with the development of warts and some types of cancer. Incremental cost‐effectiveness ratio: the additional cost of an intervention compared to the less expensive intervention (or no intervention), divided by the difference in effect or patient outcome (e.g., QALY). Intestinal metaplasia: Intestinal cells that replace the normal squamous cells lining the esophagus; their presence in the esophagus indicates Barrett’s esophagus. Intramucosal carcinoma: cancer cells in the epithelia that have not yet spread into the submucosal layer. Lower esophageal sphincter: the valve at the lower end of the esophagus, at the junction of the esophagus and stomach. Metaplasia: where abnormal cells replace the tissue normally found in that part of the body. Mucosa: a mucous secreting membrane that forms one layer of the lining of the esophagus and intestines. Neoadjuvant therapy: an initial treatment given before another treatment, such as neoadjuvant chemotherapy or radiation therapy to shrink a tumour before surgery. Odynophagia: pain when swallowing. Photodynamic therapy: a treatment used for some types of cancer, skin conditions and age‐ related macular degeneration; it uses a photosensitizing drug followed by exposure to a light source to destroy tissue. Photosensitivity: sensitivity to light. Pleural effusion: excess fluid around the lungs. Porfimer sodium: a photosensitizing drug used in photodynamic therapy. Potential years of life lost: the relative effect of a disease on premature death. Proton pump inhibitors: a class of drugs that reduce the production of stomach acids; used to treat peptic ulcers and gastroesophageal reflux disease. Quality‐adjusted life year: a measure of health care outcomes that adjusts gain (or losses) in years of life subsequent to an intervention by the quality of life during those years. Radiofrequency ablation: the use of microwave energy to ablate tissue. Reflux: in gastroesophageal reflux this means the backwards flow of food and digestive fluids from the stomach into the esophagus. Squamous cells: flat, scaly cells.

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Squamous cell carcinoma: a type of esophageal cancer that begins in the squamous cells (the normal tissue lining the esophagus). Stenosis: abnormal constriction or narrowing of a vessel, canal or cavity in the body. Stricture: narrowing caused by scar tissue; esophageal strictures may cause difficulty in swallowing. Subcutaneous: below the skin. Submucosa: a layer of the lining of the esophagus that is below the mucosa and deep mucosa, and above the muscularis propria.

Part I: Introduction & background

Esophageal cancer is a rare, but deadly, cancer. There are two main types of esophageal cancer: squamous cell and adenocarcinoma. The risk factors for each type are different, but the same diagnostic methods, staging system and treatments are used for both types. Patients with esophageal cancer have better outcomes if the cancer is detected and treated at an early stage. Unless otherwise noted, both types of esophageal cancer are discussed in this assessment using the generic term esophageal cancer.

Development of esophageal cancer The esophagus is a 25 to 35 cm long muscular tube that carries food from the mouth to the stomach (Figure 1). The walls of the esophagus consist of several layers (Figure 2).

Figure 1. The digestive system. (Image courtesy of the US National Institutes of Health)

Cancer of the esophagus typically starts from the innermost layer and grows outwards. The layer lining the inside of the esophagus is called the mucosa. It contains two parts, the epithelium and the lamina propria. The epithelium, which forms the inner lining of the esophagus, is made up of flat cells called squamous cells. The lamina propria is a thin layer of connective tissue that lies next to the epithelium. Beneath the mucosa is the submucosa, which contains mucous‐secreting glands. A thick band of muscle, called the muscularis propria, lies under it, contracting in a coordinated way to force food along the esophagus from the mouth to the stomach. The muscularis propria is surrounded by connective tissue, called the adventitia, which forms the outermost layer of the esophagus.

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Connecting the esophagus to the stomach is the gastroesophageal junction. An area of muscle near this junction, the esophageal sphincter, controls the passage of food from the esophagus into the stomach, while preventing acid and digestive enzymes of the stomach from entering the esophagus. The acid and digestive enzymes are secreted by glandular cells that line the stomach. Unique characteristics of these cells make them resistant to the stomach’s acid and the enzymes.

Figure 2. The esophageal wall. (Image © Cleveland Clinic Foundation.)

At times, acid may escape or reflux from the stomach and enter into the esophagus. When this occurs frequently, it leads to gastroesophageal reflux. If the reflux of stomach acid back into the esophagus continues over several years, it can damage the lining of the esophagus. The “injured” squamous cells may then be replaced by abnormal glandular cells resembling those normally found in the stomach.

When glandular cells are identified in the esophagus, the condition is called Barrett’s esophagus.1 Large, epidemiologic studies have demonstrated that patients with Barrett’s are at an increased risk (30‐100 fold) of developing esophageal cancer.1 Exposure of the esophageal mucosa to toxic or noxious chemicals may also stimulate or promote the production of abnormal squamous cells. Damage to the lining of the esophagus may lead to dysplasia (a precancerous condition in which cells that are similar to cancer cells (but are not yet cancerous) grow in the esophagus, carcinoma in situ (“cancer in place”), and ultimately invasive cancer.2

Esophageal cancer is usually one of two types (histologic subtypes): squamous cell carcinoma or adenocarcinoma. Squamous cell carcinoma begins in the squamous cells. Because they line the entire esophagus, squamous cell carcinoma can occur anywhere along the length of the esophagus. Adenocarcinoma begins in glandular cells that have replaced normal squamous cells ‐ typically near the end of the esophagus, where it joins the stomach (i.e., in the lower esophagus).

The symptoms are similar for both types of esophageal cancer. However, patients with early disease are often asymptomatic, making it difficult to detect. When symptoms do appear, the disease has usually progressed and spread beyond the innermost layers of the esophageal wall.2,3 More than half of patients with esophageal cancer first present with advanced disease.4,5

Common signs and symptoms of esophageal cancer include:6  difficulty swallowing (dysphagia), initially experienced for solids, but eventually progressing to include liquids  pain when swallowing (odynophagia)  chest pain that radiates towards the back  persistent heartburn  hoarseness, coughing or raspy voice (which cannot otherwise be explained)  substantial weight loss  nausea and vomiting.

When the disease spreads or metastasizes to other organs it is usually to the liver and lungs. The symptoms often include jaundice (due to liver metastasis) and respiratory problems (due to lung metastasis), such as shortness of breath, aspiration pneumonia, and pleural effusion.1

Risk factors for esophageal cancer Risk factors associated with esophageal cancer vary between histological subtypes. Squamous cell carcinoma Over the last 3 decades, numerous epidemiologic studies have identified common risk factors for squamous cell carcinoma of the esophagus:6‐9  Vitamin or nutritional deficiences: Diets low in fruits, vegetables, and certain vitamins and minerals (riboflavin and vitamins A and C) have been attributed to the high incidence of esophageal cancer in some Asian countries.  Tobacco: Over half of all squamous cancers are caused by smoking.  Alcohol: Chronic alcohol use, especially in combination with smoking, is one of the strongest contributing risk factors.  Gender: In western countries, the risk for men is 3 to 4 times greater than that for women.  Age: Risk increases with age. Approximately 75% of people with esophageal cancer are diagnosed between 55 and 85 years of age.  Occupational exposures: A higher incidence of squamous cell carcinoma has been reported in patients who, through their occupations, were exposed to solvents or chemical fumes (e.g., dry cleaning chemicals).  Human papillomavirus infection (HPV): Immunohistochemical studies have demonstrated a higher rate of HPV positive cells in squamous cell carcinoma tissue compared to normal esophageal mucosa.10

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta  Other medical conditions: Achalasia (a rare disorder in which the lower esophageal sphincter does not relax properly to allow food to pass through); tylosis (a rare inherited disease linked to a genetic mutation thought to be responsible for some esophageal cancers), and esophageal webs (abnormal protrusions of tissue into the esophagus that interfere with swallowing) have all been implicated, as roughly 6% to 10% of patients with these conditions develop squamous cell esophageal cancer.

Recent studies from the UK and the US have shown a positive correlation between lower socioeconomic status and the development of squamous cell esophageal cancer, including an earlier age at diagnosis. This may be explained by higher rates of alcohol and tobacco use, and diets deficient in fruits and vegetables in lower income groups.11,12

Adenocarcinoma Key risk factors for adenocarcinoma, although not as well delineated as those for squamous cell carcinoma, include:  Gastroesophageal reflux disease (GERD): A nationwide, population‐based study conducted in Sweden in the late 1990s found that the frequency, severity, and duration of reflux symptoms were positively correlated with an increased risk of esophageal adenocarcinoma.13  Barrett’s esophagus: Histological studies from the mid‐1970s confirmed the premalignant nature of Barrett’s esophagus in adenocarcinoma.8  Obesity: Obesity may exacerbate GERD and Barrett’s, perhaps because it creates greater pressure on the abdomen, which in turn, may result in a higher frequency of GERD. A recent cohort study from the Netherlands reported a threefold higher risk of esophageal adenocarcinoma in individuals with BMI > 30 kg/mg2 compared to patients with BMI < 25kg/mg2.5,6,9,14  Gender: Gender appears to be a contributing factor, with incidence rates in men 6 to 8 times greater than those in women.15

Diagnosis of esophageal cancer Approaches used to diagnose esophageal cancer are the same for both squamous cell carcinoma and adenocarcinoma, and begin with a review of medical history, physical examination, blood tests, and a series of imaging tests.6,16 Early identification of esophageal cancer is often accidental, resulting from tests for other medical conditions.  Medical history: A medical history is taken to collect information on symptoms, medical conditions (e.g., GERD), and other factors (e.g., tobacco and alcohol use).  Physical exam: Since esophageal cancer usually spreads to the lymph nodes first, a physical exam, which involves palpating (i.e., feeling with fingers) the lymph nodes in the neck and other parts of the body is conducted. If nodal involvement is suspected, needle aspiration or biopsy may be performed.  Blood tests: Blood tests typically include a complete blood count (CBC) to detect anemia, and liver function tests to detect liver metastasis.  Imaging tests: A barium swallow or upper gastrointestinal x‐ray can reveal any irregularities in the normally smooth surface of the esophageal wall. It involves first coating the wall with

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta barium liquid, which allows the x‐ray to show the esophagus more clearly. A barium swallow cannot provide information on how far a cancer may have spread beyond the surface of the esophageal wall.

Based on the results of these tests, if esophageal cancer is suspected, endoscopic diagnostic techniques are employed.17

Endoscopic tests include:  Esophagoscopy (upper endoscopy): Esophagoscopy, the main technique for confirming esophageal cancer, involves the use of an endoscope (a narrow flexible tube with a camera and light on the end) to visualize the esophageal wall. During the procedure, the endoscope is inserted through the mouth and into the esophagus. The camera, which is connected to a monitor, allows abnormalities to be seen clearly.18  Endoscopic biopsy: During an esophagoscopy, the endoscope may be used to collect tissue samples of suspicious lesions. These samples are then examined under a microscope to determine the presence and type of cancer (squamous cell carcinoma or adenocarcinoma). The number of tissue samples or biopsies taken varies, but current clinical practice guidelines recommend the collection of 7 to 10.18

If these test results are inconclusive and suspicion of cancer still exists, endoscopic ultrasound (EUS), with or without fine needle aspiration (FNA) biopsy may be used:18  Endoscopic ultrasound (EUS): EUS combines endoscopy and ultrasound to obtain images of the esophagus. A small ultrasound probe attached to the end of an endoscope sends out high frequency sound waves that bounce off internal tissues and organs, producing a picture on a monitor.  EUS guided FNA: EUS can be used to guide the placement of a biopsy needle through which tissue samples are extracted.

Staging esophageal cancer Once a diagnosis of esophageal cancer is made, the stage of disease (i.e., how far it has progressed) must be determined. This information is used to plan treatment and assess prognosis. The staging process involves imaging tests, combined with endoscopy and biopsy.  Computed tomography: Computed tomography produces detailed images of internal organs using a computer. It translates information from x‐rays into images of thin cross‐sections or slices of the body. Computed tomography may be used to help confirm the location of the cancer and whether it has spread to adjacent organs or lymph nodes.16,19 However, CT is limited to detecting larger masses (> 1 cm).

 Positron emission tomography (PET): During PET, a small amount of radioactive tracer in the form of glucose is injected into a vein. A scanner then rotates around the body taking pictures as the glucose is used by the body. Since cancer cells absorb greater amounts of glucose than

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta healthy cells, they appear brighter on the scan. PET is used to assess whether cancer has metastasized.

 Endoscopic ultrasound (EUS): EUS is also used to determine the extent to which the cancer has invaded the esophageal wall, and whether the adjacent lymph nodes are involved. The American Society for Gastrointestinal Endoscopy guidelines and a recent meta‐analysis have confirmed the superior accuracy of EUS over computed tomography for esophageal cancer staging.18,20 The use of fine needle aspiration of lymph nodes further improves the accuracy of EUS in nodal (N) staging.18,20

Other diagnostic procedures that may be used to check for metastases include bronchoscopy, which allows endoscopic visualization of the throat and lungs, and thoracoscopy and laparoscopy (surgical procedures used to examine inside the chest and abdomen).16

Figure 3. Esophageal cancer staging.

(Image © Cleveland Clinic Foundation.)

A clinician interprets the test results using a standardized staging system. The most common staging system is the TNM system of the American Joint Committee on Cancer (Table 1). ‘T’ refers to the size of the primary tumour and how far it has spread within the esophagus and to nearby organs. ‘N’ indicates spread to the lymph nodes. ‘M’ stands for metastasis, and describes the extent to which the cancer has spread to distant organs.17,19 Information about the tumour, lymph nodes, and metastasis are combined in order to assign a stage. There are five main stages: 0 to IV.

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta  Stage 0: Also called carcinoma in situ, Stage 0 represents the earliest stage of esophageal cancer. Cancer cells are limited to the innermost layer of the esophagus. The cancer has not spread to the lymph nodes or other organs.  Stage I: Cancer has spread from the epithelium into the lamina propria or the submucosa, but it has not grown any deeper, nor has it invaded the lymph nodes or other organs.  Stage II: Stage II is divided into two substages, IIA and IIB. Stage IIA: Cancer has spread to the muscularis propria and possibly into the outer wall (adventitia), but not to the lymph nodes or other organs. Stage IIB: Cancer has invaded the lamina propria, submucosa, and muscularis propria, (the first three layers of the esophagus), but not the adventitia. However, it has spread to lymph nodes near the esophagus.  Stage III: Stage III cancer has spread to the outer wall and to lymph nodes near the esophagus, or it has spread beyond the outer wall into nearby organs.  Stage IV: Stage IV is also divided into two substages: IVA and IVB. Stage IVA: The cancer has invaded distant lymph nodes. Stage IVB: Cancer has spread to the lymph nodes and organs.

Staging is determined using clinical judgement and interpretation. Misdiagnosis or misclassification of esophageal cancer staging is common. Studies of this issue suggest that the use of diagnostic technologies, such as endoscopic ultrasound (EUS), allow more accurate diagnosis and staging of this disease.17,19

Table 1. AJCC TNM staging system for esophageal cancer 1983 Classification (clinical) 2002 Classification (pathologic) Primary tumor (T) Tis Carcinoma in situ Same T1 Tumor involves ≤ 5 cm of esophageal length, Tumor invades lamina propria or submucosa produces no obstruction, and has no circumferential involvement T2 Tumor involves > 5 cm of esophageal length, causes Tumor invades muscularis propria obstruction, or involves the circumference of the esophagus T3 Extraesophageal spread Tumor invades adventitia T4 Not applicable Tumor invades adjacent structures Regional lymph nodes (N) Nx Regional nodes cannot be assessed Same N0 No nodal metastases No regional nodal metastases N1 Unilateral, mobile, regional nodal metastases (if Regional nodal metastases clinically evaluable) N2 Bilateral, mobile, regional nodal metastases (if Not applicable clinically evaluable) N3 Fixed nodes Not applicable Distant metastases (M) M0 No distant metastases Same M1 Distant metastases Distant metastases Tumors of lower thoracic esophagus M1a Metastases in celiac lymph nodes M1b Other distant metastases Tumors of mid‐thoracic esophagus M1a Not applicable M1b Nonregional lymph nodes and/or other distant metastases Tumors of upper thoracic esophagus M1a Metastases in cervical nodes M1b Other distant metastases Stage grouping Stage I T1 N0 or NX M0 T1 N0 M0

Stage II T2 N0 or NX M0 Stage IIA T2‐3 N0 M0 Stage IIB T1‐2 N1 M0 Stage III T3 Any N M0 T3 N1 M0 T4 Any N M0 Stage IV Any T Any N M1 Any T Any N M1 Stage IVA Any T Any N M1a Stage IVB Any T Any N M1b Source: American Joint Committee on Cancer (AJCC).21

Stage IIA esophageal cancer or less (i.e., no nodal involvement) is generally considered early cancer. Cancer including or beyond stage IIB, which indicates spread to the lymph nodes, is considered advanced disease. Individuals with advanced stages of esophageal cancer have 25

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta lower survival rates. In a 1998 outcomes study of patients diagnosed with esophageal cancer in the US, five‐year relative survival rates for stages 0, I, II, III, and IV esophageal cancer were 52%, 41%, 26%, 13%, and 3%, respectively.22

Incidence and prevalence of esophageal cancer Esophageal cancer (adenocarcinoma and squamous cell carcinoma combined) is the eighth leading cause of cancer worldwide.3,23 Over the last 20 years, its epidemiology (i.e., patterns of incidence and prevalence of each histological subtype) in the western world has changed markedly. Previously, squamous cell carcinoma was the most common type of esophageal cancer. However, the incidence of squamous cell carcinoma of the esophagus has been decreasing (possibly due to declining smoking rates). At the same time, the number of new cases of esophageal adenocarcinoma has increased (possibly due to rising obesity rates). Esophageal adenocarcinoma is now the most common type of esophageal cancer in North America. However, it has shown the most rapid rise in incidence of all cancers in the US.7,24 25,26

In Canada, esophageal cancer accounts for less than 1% of all cancers, and its prevalence is similar to that of liver cancer.27 On a national level, the incidence has remained relatively constant, with falling rates of squamous cell carcinoma appearing to offset rising rates of esophageal adenocarcinoma.28,9,27 In 2009, approximately 1,600 Canadians (1,200 men and 420 women) will be diagnosed with esophageal cancer; an incidence of 6 cases per 100,000 individuals.27

Since 1994, the number of new cases of esophageal cancer in Alberta has almost doubled ‐ from approximately 3.5 cases per 100,000 to about 6 cases per 100,000.29 Of the 1,194 Albertans diagnosed with the disease over this period, roughly two thirds were male. The average age was 68 years (range: 44 – 80 years).29 Since 2005, the incidence of esophageal cancer has been comparable to that for testicular and cervical cancer.29 In 2009, the expected incidence in Alberta is 138 (110 men, and based on a ratio of 4:1, 28 women).27,29 This is similar to the estimated number of new cases in the province last year. However, no information on the type or stage of esophageal cancer is available for Alberta patients.

Burden of esophageal cancer Societal burden Worldwide, esophageal cancer is the sixth leading cause of cancer mortality.23 Five year survival (across all stages) is one of the lowest of all cancers, ranging from 10% to 20%.30,31 In 2009, an estimated 1,350 Canadians will die from esophageal cancer.27 The latest estimate of potential years of life lost (per year) due to esophageal cancer in Canada is 21,700, a number comparable to that for kidney cancer.32

In Alberta, five‐year survival rates for esophageal cancer are approximately 11%.29 Since 2005, 110 to 120 Albertans have died each year from the disease.29, 6 In 2009, 120 Albertans are expected to die from esophageal cancer.27

No published studies examining the societal burden (i.e., direct, indirect, and intangible costs) of esophageal cancer were found. Based on an analysis of costing data obtained from Alberta Health and Wellness for 2005 through 2007, the annual direct cost associated with the treatment of esophageal cancer (all stages) was approximately $3.5 million or $11,626 per patient (source: Alberta Health and Wellness administrative data).

An attempt to estimate the indirect costs attributable to esophageal cancer was made using a human capital approach.33 This approach assumes that the value of an individual is equal to his or her earnings. Therefore, burden is measured through calculating lost income due to premature death. The average income of non‐elderly (i.e., < 65 years of age) Canadians in 2005 was $36,450.34 Based on information provided by the Alberta Cancer Registry, the incidence of esophageal cancer in Alberta from 1996 to 2006, by age, was: 44 to 49 years: 81 individuals, 50 to 59 years: 195 individuals, and 60 to 69 years: 347 individuals. If it is assumed that incidence increases linearly from 50 to 69 years (in the absence of information suggesting otherwise), the 60 to 69 year age group can be divided into the following two groups: 60 to 64 years: 158 individuals and 65 to 69 years: 189 individuals. Thus, 424 patients between the ages of 44 and 64 years (average age of approximately 57.2 years) were diagnosed with the disease during this time period. Also based on Alberta Cancer Board information, disease‐specific median survival was roughly 1 year. Therefore, assuming an age of retirement of 65 years, the number of “productive” years lost per person was 6.8 years, or 2,883.2 years for the entire group. Multiplying this value by the average income per person yielded a total of $105,092,640 over the ten‐year period. Thus, the average annual earnings lost due to esophageal cancer is estimated to be about $10 million.

Patient burden To date, published studies examining the burden of esophageal cancer on patients have focused on health‐related quality of life (HRQL) before and after chemoradiotherapy and/or surgery. In most of these studies, this information was collected using the European Organisation for Research and Treatment in Cancer (EORTC) QoL Questionnaire (QLQ) C30, a well‐validated, generic cancer instrument, along with a supplementary module (QLQ‐OES18) designed to capture considerations specific to esophageal cancer.35 The QLQ‐OES18 includes questions that address dysphagia, eating, reflux, pain, problems with swallowing, saliva and dry mouth, taste, speech and coughing. Studies assessing chemotherapy and/or radiotherapy in patients with various stages of esophageal cancer found that, while health‐related quality of life was substantially lower during treatment, it returned to baseline after 6 months. Moreover, dysphagia, dyspnea, pain, and gastrointestinal symptoms improved significantly.4,36,37 Studies of patients who underwent esophagectomy have also demonstrated decreased quality of life within the first 6 months of treatment, particularly in measures of social, emotional, and physical functioning.38 Physical symptoms included fatigue, loss of appetite, diarrhea, and eating problems (e.g., reflux, dry mouth, dysphagia, choking), cough, difficulty breathing (dyspnea) and speaking, and loss of taste. However, evidence on long term quality of life is conflicting; some studies show a return to baseline values after the post‐operative recovery period, while others describe a decreased quality of life that persists for years.37,39

No published studies that measured the quality of life of patients receiving endoscopic therapy for esophageal cancer were found. However, a trial of endoscopic therapy (endoscopic mucosal resection with or without photodynamic therapy) is currently underway, and the results, which will include quality of life outcomes, are expected to be available within a year.40

Management of early esophageal cancer The stage of esophageal cancer determines which treatment options can be used. Once cancer has spread to the lymph nodes and/or other organs (i.e., advanced disease), treatment goals focus on prolonging life and improving quality of life (relieving symptoms). Treatment options have typically included one or more of chemotherapy, radiotherapy, chemoradiotherapy (i.e., chemotherapy and radiotherapy administered concurrently), and stenting or laser therapy to relieve dysphagia (i.e., ease swallowing). In patients who have nodal involvement but no metastases and who are deemed fit for surgery, chemotherapy, radiotherapy, or chemoradiotherapy may be given as neoadjuvant treatment. Despite all of these options, survival remains poor, and there has been little controversy over which treatments to use first. Decisions are, instead, tailored to each patient, taking into consideration patient preferences and overall health.5,9,41

In contrast, there is little consensus over the management of early esophageal cancer, where the primary goal is a cure.5 Several treatment options are available. These may be used alone or as part of a multimodality treatment strategy.

Esophagectomy Esophagectomy involves surgically removing all or part of the esophagus, as well as any tissue (including lymph nodes) that may contain cancer. To replace the esophagus, the stomach is pulled into the chest and surgically joined to any remaining part of the esophagus. Alternatively, a synthetic tube or piece of small intestine may be used as a replacement for the esophagus. Esophagectomy has been the standard treatment for early esophageal cancer in patients able to tolerate surgery. The 5‐year survival rates are over 80% if the cancer has not spread to the muscularis mucosa (the top layer of the mucosa).19 However, esophagectomy is associated with high mortality and morbidity (complication) rates.38,42 Mortality rates range from 1% to 20%, but are lower at centres that perform more esophagectomies with more experienced surgeons.4,19,42,43

Complications of esophagectomy include anastomotic leaks, infections, pneumonia, myocardial infarction, heart failure, pulmonary embolism, stenosis, and chronic digestive disorders. In a survey of esophagectomy patients in Sweden, 45% of all respondents (128 of 282 patients) had at least one complication requiring medical intervention in the month following their surgery.38

Esophagectomies can be performed using various surgical techniques, such as:

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta  transhiatal where surgical incisions are made in the diaphragm and neck  transthoracic (Ivor‐Lewis or Lewis‐Tanner) where the incision is made in the chest, between the ribs  tri‐incisional (Mckeown technique) which combines aspects of both transhiatal and transthoracic procedures.

It is not clear which type of esophagectomy offers the best outcomes for patients.42,44 The recent use of less invasive surgical techniques may reduce mortality and complication rates, but longer‐term patient follow‐up data are needed.42,44

Patients who are not considered eligible for surgery, or who are unwilling to undergo esophagectomy, may be treated with other, less invasive therapies described below.

Chemotherapy Chemotherapy uses toxic drugs, or a combination of drugs, to kill cancer cells. These drugs are administered intravenously or orally, and enter the bloodstream. Because it is a systemic treatment, affecting both non‐cancerous and cancerous tissue, chemotherapy has many side effects. The side‐effects vary with the specific drug, dose and length of treatment. Drugs that may be used to treat esophageal cancer include: 5‐fluorouracil (5‐FU), cisplatin, carboplatin, bleomycin, mitomycin, doxorubicin, methotrexate, paclitaxel, vinorelbine, topotecan, and irinotecan. Several drugs and rounds of treatment, interspersed with breaks from the regimen, may be needed.6,45 Temporary side effects include nausea and vomiting, loss of appetite, fatigue, hair loss, mouth sores, rash, itching, diarrhea and shortness of breath. Chemotherapy may be used in combination with other therapies (e.g., chemoradiotherapy, which combines chemotherapy and radiation therapy). Drugs commonly used for chemoradiotherapy include 5‐ FU and cisplatin. Chemotherapy may also be used as an adjuvant treatment (after other therapies, such as surgery and radiation), or as a neoadjuvant treatment (to shrink tumours before other treatments begin).6

Radiation therapy (radiotherapy) Radiation therapy uses focused ionizing radiation to destroy or shrink tumours. It may be given definitively (as the only treatment), in combination with chemotherapy (as mentioned above), or pre‐ or post‐operatively. Radiation is usually delivered externally to the cancer, but internal radiation (brachytherapy) may also be employed. Internal radiation uses various types of implants to deliver the radiation to the cancer from within the body.6 Temporary side effects of radiation therapy include: dry mouth, sore throat, difficulty swallowing (dysphagia), swelling of the mouth and gums, dental cavities, fatigue, skin changes at the site of treatment, and loss of appetite.6

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Endoscopic treatments for early esophageal cancer Given the morbidity associated with esophagectomy, chemotherapy, and radiotherapy, attention has focused on developing targeted, less invasive, endoscopic treatments. Performed through an endoscope using various devices, the intent is to destroy or remove the cancerous tissue, while preserving healthy tissue. Depending on the depth of the tumour and the endoscopic technique applied, several treatment sessions may be required, or a combination of endoscopic treatments may be used.

Endoscopic mucosal resection In endoscopic mucosal resection (EMR)19, the tumour or cancerous tissue is cut and removed through an endoscope. The tissue is first ‘lifted’ by injecting a solution (such as saline) below it, or by applying suction, and then removed with a cap, snare, or ligator device. Typically, tumours up to 2 cm can be resected at once. Larger lesions may be resected in sections, but care must be taken to ensure they have been completely removed. An attempt is made to re‐construct each tumour by putting the resected pieces back together. The margins of all resected pieces are then examined microscopically to confirm the absence of cancer cells (i.e., negative margin).42,46.19 An emerging form of EMR, called endoscopic submucosal dissection (ESD), may also be used to treat larger lesions. This involves first marking the tumour using electrocautery, then injecting a solution to raise it, and finally cutting it out with an electrocautery knife.46 One of the main advantages of both EMR and ESD is the availability of a tissue sample for further pathological examination. This information can be used in planning subsequent treatment strategies. Potential complications of EMR include bleeding, which is typically controlled at the time of the procedure and rarely requires transfusion, and perforation of the esophageal wall. Unlike bleeding, perforation usually requires surgical repair.

The other endoscopic treatments all involve ablating or destroying cancerous tissue, rather than cutting it out. Consequently, no tissue is left for pathological assessment. These techniques vary in the ablative approach used, the depth of tissue injury achievable, and the number of treatment sessions required. They include argon plasma coagulation, cryoablation, photodynamic therapy, and radiofrequency ablation.

Argon plasma coagulation Argon plasma coagulation (APC) uses a monopolar electrical current, powered by a generator, to coagulate tissue. The depth of tissue damage is determined by the power level, the duration of treatment and the distance between the probe and the targeted tissue.42 Several treatment sessions are usually needed. The depth of ablation is about 2 mm.18

Cryoablation Cryoablation (also called cryotherapy or cryosurgery) is a promising new treatment for early esophageal cancer which uses liquid nitrogen or freezing carbon dioxide gas. The nitrogen or gas is sprayed onto the tumour through an open‐tipped catheter. The cancerous tissue is frozen

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta by the spray and then allowed to thaw before the process is repeated. The “freeze and thaw” cycle destroys cancerous tissue.

Photodynamic therapy Photodynamic therapy (PDT) is a treatment that involves the use of a photosensitizing agent. Photosensitizing agents are drugs that are selectively absorbed by fast‐growing cells, such as cancer cells. When exposed to light, these drugs are activated, causing cancer cells to die. During treatment, the drug is administered intravenously or orally and given time to be absorbed by the cancerous tissue. When enough time has passed to allow optimal uptake of the drug, the cancerous tissue is exposed to light of a particular wavelength. The light source (e.g., a laser or a fiber optic light diffuser) is delivered endoscopically via a catheter.

In Canada and the United States, the photosensitizing agent approved for systemic use in esophageal cancer is porfimer sodium (Photofrin®). Porfimer sodium is administered intravenously, typically 48 hours before the light is applied. The drug is cleared from most of the body within a few days, but some tissue (tumours, skin, eyes) remains light sensitive for four to six weeks. Patients must avoid exposure to direct sunlight and bright lights during this period.47

Another photosensitizing agent, aminolevulinic acid (ALA, Levulan®), is limited to topical treatments in Canada (e.g., the treatment of certain skin conditions). However, it has been used to treat early esophageal cancer in Europe and elsewhere. Potential advantages of ALA over porfimer sodium include: higher uptake in the mucosal layer of the esophagus, a quicker absorption time, and a shorter half life, with a correspondingly shorter period of photosensitivity.47

New photosensitizers, such as HPPH (Photochlor®, Roswell Park Cancer Institute) are currently under investigation for esophageal, lung, and other cancers.48 These drugs may offer a more targeted therapy (being absorbed by cancer cells only), and deeper tissue penetration, allowing more invasive, but still localized tumours to be treated.

Radiofrequency ablation Radiofrequency ablation (RFA) uses microwave energy to eradicate cancerous tissue. A balloon sizing catheter is used to measure the size of the inner diameter of the esophagus. Next, a balloon ablation catheter with electrodes around the tip is inserted. The balloon is inflated and radiofrequency energy is activated to destroy the tissue. Focal ablation is also used to target smaller lesions. Radiofrequency ablation can treat only the very superficial or top layer of the esophagus. Therefore, its effectiveness may be limited to the earliest stages of disease.

With the exception of photosensitivity, the ablative endoscopic procedures share a similar set of temporary side effects, which include chest pain and difficulty swallowing. More serious, 31

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta although uncommon, complications, such as stricture (narrowing of the esophagus due to scar tissue formation), or perforation may also occur. Strictures are treated using endoscopic dilation, but perforations usually require surgical repair. The risks of these complications vary depending on the ablative technique used.

Status of photodynamic therapy & other treatments for early esophageal cancer in Canada

Market status Porfimer sodium (Photofrin®) received a Health Canada Notice of Compliance in 1993.49 Axcan Pharma holds the current Canadian licenses for the product. Porfimer sodium is licensed in Canada as an antineoplastic photosensitizing drug.50

Other photosensitizing drugs, such as aminolevulinic acid (ALA, Levulan®, DUSA Pharmaceuticals, Inc.), have been used in photodynamic therapy for esophageal cancer, but these agents are not licensed in Canada for this indication.

The Diomed 630 PDT Laser (Angiodynamics UK Ltd / Diomed Inc.) used to administer photodynamic therapy, received a Health Canada medical device licence in 2001.51 Other light sources have been used, but the Diomed system is specifically licensed for use with porfimer sodium and for gastrointestinal applications.47

The HALO radiofrequency generator (BARRX Medical), and other components of the HALO 360 and HALO 90 systems (ablation catheters and sizing balloons) have received Health Canada medical device licenses.51 Radiofrequency generators from other manufacturers are also licensed in Canada (e.g., Valleylab, Medtronic). Argon plasma coagulation units and accessories from several manufacturers (e.g.,Erbe Elektromedizin, Valleylab) are licensed by Health Canada.51 Cryosurgery units for other endoscopic surgical procedures are licensed in Canada, but these are not licensed for use in treating Barrett’s esophagus or esophageal cancer.51

Esophagectomy is a surgical procedure and as such does not require Health Canada licensing.

Diffusion of photodynamic therapy According to Axcan Pharma, the Canadian distributor of Photofrin®, several centres in Canada offer photodynamic therapy. These are shown in the table below.

Table 2. Photodynamic therapy centres in Canada Province Centre British Royal Jubilee Hospital, Victoria Columbia Alberta Foothills Hospital, Calgary Royal Alexandra Hospital, Edmonton Ontario Hamilton Regional Cancer Centre, Hamilton St. Michael’s Hospital, Toronto Toronto General Hospital, Toronto Ottawa General Hospital, Ottawa Quebec Montreal General Hospital (McGill University Health Centre, MUHC), Montreal Centre Hospitalier de l’Université de Montréal ((CHUM), Notre Dame site), Montreal* Centre Hospitalier Universitaire du Québec (CHUQ), Quebec City Note: does not include PDT centres for dermatological treatments; *not yet operational

Part II: Safety & efficacy of photodynamic therapy for early esophageal cancer in comparison to other management strategies

Research questions The main question to be addressed by this review was: What is the potential role of photodynamic therapy (PDT) in the management of early esophageal cancer in adults?

Specific questions to be addressed were: In comparison with alternate treatments (esophagectomy, chemotherapy, radiation therapy, surgical resection and other ablative technologies): what is the safety of PDT for early esophageal cancer? what is the effectiveness or efficacy of PDT for early esophageal cancer? what are the patient factors related to outcomes? what are the known challenges to using PDT for early esophageal cancer?

Methods A systematic review of evidence on the safety and efficacy of photodynamic therapy (PDT) and alternative therapies for the treatment of early esophageal cancer (Stages 0 to IIA) was performed. The methods used adhered to accepted, widely used, published guidelines for undertaking systematic reviews.52 In addition, advice from a clinical expert in this field was sought to ensure the comprehensiveness of the review. The methods used to develop the economic model are described in Part IV.

Literature search An initial, comprehensive search for published and unpublished studies on PDT for early esophageal cancer was conducted in July 2008. Relevant terms used to describe early cancer and PDT were identified, along with likely synonyms. Keywords and controlled vocabulary terms (MeSH, EMTREE, etc.) used to index relevant references were also used. The search strategy was applied to the major biomedical bibliographic databases, including PubMed, EMBASE, CINAHL, The Cochrane Library, UK Centre for Reviews and Dissemination (DARE, Health Technology Assessment, NHS Economic Evaluation) databases, and to other relevant databases, such as EconLit and Web of Science. With the exception of human studies, no limits were applied. To capture new publications (those appearing after July 2008), the initial search was supplemented by monthly updates (using PubMed) throughout the project.53 Grey literature (e.g., conference proceedings, guidelines, ongoing clinical trials, etc.) was identified through searches of the American Society of Clinical Oncology and Digestive Disease Week

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta meetings abstracts, the web sites of cancer organizations, clinical practice guidelines, and clinical trials web sites. Reference lists from retrieved papers, as well as relevant technology assessments, clinical practice guidelines, and systematic reviews were hand‐searched. Researchers engaged in other systematic reviews and clinical trials of PDT were contacted to determine the status of their work. The Canadian costs of porfimer sodium were provided by the Canadian supplier, Axcan Pharma Inc. Monthly update searches were run in PubMed (MEDLINE) throughout the project, with a cut off date of the end of January 2009 for inclusion of studies.

A second search focusing on alternative treatments for early esophageal cancer was conducted using an approach similar to that described for PDT. However, for practical reasons, this search was limited to information published within the last five years (January 2003 to December 2008). Treatments captured included: EMR, RFA, APC, cryoablation, esophagectomy, radiation therapy, and chemotherapy. The search strategies for both searches are presented in Appendix A.

Selection of relevant studies Results of both the electronic and manual searches were imported Into Reference Manager®, a software program for managing bibliographic citations. After duplicate citations were removed the references (titles, and abstracts where available) were independently reviewed by two researchers in two stages. Titles and abstracts were first screened. The full papers of potentially relevant studies were then retrieved and assessed using pre‐defined study inclusion criteria (Table 3). In cases of doubt over a study’s relevance, further information was sought from the author. Where multiple citations from the same investigators appeared to report on the same patients, only the most recent study report was included. Non‐English language studies were excluded, unless an English language abstract provided sufficient detail on patients and outcomes. Editorials, opinion pieces and review articles were also excluded.Discrepancies between reviewers were resolved through discussion, and no third party adjudication was required. Consensus between reviewers was assessed using kappa statistics. Kappa values for Stages 1 and 2 were 1.0 and 0.88, respectively, indicating excellent agreement.54

Table 3. Criteria for including studies in this review Parameter Inclusion criteria Exclusion criteria Study design  Randomized or controlled (e.g.,  Single case reports pseudo‐randomized or quasi‐ (n=1) randomized) trials  Editorials & opinion  Non‐randomized clinical trials pieces  Retrospective, prospective, or concurrent cohort studies  Case or clinical series Participants  Patients diagnosed with early  Patients diagnosed with esophageal cancer (Stages 0 to IIA; no greater than Stage IIA spread to the lymph nodes) esophageal cancer Interventions  Photodynamic therapy  Esophagectomy  Radiotherapy  Chemoradiotherapy  Chemotherapy  Endomucosal resection  Other ablative treatments (including argon plasma coagulation, cryoablation, and radiofrequency ablation) Comparators Same as interventions above Outcomes  Response (tumour eradication or regression)  Recurrence  Cause‐specific/disease‐specific survival (proportion of patients who have not died from esophageal cancer within a defined period of time)  Overall survival (proportion of patients who have not died within a defined period of time)

Synthesis & critical appraisal of selected studies Two independent reviewers extracted data from studies using a standard, pre‐tested data abstraction form and a set of decision rules. The form contained elements for assessing the purpose and methods (setting, number of patients, treatment protocol, outcome measures, etc.) of each study and the validity of results presented (Table 4). When required, missing data were sought from the primary or corresponding author. Consensus between reviewers on the information collected was assessed using the Kappa statistic. The information was double‐

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta entered into RevMan, a software program for managing information for systematic reviews (The Cochrane Collaboration; http://www.cc‐ims.net/).

The quality of each study was scrutinized by the two reviewers using the Oxford Scale of Evidence, a validated, widely used set of critical appraisal guidelines that permits comparisons across different experimental designs (Appendix G). Again, discrepancies were resolved through consensus and a kappa score calculated. Agreement between reviewers was excellent (K = 0.88).

Table 4. Summary of elements comprising the data abstraction form Parameter Description of information collected Cancer/cell Adenocarcinoma/squamous cell; stage of disease type Study design Setting; country; study type (e.g., case series, cohort studies, clinical trials, etc.; retrospective or prospective; identification of patients); methods of randomization; allocation concealment; treatment(s); length of follow‐up; and funding sources Patients Number of patients recruited, randomized or assigned to treatment groups by cell type and stage, where possible; number of patients censored due to incomplete follow‐up or loos to follow‐up; age; gender; prior treatments; inclusion/exclusion criteria; and relevant co‐morbidities Intervention Details of the treatment, including the actual number of patients who completed each treatment as planned; information on any additional treatments received (co‐ interventions) Outcomes Complete/partial/no response (i.e., the extent to which cancerous tissue could be removed); recurrence (whether any of the cancerous tissue that was removed reappeared); cause‐specific survival (proportion of patients who have not died from esophageal cancer during the study’s follow‐up period), overall survival (proportion of patients who have not died during follow‐up); adverse events

Data analysis Qualitative Information collected from studies was summarized in tabular form to more easily identify trends or patterns in findings reported across studies. Overall survival at any time is defined as the percentage of patients who had not died of any cause by that time; cause‐specific survival is the percentage of patients who had not died of cancer by that time. The response to treatment was considered complete if there was clinical evidence that the lesion was completely cleared.

Quantitative Results from individual studies were pooled using weighted mean values to generate summary estimates for each of the outcomes of interest. Subgroup analyses by treatment type, cell type, and disease stage were also performed, where possible. All quantitative analyses were conducted in accordance with intention‐to‐treat principles (i.e., patients were analyzed in the

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta groups to which they were originally allocated, regardless of whether or not they received the assigned treatment).

Results Five hundred and twenty‐two papers were identified through the literature search. Of them, 75 met the selection criteria and were included in the review (Figure 4). Descriptions of all 75 studies are presented in Tables B1 through B10. Excluded studies, along with rationale for their exclusions, are listed in Table C1. Of the 75 studies selected, only 20 had recruited patients with early stage cancer only (Stages 0 to IIA). Among the remaining 55 studies, 22 included patients with dysplasia or early cancer and 33 included patients with early or advanced cancer. For these 55 studies, only data reported for patients with early esophageal cancer were extracted.

Figure 4. Literature search results, study selection process and results.

PDT search results Alternative treatments search = 2,108 citations results = 3,110 citations

Total search results = 5,218 citations

Duplicates removed = 3311 citations

Titles & abstracts reviewed

Esophageal cancer Full papers selected for review = 522 Not relevant= 301

Esophageal cancer papers Selected for appraisal = 221

Included studies = 75 Excluded studies = 146

Description of included studies The 75 studies included 3,124 patients and spanned 10 different treatment types, of which about half were endoscopic procedures (Table 5). They addressed 4 ablative techniques (APC, cryoablation, PDT, and RFA: 32 studies), and 1 non‐ablative technique (EMR: 12 studies), and originated from centres in the United States, Europe, and Asia. The studies from Asia focused on squamous cell carcinoma, while those from other countries addressed both squamous cell and adenocarcinoma. They included 1,170 patients, most of whom were male, who ranged from 38 to 90 years of age. The proportion of patients with adenocarcinoma (ACC) and squamous cell carcinoma (SCC) was similar. All but 3 of the studies were non‐comparative case series, with varying follow‐up times and numbers of treatment sessions. All 3 comparative studies were cohort studies, only one of which addressed PDT. Of the studies on PDT, which

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta accounted for all but 4 of the 32 ablative studies, most used porfimer sodium as the photosensitizing agent, including the single cohort study that compared PDT to esophagectomy.

Among the 37 studies that examined non‐endoscopic treatments, almost two thirds focused on esophagectomy, using various surgical approaches. The remaining studies assessed chemotherapy and/or radiotherapy alone or in combination with surgery. Like the studies of endoscopic treatments, they originated from centres in the United States, Europe, and Asia. Those addressing esophagectomy were mainly from the United States and Europe, and included patients with both adenocarcinoma and squamous cell carcinoma. In contrast, those assessing chemoradiotherapy or radiotherapy were mainly from Asia, and included patients with squamous cell carcinoma. Across the studies, the total number of patients was 2,249, with an age range similar to that observed for the endoscopic studies (46 to 91 years). Once again, patients were predominantly male.

Although comparative studies comprised a higher proportion (relative to those that assessed endoscopic procedures), they were mostly cohort studies, as opposed to controlled trials. Four studies compared different surgical approaches, while 3 assessed the incremental benefit of adding chemotherapy, radiotherapy or chemoradiotherapy to surgery (neoadjuvant or adjuvant treatment) over surgery, alone. It is important to note that multiple studies of the same treatments were not available. Consequently, a meta‐analysis could not be performed. Furthermore, treatment protocols, such as type and dose of chemotherapy drugs administered, varied across the chemotherapy studies, and radiation dose varied across the studies of radiotherapy.

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Table 5. Key characteristics & overall description of included studies Studies No. of No. of Studies using No. of No. of non‐ squamous adenocar‐ using Stage Treatment No. of comparative comparative No. of cell cancer cinoma TNM 0‐IIa type Treatment studies studies studies patients patients patients staging staging Endoscopic APC 2 0 2 11 8 3 2 0 CRYO 1 0 1 9 * * 1 0 EMR 12 2 10 590 398† 146† 5† 2† PDT 26 1 25 544 135†* 358†* 19† 2† RFA 1 0 1 16 * * 1 0 Chemotherapy CRT 6 2 4 215 203* 1* 2 4 and/or Radiation CT 3 3 0 334 216 118 1 2 and/or RT 6 2 4 263 240* * 4 2 surgery CRT + ESO 2 1 1 91 79* * 0 2

ESO 20 8 12 1346 352†* 317†* 5 15 Total 79‡ 19 60 3419‡ 1631†* 943* 40 29 APC=argon plasma coagulation; CRYO=cryoablation; CRT=chemoradiotherapy; CT=chemotherapy; EMR=endoscopic mucosal resection; PDT = photodynamic therapy; RFA=radiofrequency ablation; RT=radiation therapy * could not be calculated from each study in this treatment arm † not reported for all studies ‡ includes 4 comparative studies that appear twice for separate treatment modalities.

Quality of included studies In general, the quality of the evidence was low. Only 15 of the 75 studies were comparative, and of these, all but one were observational (i.e., cohort study). Consequently, it was not possible to control for biases arising from the allocation of patients to different treatment groups. The single experimental study identified was a non‐randomized controlled trial of two different surgical approaches that included 10 patients only. In many cases, critical information was inconsistently reported or missing for specific sub‐groups of patients. While some studies presented results according to disease stage (a factor known to influence treatment response), others presented only single, summary values (e.g., grouping all patients with early cancer (Stages 0, I and II) together).

Patient populations appeared to vary across studies of different treatment alternatives. Although all studies recruited patients with early esophageal cancer, some were more restrictive than others, limiting participation to patients who met additional inclusion/exclusion criteria. For example, in the majority of studies on ablative therapies, included patients had been deemed unfit for surgery. Further, surgical ineligibility was listed in the inclusion criteria of all but one of the PDT studies. In contrast, none of the studies on EMR or chemoradiotherapy restricted participation to patients unable to tolerate surgery. Disease stage also varied across studies. With the exception of those addressing PDT, the ablative studies primarily included patients in the earliest stages of disease (Stages 0 – I; Tis or TI). This was also the case with the endoscopic mucosal resection (EMR) studies, where three quarters involved patients with tumours classified as TI or less. On the other hand, almost half of the PDT studies included

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta patients with more advanced, albeit still early, cancer (T2 tumours or Stage IIA cancer), as did the studies that focused on chemoradiotherapy, chemotherapy, radiotherapy, and surgery. Treatment protocols, outcomes measured, and lengths of follow‐up often differed across studies on a common therapy. For PDT, various photosensitizing agents, light sources, and treatment sessions were used. Also, sample sizes were small, with over half involving less than 20 patients. For radiotherapy, energy source and dose varied, and for chemotherapy, the type and combination of drugs differed. Lastly, many of the studies reported patients receiving additional interventions when they experienced a treatment failure. However, none appeared to take this into account in the analyses of outcomes. Given these issues, findings from included studies were interpreted with caution.

Safety

Adverse events, reported by treatment type, are described in Appendix D (Tables D1 through D10). None of the studies of radiofrequency ablation, radiotherapy, or chemotherapy presented information on adverse events in patients with early stage esophageal cancer.

Only about half of the PDT studies reported on adverse events (Table D1). The most commonly observed adverse event was stricture, which occurred in approximately 13% of all PDT patients (pooled, weighted value). About 7% of PDT patients experienced chest pain. Photosensitivity was reported in about 3% of PDT patients. Bleeding and perforation occurred in less than 1% of patients. One patient with extrinsic compression of the esophagus died from a perforation 8 weeks after PDT. The type and frequency of adverse events varied depending on the photosensitizing agent used.In the studies of PDT with ALA, no strictures, perforations, or bleeds were reported, and only one patient experienced a photosensitivity reaction.

With respect to the other endoscopic techniques, only one small study of the argon plasma coagulation (APC) studies addressed adverse events, noting that none were observed in its 3 patients (Table D2).

Across studies of endoscopic mucosal resection (EMR), the most commonly experienced side effects were bleeding (7%) and stenosis (6%) (Table D5). Strictures appeared to be less frequent with EMR than with PDT, occurring in 0.5% of patients.

Across studies of non‐endoscopic treatments, the type and frequency of adverse events also varied. Treatment‐related deaths occurred in approximately 3% of patients who underwent radiotherapy (Table D7). The most commonly reported, non‐fatal adverse events were respiratory distress, pain on swallowing (dysphagia), esophageal fistula, perforation, and pneumonitis, all of which occurred in 1% ‐ 2% of patients (based on pooled estimates).

In the chemoradiotherapy studies, the mortality rate was 1%, lower than that associated with radiotherapy (Table D8). However, a higher proportion of patients experienced non‐fatal

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta complications, including esophagitis (30%), esophageal ulcer (22%), renal toxicity (14%), hypothyroidism (8%), pericardial effusion (5%), esophageal fistula (3%), and stricture (3%).

Just 2 of the 20 esophagectomy studies reported adverse events in patients with early stage esophageal cancer (Table D10). One of the studies was a cohort study that compared patients who received EMR and PDT to those undergoing esophagectomy. In this study, 2% of patients in the esophagectomy arm died from surgical complications. No deaths were reported in the EMR and PDT groups. Strictures occurred in 16% of esophagectomy patients, but in only 8% of EMR and PDT patients. Infections and anastomotic leaks developed in 8% of esophagectomy patients, whereas cardiovascular and respiratory complications, and delayed gastric emptying, were reported in 3% to 5% of esophagectomy patients.

Based on the studies from which information on adverse events in patients with early esophageal cancer could be extracted, the safety profiles of endoscopic techniques are generally better than those of the non‐endoscopic therapies.

Since the effect of clinician expertise on complication rates was not discussed in any of the studies, it was not possible to examine differences in the learning curve between the various treatments.

Efficacy / effectiveness

Evidence related to the efficacy or effectiveness of the various treatment alternatives was analysed according to outcome (see Appendices E and F). The main outcomes assessed were:  treatment response (tumour eradication or shrinkage)  recurrence (tumour reappearance or re‐growth)  survival (cause‐specific and overall). Few studies reported information on all of these outcomes. Many studies reported values pooled across multiple disease stages, precluding an assessment of patients with early cancer only. Information from these studies was, therefore, not included in pooled effect estimates.

Response

Endoscopic techniques Twenty‐four of the 26 photodynamic therapy (PDT) studies assessed the extent to which cancerous tissue was eradicated (Table E1). Based on pooled estimates across the non‐ comparative studies, a complete response was achieved in about 50% of the patients with adenocarcinoma and 70% of the patients with squamous cell carcinoma, after 1 to 3 treatment sessions. Two studies provided results stratified by tumour stage. In both studies, response rates decreased with advancing tumour stage.

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta For each of the remaining ablative techniques, only one study presented information on tumour response. In the single case series of argon plasma coagulation (APC), adenocarcinoma was eradicated in all 3 patients (Table E2). In the cryoablation only study, of 23 patients with either adenocarcinoma or squamous cell carcinoma, 75% achieved a complete response following an average of 4 treatment sessions (Table E3). Response rates from the single radiofrequency ablation (RFA) study were similar to those from APC. All 16 patients who had either adenocarcinoma or squamous cell carcinoma experienced total eradication of their tumours (Table E4). However, in contrast to APC, this was achieved after a median of 1 RFA treatment session. As none of these ablative studies presented results by disease stage, it was not possible to assess the effect of tumour depth on response rates.

Most of the endoscopic mucosal resection (EMR) studies reported information on complete response (Table E5). Pooled values from those comprising adenocarcinoma patients and those limited to squamous cell carcinoma patients were comparable (adenocarcinoma: 98%; squamous cell carcinoma: 88%). The number of sessions over which these rates were achieved ranged from 1 to 10. None of these studies reported results by tumour stage.

Comparing PDT to other endoscopic techniques, the proportion of patients achieving a complete response with PDT appears to be lower. However, this trend may be due to variations in patient populations across the studies of different treatments. Most of the PDT studies included patients with T2 tumours, unlike the majority of studies on other ablative techniques, in which tumour stage was limited to T1 or less.

Non‐endoscopic techniques Although none of the chemotherapy studies measured complete response (Table E6); 3 of the 5 studies in which chemotherapy was combined and delivered concurrently with radiotherapy (i.e., chemoradiotherapy) did measure complete response (Table E8). The complete response rate from the squamous cell carcinoma only study was 86%, a value similar to that observed in the single study of both squamous and adenocarcinoma (77%). There were no studies reporting on response to chemoradiotherapy for adenocarcinoma lesions. One small study presented findings according to tumour stage. As noted with PDT, the response rate decreased as tumour stage increased.

Of the comparative and non‐comparative studies of radiotherapy reviewed, all but two assessed complete response (Table E7). However, most (5 of 6) studies included patients with squamous cell carcinoma only. Across these studies, cancerous tissue was completely ablated in 81% of patients.

Among the 20 studies of esophagectomy, only a single cohort study, which compared esophagectomy to EMR and PDT, presented information on tumour response (Table E10). For the surgery group, a complete response was defined as negative margins of the resected esophagus. No statistically significant difference was found between treatment groups,

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta suggesting that both treatment arms offered a comparable level of effectiveness in terms of their potential to eradicate or remove cancerous tissue.

Recurrence

Endoscopic techniques For PDT, the single comparative study and just over half (13 of 25) of the non‐comparative studies reported the proportion of patients in whom tumours recurred during follow‐up (Table E1). Across the studies of squamous cell carcinoma, all of which used ALA as the photosensitizing agent, disease recurrence was reported in 19% of patients after an average follow‐up of 18 months. In contrast, only 3% of patients in the studies of adenocarcinoma experienced recurrence, even though the average follow‐up time was roughly 6 months longer than that in the studies of squamous cell carcinoma. In the adenocarcinoma studies, recurrence did not appear to vary with photosensitizing agent. Across studies of both cell types, the pooled recurrence rate was higher (28%) than in those of single cell types. This may be because they included more patients with Stage IIA disease. The studies of single cell types involved patients with mainly T1 tumours or Stage I disease.

With respect to the other ablative procedures, in the two case series of argon plasma coagulation (APC), differences in rates of relapse across cell type were also seen (Table E2). One study included patients with squamous cell carcinoma, while the other was limited to patients with adenocarcinoma. Tumour stage and length of follow‐up were similar. However, tumours recurred in 25% of patients with squamous cell carcinoma and in none of the patients with adenocarcinoma. The single study of cryoablation, which included patients with adenocarcinoma or squamous cell carcinoma, reported no recurrences after a follow‐up of 6 to 30 months (Table E3). The single radiofrequency ablation (RFA) study reported a recurrence rate of 0% after 21 months of follow‐up (Table E4).

Among the non‐comparative studies of endoscopic mucosal resection (EMR), all but two studies examined recurrence (Table E5). Follow‐up periods were similar across studies of adenocarcinoma and squamous cell carcinoma, and considerably longer than in the other endoscopic studies. Pooled recurrence values were also similar, with tumours reappearing in 13% of adenocarcinoma patients and 16% of squamous cell carcinoma patients.

Non‐endoscopic techniques None of the three chemotherapy studies reported rates of recurrence (Table E6). Of the radiotherapy studies, two of the four case series assessed recurrence, but neither presented information on the length of follow‐up (Table E7). However, both cohort studies, comparing conventional external beam radiotherapy to a combination of external beam therapy and brachytherapy, presented recurrence rates and median follow‐up times (Table E7). After five years, tumours had reappeared in approximately 24% of patients. Recurrence rates were similar across treatment groups, suggesting that similar outcomes could be achieved with radiotherapy alone.

No information on recurrence was reported in the chemoradiotherapy studies (Table E8) or those of chemoradiotherapy followed by esophagectomy (Table E9). In the esophagectomy studies, four of the 12 non‐comparative studies and one of the three comparative studies assessed recurrence (Table E10). However, follow‐up information was only provided for one small case series of patients with Stage IIA adenocarcinoma. In this study, 33% of patients relapsed during the four‐year follow‐up period.

Survival

Endoscopic techniques Five‐year, cause‐specific survival was reported in 2 of the 26 PDT studies (Table F1). After 5 years, 90% of patients with either adenocarcinoma or squamous cell carcinoma had not died of esophageal cancer. However, 1 of the studies indicated that patients who experienced recurrence received other additional treatments. Therefore, it was not possible to determine the precise cause‐survival benefit attributable to PDT. Four of the studies also reported overall survival at 5 years. These values were considerably lower than those of cause‐specific values. This should be expected as overall survival takes into account all causes of death. Cause‐specific and overall survival information was not reported in any of the studies involving the other ablative techniques (Tables F2 to F4). Comparable survival information was not reported in any of the studies of other ablative techniques (Tables F2 to F4).

Among studies of endoscopic mucosal resection (EMR), 3 studies presented both cause‐specific and overall survival rates after a minimum of 5 years of follow‐up (Table F5). Cause‐specific survival values were similar to those for PDT. However, as with PDT, some patients received other additional treatments following treatment failure with EMR.

Non‐endoscopic techniques The 3 cohort studies involving chemotherapy reported on overall survival only (Table F6); however, only one study reported on overall survival at 5 years. This study compared chemotherapy followed by surgery to surgery alone. Overall survival at 5 years was similar across treatment groups (82% and 88% respectively). The second study compared chemotherapy plus chemoradiotherapy followed by surgery to chemoradiotherapy followed by surgery. Again, the addition of chemotherapy did not appear to offer a survival benefit, since overall three‐year survival rates between groups were similar. The third study compared chemotherapy followed by radiotherapy to radiotherapy, alone. As in the other studies, overall survival at three years was similar between groups.

Of the radiotherapy studies, 4 reported 5‐year overall survival ranging from 47% to 59% (Table F7). In the case series reporting on cause‐specific survival, 95% of patients had not died of esophageal cancer after 5 years of follow‐up. In 1 cohort study, patients who experienced a

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta treatment failure were offered additional therapies. Therefore, the survival rate reported may not be attributable to radiotherapy alone.

None of the studies on chemoradiotherapy reported cause‐specific survival. The one non‐ comparative study reporting 5‐year overall survival reported a rate of 66%. Among the 2 cohort studies, one compared chemoradiotherapy to surgery, and found no difference in 5‐year overall survival between the two groups. The other study compared combinations of low‐ and high‐ dose chemoradiotherapy with surgery, noting a significant difference in overall survival between groups that favored high‐dose chemoradiotherapy plus surgery over low‐dose chemoradiotherapy plus surgery (Tables F8 and F9).

None of the studies of esophagectomy reported cause‐specific survival (Table F10). Of the 8 cohort studies, most compared various surgical approaches and found no differences in overall survival. Among the non‐comparative studies, the overall 5‐year survival for studies involving both cell types was 75%. However, there was a significant difference in the overall 5‐year survival reported for adenocarcinoma versus squamous cell carcinoma (96% and 39% respectively). In all studies that reported cancer stage the overall survival was considerably lower for Stage II cancers versus Stage I.

Given the gaps in the information reported and the heterogeneity of the studies, it was not possible to determine which treatments are most appropriate for early esophageal cancer.

Summary of other assessments of photodynamic therapy for early esophageal cancer

Several agencies have examined the evidence on photodynamic therapy for early esophageal cancer. The most recent assessments are the 2006 guidance from the UK National Institute for Health and Clinical Excellence (NICE), a 2004 assessment by Quebec’s Agence d’Évaluation des Technologies et des Modes d’Intervention en Santé (AETMIS), and a 2002 US assessment by the Institute for Clinical Systems Improvement (ICSI) assessment.49,55,56 The NICE guidance concluded that PDT for early esophageal cancer appeared to be safe and efficacious, but that the available evidence was of poor quality and provided only short‐term patient outcomes. Clinicians wishing to use this treatment were advised to fully inform their patients of the uncertainties that remain, and to monitor and review their patients’ clinical outcomes.55

In their 2006 guidelines, the Scottish Intercollegiate Guidelines Network concluded that, in the absence of invasive esophageal cancer, endoscopic treatments can avoid the morbidity and mortality associated with esophagectomy.17 These guidelines found that the evidence did not show a superiority of any particular endoscopic treatment, although endoscopic mucosal resection offered the benefit of additional disease staging information. Moreover, the guidelines note that individual patients may need multiple, different treatments.17

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta The 2009 guidelines from the US National Comprehensive Cancer Network recommend that esophageal cancers that have not invaded the submucosa (T1s or T1a tumours) be considered for esophagectomy, endoscopic mucosal resection or ablative treatments (including photodynamic therapy).5

A recent Cochrane Collaboration systematic review entitled, Surgery versus radical endotherapies for early cancer and high grade dysplasia in Barrett’s oesophagus, concluded that:

“...there are no randomised controlled trials to compare management options in this vital area, therefore trials should be undertaken as a matter of urgency. Current use of endotherapies in the care of patients with early cancer or high grade dysplasia of Barrett’s oesophagus should be at the recommendation of the multi‐disciplinary team involved in individual care...”57

Other assessments in progress The UK Centre for Reviews and Dissemination is preparing a systematic review on photodynamic therapy for Barrett’s esophagus, esophageal cancer, and several other types of cancer. This review is expected to be published in 2010.58

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Part III: Social & ethical implications of photodynamic therapy for early esophageal cancer

Photodynamic therapy for early esophageal cancer does not appear to entail major societal or ethical implications – other than those of other relatively new technologies. As the UK National Institute for Health and Clinical Excellence (NICE) guidance on PDT for early‐stage esophageal cancer indicates, patients should be fully informed of the current uncertainties regarding the long term efficacy of this treatment.55

The literature searches for this project did not identify any information on patient preferences regarding the different treatments for early esophageal cancer. The temporary period of photosensitivity following photodynamic therapy may be a burden for some patients and their families, but studies to date have not assessed the impact of this restriction. There is a similar lack of evidence on the effect on patient quality of life of PDT and other endoscopic treatments for early esophageal cancer. The NICE guidance recommends that clinicians audit and review their patients’ outcomes from photodynamic therapy, and where possible, enter patients into ongoing clinical trials that will provide information on long‐term outcomes.55

Photodynamic therapy is provided in specialist, tertiary care centres. As with other types of specialty care, patients in rural or remote areas of Alberta may have more difficulty in accessing this treatment.

Part IV: Economic and fiscal considerations

Research question

The primary question to be addressed in the economic component of this assessment was:

Is photodynamic therapy (PDT) for early esophageal cancer less costly than standard procedures, and, if not, do the benefits of using PDT outweigh its cost?

Methods

Literature search Published economic evaluations of PDT for treating early esophageal cancer were obtained from the broader literature searches for the project (see Appendix A). Further searches were run to capture costs associated with esophageal cancer in general. These searches used the bibliographic databases PubMed, EconLit, and EMBASE and coverage was limited to the most recent 10 years. The keywords used for these additional searches included: esophageal neoplasms OR esophagus tumor (various spellings), and truncations of esophagus AND cancer, combined with terms such as cost‐benefit analysis, costs and cost analysis, cost‐effective*, economics, ec (subheading in PubMed), cost, costs, costing or sensitivity analysis (as title or abstract terms). In EMBASE, the EMTREE Thesaurus terms health care cost OR economic aspect were also used.

Selection of relevant studies Inclusion criteria used for the economic studies were: English language publications, relevant to the subject of this review, and published within the last ten years.

Results

No published economic evaluations of treatments of early esophageal cancer were located through the search.

Development of the economic model Previously published decision models for PDT were constructed assuming that a patient receives only one intervention, e.g., PDT or esophagectomy. The model developed for this project allowed for the use of multiple treatment modalities to be used at one or several points in the treatment pathway, depending on disease stage, recurrence rate and patient, as well as physician, preferences. In the model, patients were initially treated with of one of the

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta endoscopic therapies (argon plasma coagulation, cryotherapy, endoscopic mucosal resection, photodynamic therapy or radiofrequency ablation), esophagectomy or chemotherapy, radiotherapy or chemoradiotherapy with or without a subsequent esophagectomy. Patients were monitored by scheduled endoscopies, the frequency of which was determined by current disease state as well as recent history. The failure of any of the endoscopic therapies, either initially or due to cancer recurrence, precipitated an esophagectomy. Failure of chemotherapy (radiotherapy) was followed by radiotherapy (chemotherapy) and, if necessary, a randomly determined endoscopic procedure, and, if necessary, an esophagectomy. Failure of chemoradiotherapy was followed by a randomly determined endoscopic procedure and, if necessary, an esophagectomy. Based on consultation with local experts, this model is more reflective of clinical practice in Alberta. By evaluating each treatment in this manner, cost and efficacy/effectiveness comparisons were made in the context of complementary and overlapping technologies.

A Markov model in which health state transitions are determined every three months was constructed and validated. Patient transitions between health states were dependent on the natural history of the disease and the efficacy of the treatment received. The health states represented in the model included: no esophageal cancer (a complete response to treatment), early stage esophageal cancer, late stage esophageal cancer and death. If treatment failed or if a patient's cancer recurred following treatment, the option of additional therapy remained available until late stage cancer was diagnosed, an esophagectomy was performed or the patient dieds.

The effect of misdiagnosis on cost and effectiveness of patient care was incorporated in this model by making treatment outcomes dependent on the actual health state of the patient while making treatment choice dependent on the perceived health state of the patient. Since the perceived health state was evaluated at every endoscopy and treatment, the model allowed for correction of misdiagnosis.

The model used clinical data from the synthesis of clinical studies described earlier in this report, supplemented by expert opinion when there was inadequate published evidence, and cost data provided by Alberta Health & Wellness. These data are presented in Tables 6 and Table 7.

The model for early stage esophageal cancer assumed the following as the base case scenario. All patients started with early stage esophageal cancer. The first treatment a patient may receive was one of: argon plasma coagulation, cryoablation, endoscopic mucosal resection, photodynamic therapy, radiofrequency ablation, radiotherapy, chemotherapy, chemoradiotherapy, esophagectomy, radiotherapy then esophagectomy, chemotherapy then esophagectomy, or chemoradiotherapy then esophagectomy. Following treatment, patients underwent endoscopic surveillance based on recommendations of the American College of Gastroenterology.59 The schedule depended on the historical health state and past frequency of endoscopies as well as the current health state of the patient. For the model, we assumed that a complete response corresponded to a state of no dysplasia and the frequency of endoscopy

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta following treatment of early stage esophageal cancer was the same as that for treatment of high‐grade dysplasia. For each ablative therapy, a patient received one or more sessions. Each session occurred in a separate three‐month window and the number of sessions was randomly determined based on the average number of sessions for each modality as reported in the literature. Esophagectomy was available after the failure of ablative therapy, chemotherapy, radiotherapy or chemoradiotherapy. After esophagectomy, performed as either the initial treatment strategy or as a result of the failure of another treatment strategy, patients underwent endoscopic surveillance based on the American College of Gastroenterology guidelines.59 If cancer recurred, a patient could receive chemotherapy or radiotherapy, with the limitation that these could each be given to a patient only once in their lifetime. The model continued until a diagnosis of late stage esophageal cancer or death occurs.

Table 6. Summary of variables included in the economic model Model variable Value Range Reference (Level of evidence) Rates of misdiagnosis Low grade dysplasia called cancer 0.050 0.010 – 0.10 60(2b) 61(5) 62(2b) 63(4) High grade dysplasia called 0.11 0.010 – 0.20 60(2b) 61(5) 62(2b) 63(4) cancer Cancer called low grade dysplasia 0.050 0.010 – 0.20 60(2b) 61(5) 62(2b) 63(4) Cancer called high grade 0.18 0.010 – 0.020 60(2b) 61(5) 62(2b) 63(4) dysplasia Cancer called Barrett’s 0.00 0.000 – 0.001 60(2b) 61(5) 62(2b) 63(4)

Efficacy of treatment for early cancer Argon plasma coagulation Complete response 1.0 1.0 – 1.0 Table E2 Recurrence 0.18 0.0 – 0.25 Table E2 Stricture 0.0 0.0 – 0.0 Table B2, Table D2 Perforation 0.0 0.0 – 0.0 Table B2, Table D2 Mortality from treatment 0.0 0.0 – 0.0 Table B2, Table D2 Mortality from surgery to repair 0.080 0.05 – 0.15 64 65 66 67(4) perforation Number of treatment sessions 2.7 1 ‐ 5 Table B2

Cryoablation Complete response 0.75 0.25 – 1.0 Table E368(5) Recurrence 0.0 0.0 Table E3 Stricture 0.0 0.0 – 0.0 Table B3, Table D3 Perforation 0.0 0.0 – 0.0 Table B3, Table D3 Mortality from treatment 0.0 0.0 – 0.0 Table B3, Table D3 Mortality from surgery to repair 0.080 0.05 – 0.15 64 65 66 67(4) 52

Endoscopic mucosal resection Complete response 0.93 0.67 – 1.0 Table E5 Recurrence 0.15 0.0 – 0.28 Table E5 Stricture 0.005 0.0 – 0.50 Table D5 Perforation 0.0 0.0 – 0.0 Table D5 Mortality from treatment 0.0 0.0 – 0.0 Table D5 Mortality from surgery to repair 0.080 0.05 – 0.15 64 65 66 67(4) perforation Number of treatment sessions 2.2 1 ‐ 9 Table B5

Photodynamic therapy Complete response 0.69 0.37 – 1.0 Table E1 Recurrence 0.28 0.0 – 0.61 Table E1 Stricture 0.13 0.0 – 0.52 Table D1 Perforation 0.01 0.0 – 0.07 Table D1 Mortality from treatment 0.0 0.0 – 0.0 Table D1 Mortality from surgery to repair 0.080 0.05 – 0.15 64 65 66 67(4) perforation Number of treatment sessions 1.6 1 – 4 Table B1

Radiofrequency ablation Complete response 1.0 1.0 – 1.0 Table E4 Recurrence 0.0 0.0 – 0.0 Table E4 Stricture 0.0 0.0 – 0.0 Table D4 Perforation 0.0 0.0 – 0.0 Table D4 Mortality from treatment 0.0 0.0 – 0.0 Table D4 Mortality from surgery to repair 0.080 0.05 – 0.15 64 65 66 67(4) perforation Number of treatment sessions 1 1 – 2 Table B4

Radiotherapy Complete response 0.81 0.61 – 1.0 Table E6 Recurrence 0.23 0.21 – 0.59 Table E6 Stricture 0.0 0.0 – 0.0 Table D6 Perforation 0.005 0.0 – 0.010 Table D6 Mortality from treatment 0.0 0.0 – 0.0 Table D6 Mortality from surgery to repair 0.080 0.05 – 0.15 64 65 66 67(4) perforation 53

Chemotherapy Complete response 0.50 0.19 – 0.61 69 70 (2c) Recurrence 0.50 0.40 – 0.60 69 70(2c) Stricture 0.0 0.0 – 0.0 Table D7 Perforation 0.005 0.0 – 0.010 Table D7 Mortality from treatment 0.0 0.0 – 0.0 Table D7 Mortality from surgery to repair 0.080 0.05 – 0.15 64 65 66 67(4) perforation Number of treatment sessions 1 1 – 1 Table B7

Chemoradiotherapy Complete response 0.77 0.50 – 0.82 Table E8 Recurrence 0.35 0.35 – 0.35 71(2c) Stricture 0.0 0.0 – 0.0 Table D8 Perforation 0.0 0.0 Table D8 Mortality from treatment 0.010 0.0 – 0.020 Table D8 Mortality from surgery to repair 0.080 0.05 – 0.15 64 65 66 67(4) perforation Number of treatment sessions 1 1 – 1 Table B8

Esophagectomy Complete resection 1.0 1.0 ‐ 1.0 Table B10, Table E10 Recurrence 0.20 0.0 – 0.33 Table E10 Mortality from treatment 0.010 0.0 – 0.020 Table D10

Health state utilities Esophageal cancer Early stage 0.79 0.61 – 0.87 28 39,72(2c) Late stage 0.55 0.47 – 0.60 28,73(2c) Recurrence of cancer 0.41 0.32 – 0.50 74(2c) Unresectable cancer 0.34 0.25 – 0.43 74(2c)

Endoscopic techniques Argon plasma coagulation 0.93 0.55 ‐ 0.99 † Cryoablation 0.93 0.55 ‐ 0.99 † Endoscopic mucosal resection 0.93 0.55 ‐ 0.99 † Photodynamic therapy 0.92 0.55 ‐ 0.99 75(4) Radiofrequency ablation 0.93 0.55 ‐ 0.99 † Esophagectomy 54

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Table 6. Summary of variables included in the economic model Model variable Value Range Reference (Level of evidence) 3 months 0.72 0.69 ‐ 0.73 28 72(2c) 6 months 0.77 0.61 ‐ 0.83 37,72,76(2c) 9 months 0.80 0..77 – 0.83 72(2c) 12 months 0.86 0.85 – 0.87 72(2c) 3 years 0.73 0.71 – 0.76 37,39(2c) Chemotherapy 3 months 0.60 0.58 – 0.61 28(2c) Radiotherapy 3 months 0.60 0.58 – 0.61 28(2c) Chemoradiotherapy 1 week 0.60 0.52 – 0.69 72(2c) 3 months 0.63 0.56 – 0.67 36 28(2c) Chemoradiotherapy + surgery 3 months 0.59 0.56 – 0.62 4(2c) 6 months 0.72 0.69 – 0.75 4(2c) 12 months 0.84 0.81 – 0.86 4(2c)

 See Appendix G for levels of evidence table † Estimates based on single study of utilities related to PDT; Assumes a slightly higher utility because patients are able to resume their normal activities more quickly (i.e., no photosensitivity‐related concerns)

Table 7. Estimated per procedure costs of treatment alternatives Base case Range value (2006 (2006 Cdn Reference Treatment costs (per session) Cdn dollars) dollars) (Level of evidence) Argon plasma coagulation Amortized fixed cost of laser 77(3a) source assuming 1000 procedures $26 $19 – $31 over 5 years Hospital costs and physician fees $1,326 78(2c)δ $171 ‐ 77(3a) Probe $197 $303 Total cost $1,549

Cryoablation Amortized fixed cost of laser 77(3a) source assuming 1000 procedures $27 $10 ‐ $218 over 5 years Hospital costs and physician fees $1,326 78(2c) δ Single use ablation catheter $644 $358 ‐ 77(3a)

Endoscopic mucosal resection Hospital costs and physician fees $1,326 78(2c) δ Cap, snare, injection needle, and $210 ‐ 46(3a) $254 tissue collection kits $299 Total cost $1,580

Photodynamic therapy Amortized fixed cost of laser 47 79(3a) source assuming 1000 procedures $95 $86 ‐ $101 over 5 years Hospital costs and physician fees $1,326 78(2c)δ Light diffusion catheter, centering Axcan 47 79(3a) $4,200 ‐ balloon, fiber optic diffuser, and $5,100 $6,600 Porfimer sodium** Total cost $6,521

Radiofrequency ablation Amortized fixed cost of laser 77(3a) source assuming 1000 procedures $24 $14 ‐ $34 over 5 years Hospital costs and physician fees $1,326 78(2c)δ Centering balloon and ablation $992 ‐ 77(3a) $1,185 balloon $1,378 Total cost $2,535

Chemotherapy Analysis of administrative $1,940 ‐ Hospital costs and physician fees $3,880 data from Alberta Health & $5,163 Wellness; 78(2c)

Radiotherapy Analysis of administrative $546 ‐ Hospital costs and physician fees $957 data from Alberta Health & $1,369 Wellness

Chemoradiotherapy Based on sum of estimated $2,486 ‐ Hospital costs and physician fees $4,837 case costs of chemotherapy $6,532 and radiotherapy

Esophagectomy

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Analysis of administrative $23,951 ‐ Hospital costs and physician fees $34,481 data from Alberta Health & $129,735 Wellness  See Appendix G for levels of evidence table * Values adjusted for inflation using the Consumer Price Index and converted from US to Cdn dollars using Bank of Canada historical exchanges rates for 2006 and inflation http://www.bankofcanada.ca/en/review/autumn06/r06‐ 4‐ed.html δ Assumes cost equal to that of an ERCP (personal communication, C. Wong, March 2009) reported in the Health costing in Alberta 2006 annual report78 † Assumes costs equivalent to EMR since no cost information could be found ‡ Personal communication (W. Austin, April 2009) ** Porfimer sodium costs $2,200 per 75 mg vial (Axcan Pharma Inc.). A typical patient requires 2‐3 vials per treatment based on a dosage of 2 mg/kg of body weight.

Results

Economic model A baseline model was constructed using the mean values extracted from the literature, if available, or from expert opinion, if necessary. The model creates 100,000 consecutive 50‐year old patients, with gender randomly determined. Each patient is "treated" in parallel using each of the comparator therapies as the initial treatment. The true patient health state is evaluated every three months, whereas the diagnosed (perceived) health state is evaluated during treatment and endoscopic surveillance only. Treatment decisions are based on the perceived health state and the randomly determined treatment outcomes, including all cause mortality are based on the true health state. Treatment effectiveness, based on the utility of living in the current state, and costs are calculated every three months and their discounted values (3%) are accumulated. The results of the base case analysis are presented below.

The table shows the average discounted cost and effectiveness for each of the comparators. In addition, the incremental cost‐effectiveness ratios (ICERs) are shown using esophagectomy as the baseline standard of care. For each comparator, the ICER specifies how much it would cost to gain one additional “quality‐adjusted life year” (QALY) when compared to esophagectomy. The QALY integrates of the length of life gained as a result of an intervention with the quality of life resulting from the intervention, and is often used to compare the cost‐effectiveness of competing interventions or technologies.

Table 8. Summary of ICERs for treatment options included Incremental Treatment Cost (Cdn$) Outcome (QALY) $ Cost/QALY Esophagectomy 48,761 5.80 EMR 38,364 10.06 ‐2441 RT 41,852 8.96 ‐2184 APC 38,565 10.49 ‐2176 RFA 40,323 10.55 ‐1777 Cryoablation 44,173 9.46 ‐1255 CT 45,873 8.39 ‐1113 CRT 46,577 8.78 ‐732 PDT 47,127 8.83 ‐540 RT + ESO 49,416 8.01 296 CRT + ESO 53,371 7.27 3133 CT + ESO 52,661 6.34 7200 EMR=endoscopic mucosal resection; RT=radiotherapy; APC=argon plasma coagulation; RFA=radiofrequency ablation; CT=chemotherapy; CRT=chemoradiotherapy; PDT=photodynamic therapy; ESO=esophagectomy

Baseline costs, outcomes and incremental cost‐effectiveness ratios for the treatment of early esophageal cancer All of the comparator therapies produce more health gain (QALYs) than esophagectomy, and with the exception of CRT + ESO and CT + ESO, at a lower cost than esophagectomy. The ICERs range from $‐2,441/QALY for EMR, to $7,200/QALY for CT + ESO – well within what is commonly deemed an “acceptable” ICER.

The baseline analysis indicates that all of the comparator therapies that do not include an initial esophagectomy are cheaper than esophagectomy, and that all comparators were more effective than esophagectomy. For those therapies that were more expensive than esophagectomy the increase in cost per treatment was less than $5,000. The negative ICER values indicate that most comparators are both cheaper and better while the positive ICER values indicate an increased cost for a better therapy.

Probabilistic sensitivity analysis The inherent uncertainty in the parameter estimates complicates the interpretation of the results of any complex model. One method for dealing with this uncertainty is to use deterministic sensitivity analysis. That is, each of the parameters is systematically varied between two extremes and many iterations of the model are run with each change. While this method does yield insight into the range of outcomes which could be expected with changes in the parameters, it does not give us a good sense of the probability that we would experience

 If the comparator is both cheaper and more effective than esophagectomy, the ICER will be negative. If the comparator is more expensive, but also more effective than esophagectomy then the ICER will be positive. 58

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta any of the outcomes. In addition, there are likely to be interactions between the various parameters that cannot be accounted for in a deterministic sensitivity analysis. Both of these problems can be addressed using a probabilistic sensitivity analysis, where model parameters are defined as distributions rather than as fixed values.80

With each iteration of the model, a new random sample of each parameter is taken. Over many iterations, the value for each parameter averages out to the mean estimate. However, since all parameter distributions are resampled every iteration, the effects of parameter variability and parameter interactions are propagated through the model on each run. Over many iterations, this generates a cost and effectiveness “surface” for each therapy. Average cost and effectiveness for each therapy can be calculated over all trials and incremental cost‐ effectiveness ratios can be determined. In addition, the incremental cost‐effectiveness ratios can be calculated for each individual study. Then, for a given cost / effectiveness ceiling, the fraction of each therapy which is cost‐effective can be calculated. By varying the cost / effectiveness ceiling, so‐called cost‐effectiveness acceptability curves (CEAC) are generated. CEACs plot the percentage of simulations where the technology of interest was both cost‐ effective compared to standard care and below a given Cost / QALY ceiling ratio. This curve can be interpreted as the probability that the technology of interest will be cost effective at a given Cost / QALY level.80

For this analysis, it is assumed that the "true" value of a parameter lies somewhere within the range of values taken from the literature. Thus, all variables were modeled as Beta distributions using the minimum, maximum and mean values taken from the literature (where available) or estimated (where not available, as indicated). First, all variables were normalized so that the minimum value was 0.0 and the maximum value was 1.0. This was done by subtracting the minimum value from each of the minimum, mean and maximum values and then dividing these numbers by the new, adjusted maximum value. For example, the minimum and maximum values for the Cost of Disposables for PDT were $4,200 and $6,600 with a mean value of $5,100. This yields: Normalized Minimum Value= ($4,200 ‐ $4,200) / ($6,600 ‐ $4,200) = 0.0 Normalized Mean Value = ($5,100 ‐ $4,200) / ($6,600 ‐ $4,200) = 0.375 Normalized Maximum Value= ($6,600 ‐ $4,200) / ($6,600 ‐ $4,200) = 1.0 These values are then used to generate a Beta distribution, a distribution with 2 parameters, α and β. Estimates of α and β can be determined from the mean and the variance of the parameter using the method of moments80, where α = [ (mean)^2 * (1 ‐ mean) / variance ] ‐ mean β = α * (1 ‐ mean) / mean

To simplify the modeling process, we have estimated the variance using the assumption that the Beta distribution approximates a normal distribution, with 95% of the distribution laying within +/‐ 1.96 standard deviations from the mean. Thus we estimated the variance for each variable as Variance ≈ [ (Normalized Mean ‐ 0 ) / 1.96 ]2 for variables with a Normalized Mean <= 0.5

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Variance ≈ [ (1 ‐ Normalized Mean ) / 1.96 ]2 for variables with a Normalized Mean > 0.5 The Beta(α, β) distribution for each parameter is given in following tables along with the maximum, minimum and mean values used to generate the distributions. Values were calculated during each model iteration as Variable value = Minimum value + Beta distribution * (Maximum value ‐ Minimum value) e.g. Cost of disposables, PDT = $4,200 + Random draw from Beta(2.03, 3.38) * ($6,600 ‐ $4,200) For some highly skewed variables (e.g. cost of esophagectomy), the distributions were constructed after first taking the logarithm of the variable values. This was taken into account when calculating each random sample of the parameter during the probabilistic sensitivity analysis.

Table 9. Probabilistic sensitivity analysis ‐ Costs Parameter Distribution Minimum Value Maximum Value Mean Value Cost of combined RT CT Beta(2.52, 1.81) 2486 6532 4837 Cost of CT Beta(2.89, 1.91) 1940 5163 3880 Cost of esophagectomy1 Beta(2.80, 10.17) 23951 129735 34481 Cost of RT Beta(1.42, 1.43) 546 1369 957 Cost of disposables, APC Beta(2.89, 11.77) 171 303 197 Cost of disposables, CRYO Beta(1.42, 1.42) 358 930 644 Cost of disposables, EMR Beta(1.45, 1.48) 210 299 254 Cost of disposables, PDT Beta(2.03, 3.38) 4200 6600 5100 Cost of disposables, RFA Beta(1.42, 1.42) 992 1378 1185 Fixed cost, APC Beta(2.55, 1.82) 19 31 26 Fixed cost, CRYO1 Beta(2.28, 4.80) 10 218 27 Fixed cost, EMR2 Beta(2.55, 1.82) 19 31 26 Fixed cost, PDT Beta(2.86, 1.9) 86 101 95 Fixed cost, RFA Beta(1.42, 1.42) 14 34 24 Hospital and physician fees, APC3 Beta(1.42, 1.42) 663 1989 1326 Hospital and physician fees, CRYO3 Beta(1.42, 1.42) 663 1989 1326 Hospital and physician fees, EMR3 Beta(1.42, 1.42) 663 1989 1326 Hospital and physician fees, PDT3 Beta(1.42, 1.42) 663 1989 1326 Hospital and physician fees, RFA3 Beta(1.42, 1.42) 663 1989 1326 Cost of surgery to repair perforation4 Beta(2.80, 10.17) 23951 129735 34481 Cost of dilation of treat stricture3 Beta(1.42, 1.42) 319 957 638 Cost of visit with endoscopy3 Beta(1.42, 1.42) 319 957 638 1Distributions were constructed after first taking the logarithm of the variable values 2Costs not available. Values were estimated to be equal to that of "Fixed cost, APC" 3Cost variability not available. Maximum and minimum values represent mean value +/‐ 50% 4Costs not available. Costs were assumed to be the same as for esophagectomy.

Table 10. Probabilistic sensitivity analysis ‐ Probabilities, rates and treatment effects Parameter Distribution Minimum Maximum Mean Value Value Value Proportion of male patients Beta(1.42, 1.42) 0.5 1 0.75 Average treatments / patient, APC Beta(1.78, 2.41) 1 5 2.7 Average treatments / patient, CRYO Beta(2.23, 4.46) 1 10 4 Average treatments / patient, EMR Beta(3.12, 17.65) 1 9 2.2 Average treatments / patient, PDT Beta(2.87, 11.49) 1 4 1.6 Average treatments / patient, RFA1 Beta(3.36, 30.22) 1 2 1.1 Efficacy of APC; early stage cancer ‐> no dysplasia2 Beta(10.45, 2.81) 0.67 1 0.93 Efficacy of CRTCT; early stage cancer ‐> no dysplasia Beta(16.66, 3.09) 0.5 0.82 0.77 Efficacy of CRYO; early stage cancer ‐> no dysplasia Beta(4.46, 2.23) 0.25 1 0.75 Efficacy of CT; early stage cancer ‐> no dysplasia Beta(7.25, 2.57) 0.19 0.61 0.5 Efficacy of EMR; early stage cancer ‐> no dysplasia Beta(10.45, 2.81) 0.67 1 0.93 Efficacy of ESO; early stage cancer ‐> no dysplasia3 Beta(6.49, 2.5) 0.82 1 0.95 Efficacy of PDT; early stage cancer ‐> no dysplasia Beta(1.51, 1.46) 0.37 1 0.69 Efficacy of RFA; early stage cancer ‐> no dysplasia2 Beta(10.45, 2.81) 0.67 1 0.93 Efficacy of RT; early stage cancer ‐> no dysplasia Beta(1.56, 1.48) 0.61 1 0.81 Probability of death resulting from esophagectomy Beta(1.42, 1.42) 0 0.02 0.01 Probability of misdiagnosing cancer‐in‐remission as Beta(1.72, 1.55) 0.01 0.2 0.11 early‐stage cancer Probability of misdiagnosing early‐stage cancer as Beta(2.07, 1.68) 0.02 0.4 0.23 cancer‐in‐remission Probability of esophageal perforation during APC Beta(1.42, 1.42) 0 0.02 0.01 Probability of esophageal perforation during CRTCT4 Beta(1.42, 1.42) 0 0.01 0.005 Probability of esophageal perforation during CRYO Beta(1.57, 1.77) 0 0.2 0.094 Probability of esophageal perforation during CT Beta(1.42, 1.42) 0 0.01 0.005 Probability of esophageal perforation during EMR Beta(1.84, 2.62) 0 0.046 0.019 Probability of esophageal perforation during PDT Beta(2.21, 4.34) 0 0.086 0.029 Probability of esophageal perforation during RFA Beta(1.42, 1.42) 0 0.006 0.003 Probability of esophageal perforation during RT Beta(1.42, 1.42) 0 0.01 0.005 Probability of death due to surgery to repair Beta(2.39, 5.57) 0.05 0.15 0.08 perforation Yearly rate of progression, cancer‐in‐remission to Beta(1.87, 2.72) 0.077 0.131 0.099 early‐stage cancer Yearly rate of progression, cancer‐in‐remission to Beta(2.23, 4.48) 0.00385 0.0524 0.02 late‐stage cancer Yearly rate of progression, early‐stage cancer to Beta(1.77, 2.36) 0.05 0.4 0.2 late‐stage cancer Yearly rate of cancer recurrence following APC Beta(6.39, 2.49) 0 0.25 0.18 Yearly rate of cancer recurrence following CRTCT Beta(3.38, 2.03) 0.1 0.5 0.35 Yearly rate of cancer recurrence following CRYO5 Beta(1.84, 1.59) 0 0.28 0.15 Yearly rate of cancer recurrence following CT Beta(1.42, 1.42) 0.4 0.6 0.5 Yearly rate of cancer recurrence following EMR Beta(1.84, 1.59) 0 0.28 0.15 Yearly rate of cancer recurrence following ESO Beta(2.98, 1.93) 0 0.33 0.2 Yearly rate of cancer recurrence following PDT Beta(1.62, 1.91) 0 0.61 0.28 Yearly rate of cancer recurrence following RFA5 Beta(1.84, 1.59) 0 0.28 0.15 Yearly rate of cancer recurrence following RT Beta(3.59, 64.56) 0.21 0.59 0.23 Probability of stricture following APC Beta(2.81, 10.38) 0 0.23 0.049 Probability of stricture following CRYO6 Beta(1.42, 1.42) 0 0.031 0.0155 Probability of stricture following EMR Beta(3.54, 53.9) 0.043 0.27 0.057 Probability of stricture following ESO Beta(3.17, 1.98) 0 0.13 0.08 Probability of stricture following PDT Beta(2.63, 7.89) 0 0.52 0.13 Probability of stricture following RFA Beta(6.15, 2.46) 0 0.007 0.005 61

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta 1Variability data not available. Average value estimated. 2Variability data not available. Values estimated to be equal to "Efficacy of EMR; early stage cancer ‐> no dysplasia". 3Mean value estimated. 4Data not available; used values for "Probability of esophageal perforation during CT". 5Data not available; used values for "Yearly rate of cancer recurrence following EMR". 6 Variability data not available; used average of maximum and minimum values as the mean value.

Table 11. Probabilistic sensitivity analysis ‐ Utilities Parameter Distribution Minimum Maximum Mean Value Value Value Utility following APC Beta(6.15, 2.46) 0.78 0.99 0.93 Utility at 3 months following CRTCT Beta(3.64, 2.08) 0.56 0.67 0.63 Utility following CRYO Beta(6.15, 2.46) 0.78 0.99 0.93 Utility at 3 months following CT Beta(4.46, 2.23) 0.58 0.61 0.6 Utility of living with cancer‐in‐remission Beta(17.65, 3.12) 0.78 0.98 0.95 Utility following EMR Beta(6.15, 2.46) 0.78 0.99 0.93 Utility of living with early‐stage cancer Beta(5.29, 2.35) 0.61 0.87 0.79 Utility at 3 months following esophagectomy Beta(7.89, 2.63) 0.69 0.73 0.72 Utility at 9 months following esophagectomy Beta(1.42, 1.42) 0.77 0.83 0.8 Utility at 6 months following esophagectomy Beta(6.72, 2.52) 0.61 0.83 0.77 Utility at 12 months following esophagectomy Beta(1.42, 1.42) 0.85 0.87 0.86 Utility at 36 months following esophagectomy Beta(1.9, 2.86) 0.71 0.76 0.73 Utility of living with late‐stage cancer Beta(3.17, 1.98) 0.47 0.6 0.55 Utility following PDT Beta(16.23, 3.07) 0.55 0.99 0.92 Utility of living with recurrent cancer Beta(1.42, 1.42) 0.32 0.5 0.41 Utility following RFA Beta(6.15, 2.46) 0.78 0.99 0.93 Utility at 3 months following RT / CT / CRTCT + Beta(1.42, 1.42) 0.56 0.62 0.59 esophagectomy Utility at 6 months following RT / CT / CRTCT + Beta(1.42, 1.42) 0.69 0.75 0.72 esophagectomy Utility at 12 months following RT / CT / CRTCT Beta(2.86, 1.9) 0.81 0.86 0.84 + esophagectomy Utility at 36 months following RT / CT / CRTCT Beta(1.9, 2.86) 0.71 0.76 0.73 + esophagectomy Utility at 3 months following RT Beta(4.46, 2.23) 0.58 0.61 0.6 Utility following endoscopy1 Beta(30.22, 3.36) 0.9 1 0.99 1Variability data not available. Minimum value was estimated at 0.9. Mean value was estimated at 0.99.

Table 12. Probabilistic sensitivity analysis ‐ Average costs, effectiveness & ICERS Treatment Cost QALY ICER ESO 50218 6.08 EMR 38470 10.38 ‐2735 APC 39090 10.48 ‐2531 RT 44255 8.84 ‐2163 RFA 40708 10.50 ‐2150 PDT 47718 9.15 ‐814 CT 48750 8.11 ‐722 CRYO 48152 9.01 ‐704 CRT 49216 8.62 ‐394 RT+ESO 50739 8.03 267 CRT+ESO 54817 7.41 3456 CT+ESO 54124 6.58 7850 Average costs, effectiveness and incremental cost‐effectiveness ratios (ICER) from 100,000 runs of the model using probabilistic sensitivity analysis. The ICERs were calculated from the difference in average cost divided by the difference in average effectiveness (measured as quality‐adjusted life years) between the comparator therapy and the baseline therapy, esophagectomy.

Uncertainty in the model was explored by defining the model parameters as distributions rather than fixed values. For this analysis, it was assumed that the "true" value for each of the parameters was distributed around the mean value and between the lowest and highest values found from the literature search. The figure below shows the results after 100,000 runs. For each run of the model, incremental cost and incremental effectiveness were calculated for each therapy using esophagectomy as the comparator. The data points represent the percentage of the simulations where the therapy was both cost‐effective compared to esophagectomy and below a given Cost / QALY ceiling ratio. The intercept of each curve on the Probability Cost‐ effective axis represents the percentage of simulations where the therapy was cheaper than esophagectomy. The plateau value observed for each curve with increasing Cost / QALY represents the percentage of simulations where the therapy was more effective than esophagectomy.

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Figure 5. Probabilistic sensitivity analysis for treatments of esophageal cancer

The average costs and effectiveness seen with the probabilistic sensitivity analysis did not change the conclusions taken from the baseline case that all comparator therapies which do not include an initial esophagectomy are cheaper than esophagectomy and that all comparators were more effective than esophagectomy. By aggregating the results of individual trials, the probability that any particular treatment was cost‐effective for a given patient can be considered. These results show that as the cost / QALY ceiling increases, all of the comparators except the more expensive therapies were more probable than not to be cost‐effective on an individual basis. For the more expensive therapies, these results indicate that less than half of the patients would benefit from RT + ESO, CT + ESO or CRT + ESO compared to esophagectomy, but that the total health gains of those that do benefit from those therapies results in an average effectiveness greater than that for esophagectomy.

Budget impact analysis A budget impact analysis estimates the potential costs to a particular health care budget (provincial government, regional health authority, hospital, etc.) of adopting and using a new technology. The budget impact analysis for this assessment includes an analysis of how the incorporation of the new technology with existing treatments (as a replacement for, or in addition to existing treatments) might affect the overall costs of treating the condition.81

An estimate of the costs incurred for treating esophageal cancer in Alberta annually was calculated. Data provided by Alberta Health Services – Alberta Cancer Board for the period 1996‐2006 were used to obtain average annual utilization rates for chemotherapy, radiotherapy, esophagectomy and combinations of these treatments. Alberta Health & Wellness administrative data were used to obtain estimates of costs for each of these therapies. Based on this, it is estimated that an annual average of just over $1.3 million was spent in this 10‐year period for existing treatments for esophageal cancer. Table 13. Estimated treatment costsTable 13 presents these figures in detail.

Table 13. Estimated treatment costs Procedure Average number Average cost Total cost for annually procedure Chemotherapy (CT) 1.4 $3,880 $5,432 Radiotherapy (RT) 33.0 $957 $31,581 Esophaghectomy 21.7 $34,481 $748,238 (ESO) CT+ESO 1.6 38,361 $61,378 CT+RT 18.8 $4,837 $90,936 RT+ESO 1.6 $35,438 $56,701 CT+RT+ESO 8.2 $39,318 $322,408 Total cost $1,316,674

The total overall cost of treating patients with esophageal cancer is likely to be greater than the figure obtained above, as there could also be costs for re‐treatment, as well as for physician visits, treatment of complications, etc. An estimate of the overall cost to the provincial government was obtained using Alberta Health & Wellness data. A prevalence cohort (of 301 patients) was followed in 2006/2007, and all esophageal cancer‐related health care services were tracked. This yielded a total expenditure value of approximately $3.5 million for that year.

The projected costs of treating this condition in Alberta will depend on the extent to which the newer techniques reviewed in this project are deployed, and in which patient sub‐groups.

Implications of the clinical evidence: Although 75 studies were found and reviewed, their overall quality was low. In most of these studies, the treatment used was either PDT or esophagectomy; relatively little information is available on the newer techniques of APC, RFA or cryoablation. The patient populations were heterogeneous, both in terms of cell type (squamous cell or adenocarcinoma) and disease stage. There was no consistent reporting of follow‐up data.

No firm conclusions about the effectiveness of PDT relative to alternative treatment options can be drawn from the evidence reviewed. Nevertheless, it does appear to be as safe as other endoscopic techniques and may result in fewer complications than chemotherapy, radiotherapy, chemoradiotherapy and esophagectomy.In general, patients treated with PDT in the published studies reviewed had deeper tumours than did those treated with the other ablative technologies. If tumour stage had been the same across all of the ablative studies, PDT may have achieved a similar effectiveness.

Current clinical practice: In Alberta, PDT is not currently used to treat patients with early esophageal cancer. The extent to which there is a demand for this treatment remains unclear. However, the infrastructure required for PDT is already in place at centres in Edmonton and Calgary, should there be a need or desire to expand its use to patients with early esophageal cancer.

Patient preference: Patients generally prefer non‐invasive (e.g., endoscopic) treatments over invasive surgery, such as esophagectomy. A number of endoscopic therapies for early esophageal cancer exist. However, only one is associated with a systemic side‐effect, namely PDT and photosensitivity. If other ablative techniques are available, it is not clear whether patients would be willing to endure the temporary changes in lifestyle required during the period of light sensitivity (4‐6 weeks).

Funding issues: The estimated cost of one PDT treatment is $6,500, compared to $34,500 for esophagectomy. Photodynamic therapy, like other ablative techniques, often requires multiple sessions in order to achieve a complete response (total eradication of the tumour). Therefore, ultimately, there may be little cost savings resulting from the substitution of PDT for esophagectomy. Currently, a major component of the cost of PDT is the cost of the photosensitizing agent (porfimer sodium, Photofrin©). The cost of porfimer sodium is $2,200 per 75 mg vial, and most patients require at least 2 vials per treatment (based on a dosage of 2 mg/kg of body weight). One way of reducing this cost is to negotiate a lower price for the drug. But, this may not be possible due to current market circumstances. The manufacturer of ALA, the only other widely‐used agent for PDT, has indicated that it will not be seeking regulatory approval for the use of ALA to treat

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta esophageal cancer in Canada. This might leave the manufacturer of porfimer sodium with a monopoly of the Canadian market.

Unless a substantial proportion of the eligible patient pool is switched to PDT from current therapies, significant cost savings are unlikely.

Part VI: Conclusions

This review assessed the evidence on photodynamic therapy (PDT), other endoscopic treatments (i.e., endoscopic mucosal resection, radiofrequency ablation, argon plasma coagulation and cryoablation), chemotherapy, radiotherapy, combined chemoradiotherapy, and esophagectomy for the treatment of early stage esophageal cancer.

While quality evidence on many of these treatments is limited, the safety and effectiveness of PDT for early esophageal cancer appears to be comparable to those of other endoscopic techniques, and superior to those of chemotherapy, radiotherapy, and esophagectomy.

To date, no guidelines define best clinical practice in the use of the various endoscopic treatment options for early esophageal cancer, and patients may receive multiple treatments. The use of multimodality endoscopic treatments may improve patient outcomes.

The economic model developed for this review found that PDT is as cost‐effective as other endoscopic techniques.

There is little information available on the social burden of photodynamic therapy, and on patient preferences for the various treatment options, particularly for the newer endoscopic treatments.

Expertise in the use of PDT is already established at medical centres in Edmonton and Calgary.

Appendix A Literature searches

Part 1. Photodynamic therapy (PDT) for the treatment of Barrett’s esophagus or esophageal cancer Searches run July 2008

1. PubMed Total = 606 references Search Most Recent Queries Time Result #25 Search #24 OR #23 13:39:50 606 #24 Search #22 Limits: Humans 13:23:42 585 #23 Search #22 AND (in process [sb] OR publisher [sb]) 13:23:03 21 #22 Search #11 AND #21 13:22:38 659 #21 Search #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR 13:22:06 80948 #20 #20 Search "Barrett's oesophagus" 13:21:02 803 #19 Search "oesophageal cancer*" 13:20:49 1403 #18 Search "esophageal cancer*" 13:20:41 7523 #17 Search Barrett's 13:20:32 4330 #16 Search "barrett epithelium" 13:20:26 32 #15 Search "barrett syndrome" 13:20:18 28 #14 Search esophagus 13:20:08 64117 #13 Search esophageal neoplasms 13:20:04 32717 #12 Search barrett esophagus 13:19:56 4295 #11 Search #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 13:19:18 62377 #10 Search temoporfin 13:18:40 238 #9 Search hematoporphyrin derivative 13:18:33 1936 #8 Search dihematoporphyrin ether 13:18:17 801 #7 Search porphyrins 13:17:52 41066 #6 Search aminolevulinic acid 13:17:33 5031 #5 Search "photodynamic therapies" 13:17:19 19 #4 Search "photodynamic therapy" 13:17:11 6742 #3 Search photosensitizing agents 13:16:56 21357 #2 Search hematoporphyrin photoradiation 13:16:44 760 #1 Search photochemotherapy 13:16:34 9492

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta 2. The Cochrane Library (issue 3, 2008) Total = 37 refs ""photodynamic therapy" OR photochemotherapy OR hematoporphyrin photoradiation OR photosensitizing agents in Title, Abstract or Keywords and barrett esophagus OR esophageal neoplasms OR esophagus OR barrett's OR "oesophageal cancer*" OR "esophageal cancer*" in Title, Abstract or Keywords

3. UK Centre for Reviews & Dissemination (DARE, NHS EED, HTA) databases

Total =17 refs

(photodynamic OR photochemotherapy OR photosensitizing OR aminolevulinic acid OR porphyrins OR hematoporphyrin OR dihematoporphyrin ether OR temoporfin) AND (Barrett esophagus OR esophageal neoplasms OR esophagus OR Barrett's OR esophageal OR oesphageal): 17 documents found

4. EMBASE (EMBASE 1988 to 2008 Week 30) Total =784 refs

# Searches Results 1 photodynamic therapy.mp. or exp Photodynamic Therapy/ 8786 2 limit 1 to human 6235 3 exp PHOTOCHEMOTHERAPY/ 1255 4 limit 3 to human 1096 5 exp Hematoporphyrin Derivative/ 914 6 limit 5 to human 572 7 exp HEMATOPORPHYRIN/ 497 8 limit 7 to human 254 9 exp Aminolevulinic Acid/ 2931 10 limit 9 to human 2058 11 exp PORPHYRIN/ 7870 12 limit 11 to human 3265 13 exp Photofrin II/ 557 14 limit 13 to human 329 15 exp TEMOPORFIN/ 282 16 limit 15 to human 213 17 exp PHOTOFRIN/ or exp PHOTOFRIN I/ 1219 18 limit 17 to human 887 19 exp "Tetrakis(3 Hydroxyphenyl)Chlorin"/ 144 20 limit 19 to human 101 21 2 or 4 or 6 or 8 or 10 or 12 or 14 or 16 or 18 or 20 10509 22 exp Barrett Esophagus/ 5230 23 limit 22 to human 4931 24 exp ESOPHAGUS/ or exp ESOPHAGUS CANCER/ or exp ESOPHAGUS CARCINOMA/ 28191 25 limit 24 to human 24988 26 23 or 25 27097 27 21 and 26 784

5. CINAHL

Search modes ‐ S3 S2 and S1 64 Boolean/Phrase barrett esophagus or esophageal neoplasms Search modes ‐ S2 or esophagus or barrett's or ( oesophageal OR 2970 Boolean/Phrase oesophagus ) photodynamic therapy or ( photochemotherapy OR hematoporphyrin Search modes ‐ S1 550 radiation OR photosensitizing agents OR Boolean/Phrase "photodynamic therapy" )

6. Web of Knowledge

Total = 598 refs

Topic=("photodynamic therapy" OR photochemotherapy OR hematoporphyrin OR aminolevulinic) AND Topic=("barrett's esophagus" OR "esophageal neoplasms" OR "esophageal cancer*" OR "barrett syndrome" OR "barrett's oesophagus") Timespan=All Years. Databases=SCI-EXPANDED, SSCI, A&HCI.

7. EconLit

Total = 2 refs

Photodynamic OR PDT

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Part 2. Alternative treatments for Barrett’s esophagus and early stage esophageal cancer

Initial searches run September 2008 (covering period 2006 to 2008) Additional search to extend timelines, databases & terms run in December 2008 Limits: Human, English language, 5 years (2003‐2008)

1. PubMed Total = 565 refs Search Most Recent Queries Time Result #120 Search #114 OR #117 OR #119 Limits: Publication Date from 2006 to 16:42:20 565 2009 #119 Search #115 AND in process [sb] Limits: Publication Date from 2006 16:38:19 78 to 2009 #117 Search #115 AND technology assessment, biomedical 16:28:41 3 #115 Search #106 OR #107 OR #108 OR #109 OR #110 OR #111 OR #112 13:26:06 2479 Limits: Publication Date from 2006 to 2009 #114 Search #106 OR #107 OR #108 OR #109 OR #110 OR #111 OR #112 13:24:38 484 Limits: Publication Date from 2006 to 2009, Humans, Clinical Trial, Meta‐Analysis, Practice Guideline, Randomized Controlled Trial, Clinical Trial, Phase III, Clinical Trial, Phase IV, Comparative Study, Controlled Clinical Trial, Evaluation Studies, Multicenter Study, English #113 Search Limits: Publication Date from 2006 to 2009, Humans, Clinical 13:24:01 169892 Trial, Meta‐Analysis, Practice Guideline, Randomized Controlled Trial, Clinical Trial, Phase III, Clinical Trial, Phase IV, Comparative Study, Controlled Clinical Trial, Evaluation Studies, Multicenter Study, English #112 Search #62 AND #105 Limits: Publication Date from 2006 to 2009 13:22:56 548 #111 Search #62 AND #102 Limits: Publication Date from 2006 to 2009 13:22:48 986 #110 Search #62 AND #98 Limits: Publication Date from 2006 to 2009 13:22:42 826 #109 Search #62 AND #95 Limits: Publication Date from 2006 to 2009 13:22:36 84 #108 Search #62 AND #89 Limits: Publication Date from 2006 to 2009 13:22:30 62 #107 Search #62 AND #81 Limits: Publication Date from 2006 to 2009 13:22:25 1094 #106 Search #62 AND #71 Limits: Publication Date from 2006 to 2009 13:22:06 690 #105 Search #103 OR #104 13:20:50 202292 #104 Search radiotherapy 13:20:42 202292 #103 Search radiotherapy, adjuvant 13:20:38 21020 #102 Search #99 OR #100 OR #101 13:20:00 1614671 #101 Search chemotherapy 13:19:50 1614671

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta #100 Search chemotherapy, adjuvant 13:19:43 33306 #99 Search drug therapy 13:19:36 1549020 #98 Search #96 OR #97 13:19:15 5654 #97 Search oesophagectomy 13:19:05 5654 #96 Search esophagectomy 13:18:56 5654 #95 Search #90 OR #91 OR #92 OR #93 OR #94 13:17:36 162985 #94 Search coagulation 13:17:18 121432 #93 Search "laser thermocoagulation" 13:17:11 10 #92 Search "argon plasma coagulation" 13:17:02 458 #91 Search laser therapy 13:16:53 48421 #90 Search laser coagulation 13:16:48 8082 #89 Search #82 OR #83 OR #84 OR #85 OR #86 OR #87 OR #88 13:16:13 44178 #88 Search "radiofrequency ablation" 13:15:52 4548 #87 Search "radio frequency ablation" 13:15:44 329 #86 Search "radiofrequency catheter ablation" 13:15:34 1705 #85 Search "rf ablation" 13:15:21 1123 #84 Search radio waves 13:15:13 12388 #83 Search electrocoagulation 13:15:07 30812 #82 Search catheter ablation 13:15:00 13383 #81 Search #72 OR #73 OR #74 OR #75 OR #76 OR #77 OR #78 OR #79 13:13:48 40104 OR #80 #80 Search "submucosal resection" 13:13:05 82 #79 Search "submucosal dissection" 13:12:55 216 #78 Search EMR 13:12:45 1890 #77 Search "mucosal resection" 13:12:38 958 #76 Search intestinal mucosa/surgery 13:12:28 1247 #75 Search esophageal neoplasms/surgery 13:12:08 8892 #74 Search barrett esophagus/surgery 13:11:59 641 #73 Search mucous membrane/surgery 13:11:49 4968 #72 Search microsurgery 13:11:33 24072 #71 Search #63 OR #64 OR #65 OR #66 OR #67 OR #68 OR #69 OR #70 13:06:43 459788 #70 Search "endoscopic ultrasound" 13:06:11 1845 #69 Search monitoring [ti] 13:05:59 51520 #68 Search surveillance [ti] 13:05:52 17269 #67 Search ultrasonography 13:05:42 257945 #66 Search endosonography 13:05:35 5873

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta #65 Search esophagoscopy 13:05:25 10030 #64 Search mass screening 13:04:59 98748 #63 Search population surveillance 13:04:51 42193 #62 Search #54 OR #55 OR #56 OR #57 OR #59 OR #60 OR #61 13:04:03 36537 #61 Search "oesophageal cancer*" 13:03:28 1413 #60 Search "esophageal cancer*" 13:03:20 7579 #59 Search esophageal neoplasms 13:03:11 32876 #57 Search Barrett's 13:02:29 4367 #56 Search "barrett epithelium" 13:02:05 33 #55 Search "barrett syndrome" 13:01:56 28 #54 Search barrett esophagus 13:01:32 4338

Dec. 2, 2008 Total = 1156 refs Search Most Recent Queries Time Result #71 Search #69 AND (case‐control studies [mh] OR follow‐up studies [mh] 14:10:54 95 OR retrospective studies [mh]) Limits: Publication Date from 2003/01/01 to 2008/12/31, Humans, English #69 Search #54 Limits: Publication Date from 2003/01/01 to 2008/12/31, 14:04:04 504 Humans, Clinical Trial, English #68 Search #8 AND #53 Limits: Publication Date from 2006/01/01 to 13:59:02 1 2008/12/31, Humans, Clinical Trial, Meta‐Analysis, Practice Guideline, Randomized Controlled Trial, Case Reports, Clinical Trial, Phase I, Clinical Trial, Phase II, Clinical Trial, Phase III, Clinical Trial, Phase IV, Comparative Study, Controlled Clinical Trial, Evaluation Studies, Multicenter Study, Validation Studies, English #67 Search #63 NOT (#64 OR #65 OR #66) 13:52:50 121 #66 Search #63 Limits: Publication Date from 2005/01/01 to 2005/12/31 11:11:44 346 #65 Search #63 Limits: Publication Date from 2004/01/01 to 2004/12/31 11:10:14 301 #64 Search #63 Limits: Publication Date from 2003/01/01 to 2003/12/31 11:07:01 294 #63 Search #57 OR #59 OR #60 10:53:01 1059 #60 Search #54 AND in process [sb] 10:44:20 120 #59 Search #8 AND #53 Limits: Humans, Clinical Trial, Meta‐Analysis, 10:39:44 6 Practice Guideline, Randomized Controlled Trial, Case Reports, Clinical Trial, Phase I, Clinical Trial, Phase II, Clinical Trial, Phase III, Clinical Trial, Phase IV, Comparative Study, Controlled Clinical Trial, Evaluation Studies, Multicenter Study, Validation Studies, English #57 Search #54 Limits: Publication Date from 2003/01/01 to 2005/12/31, 10:37:07 933 Humans, Clinical Trial, Meta‐Analysis, Practice Guideline, Randomized

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Controlled Trial, Case Reports, Clinical Trial, Phase I, Clinical Trial, Phase II, Clinical Trial, Phase III, Clinical Trial, Phase IV, Comparative Study, Controlled Clinical Trial, Evaluation Studies, Multicenter Study, Validation Studies, English #55 Search #54 AND technology assessment, biomedical 10:28:39 6 #54 Search #8 AND (#17 OR #26 OR #34 OR #40 OR #43 OR #47 OR #50 10:28:04 19312 OR #53) #53 Search #51 OR #52 10:26:13 27911 #52 Search cryotherapy 10:26:05 19926 #51 Search cryosurgery 10:26:00 9944 #50 Search #48 OR #49 10:25:36 204617 #49 Search radiotherapy 10:25:27 204617 #48 Search radiotherapy, adjuvant 10:25:20 21400 #47 Search #44 OR #45 OR #46 10:25:02 1633803 #46 Search chemotherapy 10:24:48 1633803 #45 Search chemotherapy, adjuvant 10:24:43 33912 #44 Search drug therapy 10:24:35 1567010 #43 Search #41 OR #42 10:24:20 5735 #42 Search oesophagectomy 10:24:05 5735 #41 Search esophagectomy 10:23:54 5735 #40 Search #35 OR #36 OR #37 OR #38 OR #39 10:23:35 164484 #39 Search coagulation 10:23:21 122464 #38 Search "laser thermocoagulation" 10:23:11 11 #37 Search "argon plasma coagulation" 10:23:03 475 #36 Search laser therapy 10:22:51 48943 #35 Search laser coagulation 10:22:45 8158 #34 Search #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 10:22:29 44911 #33 Search "radiofrequency ablation" 10:22:04 4668 #32 Search "radio frequency ablation" 10:21:56 336 #31 Search "radiofrequency catheter ablation" 10:21:44 1728 #30 Search "rf ablation" 10:21:32 1153 #29 Search radio waves 10:21:26 12612 #28 Search electrocoagulation 10:21:21 31266 #27 Search catheter ablation 10:21:15 13710 #26 Search #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 10:20:51 39031 #25 Search "submucosal resection" 10:20:28 82 #24 Search "submucosal dissection" 10:20:20 230

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta #23 Search "mucosal resection" 10:20:10 971 #22 Search intestinal mucosa/surgery 10:19:59 1263 #21 Search esophageal neoplasms/surgery 10:19:49 8958 #20 Search barrett esophagus/surgery 10:19:37 649 #19 Search mucous membrane/surgery 10:19:26 5036 #18 Search microsurgery 10:19:15 24338 #17 Search #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 10:18:42 466399 #16 Search "endoscopic ultrasound" 10:18:15 1902 #15 Search monitoring [ti] 10:18:01 52356 #14 Search surveillance [ti] 10:17:39 17564 #13 Search ultrasonography 10:17:30 261149 #12 Search endosonography 10:17:24 5997 #11 Search esophagoscopy 10:17:12 10097 #10 Search mass screening 10:17:02 100339 #9 Search population surveillance 10:16:55 43160 #8 Search #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 10:16:31 36951 #7 Search "oesophageal cancer*" 10:15:57 1432 #6 Search "esophageal cancer*" 10:15:46 7685 #5 Search esophageal neoplasms 10:15:40 33201 #4 Search Barrett's 10:15:32 4453 #3 Search "barrett epithelium" 10:15:16 33 #2 Search "barrett syndrome" 10:15:07 28 #1 Search barrett esophagus 10:14:55 4394

2. Cochrane Library (issue 4 , 2008) Total = 286 refs Barrett esophagus (in title, abstract or keywords) OR esophageal neoplasms (in title, abstract or keywords), limited to 2003 to 2008, in all Cochrane databases = 6 Cochrane reviews; 12 other reviews, 196 clinical trials, 1 methods studies, 26 technology assessments, 45 economic evaluations.

3. Centre for Reviews and Dissemination (CRD): HTA, NHS EED, DARE databases Total = 23 refs barrett esophagus OR "barrett's oesophagus" OR "barrett's esophagus" OR esophageal neoplasms OR "esophageal cancer*" OR "oesophageal cancer*" RESTRICT YR 2006 2009 Dec. 8, 2008 Total = 38 refs barrett esophagus OR "barrett's oesophagus" OR "barrett's esophagus" OR esophageal neoplasms OR "esophageal cancer*" OR "oesophageal cancer*" RESTRICT YR 2003 2005

4. EMBASE 1988 – 2008 (Week 49) Dec. 8, 2008 Total =1042 references Results Search Type Display *Barrett Esophagus/dt, si, dm, th, rt, su [Drug Therapy, Side Effect, Disease 1 1091 Management, Therapy, Radiotherapy, Surgery] *Esophagus Cancer/dt, dm, su, rt, si, th [Drug Therapy, Disease 2 3568 Management, Surgery, Radiotherapy, Side Effect, Therapy] *Esophagus Carcinoma/dt, dm, su, rt, si, th [Drug Therapy, Disease 3 3156 Management, Surgery, Radiotherapy, Side Effect, Therapy] 4 1 or 3 or 2 7646 5 limit 4 to (human and English language and yr="2003 ‐ 2009") 2455 comparative study/ or controlled study/ or case control study/ or 6 2803977 controlled clinical trial/ 7 exp Case Study/ 4035 8 exp Practice Guideline/ 143169 9 Meta Analysis/ 34296 10 8 or 6 or 7 or 9 2945737 11 10 and 5 1042

Table B 1. Studies of photodynamic therapy (PDT) for esophageal cancer

Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality Non‐comparative studies Corti L, et al ∙ Adenocarcinoma ∙ Case series Number of patients: 62 Drug: Hematoporphyrin Tumour response Tumour response: (2000)82 9 patients (15%) ∙ Prospective derivative (assessed through endoscopy, ∙ Overall: 4 Gender: Dosage: 5 mg/kg CT and biopsy) CR: 23 patients (37%) ∙ Squamous cell Number of sites: Male: 55 (89%) Route of administration: ∙ Complete response (CR): no PR: 30 patients (48%) Italy carcinoma 1 centre Female: 7 (11%) Intravenous evidence of tumour MR: 9 patients (15%) 53 patients (85%) Time to photoactivation: ∙ Partial response (PR): more Length of follow‐up: Age: 48‐72 hours than 50% shrinkage of tumour ∙ By stage : Stage: Every 3‐4 months ≤ 60yrs: 26 (42%) Light source: 630 nm argon ∙ Mininal response (MR): Tis (18 patients): Tis: 18 patients (29%) > 60yrs: 36 (58%) dye laser minimal response, stable or CR: 8 patients (44%) T1N0: 30 patients (48%) Median: 32 months Total light dose: 200‐300 progressive disease PR: 7 patients (39%) T2N0: 7 patients (11.5%) Range: 3‐90 months Tumour size: J/cm MR: 3 patients (17%) Recurrent disease (no < 3cm: 62 patients (100%) Treatment time: Not Median overall survival staging information): reported T1 (30 patients): 7 patients (11.0%) Tumour location: Number of treatments: Adverse events CR: 13 patients (43%) Esophagus: Range: 1‐2 PR: 14 patients (47%) Upper third: 22 patients Additional interventions: MR: 3 patients (10%) (35%) ∙ Radiotherapy for Middle third: 26 patients recurrent disease (in T2 (7 patients): (42%) patients with partial or no CR: 2 patients (29%) Lower third: 14 patients response after 2 PDT PR: 5 patients (71%) (23%) sessions): 41 patients MR: 0 patients (0%) (66%) Inclusion criteria: ∙ Surgical resection after Time to recurrence: ∙ Ineligible for surgery (87%) recurrence: 3 patients (5%) CR: 68 months ∙ Refused surgery (13%) ∙ Chemoradiotherapy: 5 PR: 41 months patients (8%) MR: 27 months Exclusion criteria: ∙ Nodal involvement Median overall survival: CR: 50 months Previous treatment: PR: 32 months Esophagectomy: 7 patients MR: 20 months (11%) Median local progression free survival CR: 68 months PR: 47 months 80

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Table B 1. Studies of photodynamic therapy (PDT) for esophageal cancer

Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality MR: 27 months

Adverse events: ∙ Photosensitivity, mild: 5 patients (8%) ∙ Stenosis: 3 patients (7%) ∙ Tracheo‐esophageal fistula: 1 patient (3%) Craig C, et al ∙ Adenocarcinoma ∙ Case series Number of patients: 28 Drug: Porfimer sodium Tumour response Tumour response: 4 (2007)83 22 patients (78.6%) ∙ Prospective Dosage: 2 mg/kg Assessed through endoscopy CR ∙ Squamous cell Gender: Route of administration: and biopsy at 6‐8 weeks 18 patients (64.3%) carcinoma Number of sites: Male: 19 (67.9%) Intravenous follow‐up For patients who underwent United Kingdom 6 patients (21.4%) 1 centre Female: 9 (32.1%) Time to photoactivation: ∙ Complete response (CR) staging by endoscopic ultrasound : 48 hours ∙ No response (NR) Tis: 1 patient (100%) Stage: Length of follow‐up: Age: Light source: 630 nm laser ‐evidence of persisting T1N0: 8 patients (100%) Tis – T3N0 Every 4‐6 weeks, and Median: 74 yrs Total light dose: 300 J/cm disease T2N0: 0 patients (0%) every 3‐6 months Range: 61‐90 yrs Treatment time: Not T2/3N0: 0 patients (0%) thereafter reported Median survival Overall: 9 patients (60%) Tumour size: Number of treatments: Mean: 30 months Not reported 1 session: 23 patients Cause‐specific survival Median survival: Range: 2‐56 months 2 sessions: 5 patients 750 days (54‐2049 days) Tumour location: Additional interventions: Overall survival Not reported Radiotherapy: 1 patient Cause‐specific survival at end of (8%) Adverse events follow‐up: Inclusion criteria: Esophagectomy: 2 22 patients (78.6%) ∙ Ineligible for surgery patients ∙ No previous treatment Overall survival at end of follow‐ with endoscopic mucosal up: resection (EMR) 19 patients (67.9%)

Previous treatment: Adverse events: None ∙ Stricture: “majority” of patients (median number of dilations: 5) ∙ Chest pain: “most” patients DuVall GA, et al ∙ Adenocarcinoma: 1 ∙ Case series Number of patients: 5 Drug: Porfimer sodium Recurrence Recurrence: 4 (1996)84 patient (20%%) ∙ Prospective Dosage: 2 mg/kg 2 patients (40%) Gender: Not reported for Route of administration: Overall survival at end of Canada ∙ Squamous cell Number of sites: cancer only Intravenous follow‐up (study’s end) Overall survival at end of follow‐ carcinoma: 4 patients 1 centre Time to photoactivation: up:

Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality Note: (80%) Age: Not reported for Not reported Adverse events 5 patients (100%) ∙ Included patients Length of follow‐up: cancer only Light source: 630 nm laser with high grade Stage: At 2 weeks and every Total light dose: 300 J/cm Adverse events: dysplasia and T1N0M0: 5/5 (100%) month thereafter Tumour size: 1‐5 cm Treatment time: Not ∙ Dysphagia early esophageal Mean: Not reported reported At 2 weeks follow‐up: cancer for cancer only Tumour location: Number of treatments: Improved: 3 patients (60%) ∙ Information Range: Not reported Not reported 1 session: 3 patients Same: 1 patient (20%) extracted for early for cancer only 2 sessions: 2 patients Worsened: 1 patient (20%) esophageal cancer Inclusion criteria: patients only ∙ Ineligible for surgery Additional interventions: At 1 month follow‐up: ∙ Refused surgery None Improved: 2 patients (40%) Same: 2 patients (40%) Previous treatment: Worsened: 1 patients (20%) None ∙ Stricture: 2 patients (40%)

Etienne J, et al ∙Adenocarcinoma ∙ Case series Number of patients: 7 Drug: M‐tetra‐ Tumour response Tumour response: 4 (2004)85 ∙ Non‐consecutive hydroxyphenyl chlorin (assessed through endoscopy CR: 7 patients (100%) Stage: Gender: Not reported for (mTHPC) and biopsy at 3 months) France T1aN0M0 Number of sites: cancer only Dosage: 0.15 mg/kg Complete response (CR) Recurrence: 1 centre Route of administration: 0 patients (0%) Note: Age: Not reported for Intravenous Recurrence ∙ Included patients Length of follow‐up: cancer only Time to photoactivation: Cause‐specific survival at end of with high grade At 2, 3, 6 and 12 96 hours Cause‐specific survival at end follow‐up: dysplasia and months and annually Tumour size: Light source: of follow‐up 7 patients (100%) early esophageal thereafter Not reported 514 nm green light argon Mean: 35.4 months (13 – 68 cancer laser Overall survival at end of months) ∙ Information Mean: 34 months Tumour location: Total light dose: 75 J/cm follow‐up extracted for early Range: 13‐68 months Not reported for cancer Treatment time: Overall survival: esophageal cancer only 750 seconds Adverse events 4 patients (57%) patients only Number of treatments: Mean: 35.4 months (13 – 68 Previous treatment: Range: 1‐3 months) Nd:YAG: 1 patient (Extracted from graph)

Adverse events ∙ Stricture: 1 patient (14%) ∙ Photosensitivity: 1 patient (14%)

Foroulis C, et al ∙Adenocarcinoma ∙ Case series Number of patients: 6 Drug: Porfimer sodium Tumour response Tumour response: 4

Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality (2006) 86 Stage: ∙ Retrospective Dosage: 2 mg/kg (assessed through endoscopy CR: 2 patients (33.3%) T1b‐T2 Gender: Not reported for Route of administration: and biopsy) PR: 3 patients (50.0%) United Kingdom Number of sites: cancer only Intravenous Complete response (CR) NR: 1 patient (16.7%) 1 centre Time to photoactivation: Partial response (PR) Note: Age: Not reported for 24 hours No response (NR) Overall survival: ∙ Included patients Length of follow‐up: cancer only Light source: 630 nm red At 2 years: 5 patients (83.3%) with high grade 2‐4 months after PDT laser light Overall survival at 2 and 4 At 4 years: 4 patients (66.7%) dysplasia and and every 6 and 12 Tumour size: Total light dose: 300 J/cm years early esophageal months thereafter Not reported Treatment time: 500 Adverse events cancer seconds ∙ Stricture: 2 patients (33%) ∙ Information Mean: 22.2 months Tumour location: Number of treatments: ∙ Pleural effusion: 1 patient (16%) extracted for early SD: 12.4 months Not reported Range: 1 ‐ 3 esophageal cancer Additional interventions: patients only Previous treatment: None ∙ Nd:YAG ∙ Endoscopic mucosal resection Gossner L, et al ∙Adenocarcinoma ∙ Case series Number of patients: 58 Drug: 5‐Aminolevulinic Tumour response: Tumour response: 4 (1999)87 Stage: ∙ Prospective Acid (5‐ALA) or Complete response (CR) CR: 43 patients (74%) “Early cancer” Gender: Not reported for Metahydroxy‐phenyl‐ Germany Number of sites: 1 cancer only chlorin (mTHPC) Recurrence Recurrence: centre Dosage: ALA: 60 mg/kg 10 patients (23%) Note: Age: Not reported for mTHPC: 0.075 mg/kg Adverse events: ∙ Included patients Length of follow up: cancer only Route of administration: Not reported with high grade Oral dysplasia and Mean: Not reported Tumour size: Time to photoactivation: early esophageal Range: 2‐48 months Not reported Not reported cancer Light source: 635 nm dye ∙ Information Tumour location: laser or 652 nm dye laser extracted for early Not reported Total light dose: esophageal cancer Not reported patients only Treatment time: Not reported Number of treatments: Mean: 2.4 Additional Interventions: ∙ Endoscopic mucosal resection: 7 patients (12%) ∙ Thermal ablation: 3

Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality patients (5%) Gossner L, et al ∙ Squamous cell ∙ Case series Number of patients: 18 Drug: 5‐aminolevulinic acid Tumour response: Tumour response: 4 (1999)88 carcinoma ∙ Prospective (5‐ALA) Complete response (CR) for CR: 10 tumours (53%) Gender: Dosage: 60 mg/kg lesions PR: 9 tumours (47%) Germany Stage: Number of sites: Male: 14 (78%) Route of administration: Partial response (PR) for T1N0M0: 19 tumours 2 centres Female: 4 (22%) Oral suspension lesions Recurrence: (100%) Time to photoactivation: 1 tumour (10%) Note: Length of follow‐up: Age: 4‐6 hours Recurrence ∙ Included patients 48 hrs after first Mean: 63.5 yrs Light source: 635 nm dye Mean period of remission: 16.9 with high grade session, then at 4 Range: 47‐75 yrs laser Mean period of remission months dysplasia and weeks, 2, 3, 6, 9 and Total light dose: 150 J/cm Range: 3‐37 months early esophageal 12 months, Tumour size: Treatment time: Not Overall survival at end of cancer and 6 months Mean: 2.5 cm reported follow‐up Overall survival: ∙ Information thereafter Range: 0.5‐9.0 cm Number of treatments: 16 patients (89%) extracted for early Mean 15.8 months 1 session: 8 patients Adverse events esophageal cancer Range: 3‐37 months Tumour location: 2 sessions: 5 patients Adverse events: patients only Not specified 3 sessions: 4 patients “No method related mortality or Mean: 1.7 morbidity” Inclusion criteria: Range: 1‐3 ∙ Ineligible for surgery Additional interventions: ∙ No nodal involvement ∙ Esophagectomy: 1 patient (5.5%) Previous treatment: ∙ Radiotherapy: 3 patients None (16%) Jamieson NF, et al ∙Adenocarcinoma ∙ Case series Number of patients: 4 Drug: 5‐Aminolevulinic Tumour response: Tumour response: 4 (2002)89 Acid (ALA) Complete response (CR) CR: 3 patients (75%) Stage: Number of sites: Gender: DosageALA: 60 mg/kg United Kingdom T1m (mucosal layer) 1 centre Not reported for cancer Route of administration: Overall survival (alive by Overall survival: only Not reported study’s end) 4 patients (100%) Note: Information Length of follow up: Time to photoactivation: extracted for early Median: Not reported Age: Not reported Adverse events: esophageal cancer for cancer only Not reported for cancer Light source: 635nm Not reported patients only Range: Not reported only Total light dose: for cancer only Range: 500‐1000 J/cm Tumour size: Treatment time: 40 Not reported minutes/4cm length of columnar mucosa Tumour location: Not reported Number of treatments:

Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality Median: 2 Previous treatment: Range: 1‐3 None Additional Interventions: mTHPC 0.15 mg/kg PDT

Keeley SB, et al ∙Adenocarcinoma ∙ Case series Number of patients: 36 Drug: Porfimer sodium Tumour response: Tumour response: 4 (2007)90 29 patients (81%) ∙ Non consecutive Dosage: Not reported Complete response (CR) CR: 10 patients (28%) ∙ Retrospective Gender: Route of administration: No response (NR) NR: 23 patients (64%) United States ∙ Squamous cell Not reported for cancer “Injection” carcinoma Number of sites: 1 only Time to photoactivation: Cause‐specific survival at end Cause‐specific survival at end of Note: 7 patients (19%) centre 48 hours of follow‐up follow‐up: ∙ Included patients Age: Not reported for Light source: 13 patients (37%) with high grade Stage: Length of follow‐up: cancer only 630 nm red dye laser Overall survival at end of dysplasia and Tis: 6 patients (17%) Not reported for Total light dose: 300‐400 follow‐up Overall survival at end of follow‐ early esophageal T1: 16 patients (44%) cancer only Tumour size: J/cm up: cancer T2: 14 patients (39%) Not reported Overall survival at 1, 2, 3, and 10 patients (29%) ∙ Information Treatment time: 5 years ∙ Adenocarcinoma: 8 patients extracted for early Tumour location: Not reported (30.8%) esophageal cancer Middle esophagus: 7 Adverse events ∙ Squamous cell carcinoma: 2 patients only patients (14%) Number of treatments: patients (28.6%) Range: 1 ‐ 2 Inclusion criteria: Overall survival at 1, 2, 3, and 5 ∙ Ineligible for surgery Additional interventions: years ∙ Refused surgery ∙ Chemotherapy or Stage I: radiotherapy At 1 year: 86% Previous treatment: At 2 years: 63% None At 3 years 31% At 5 years: 15% (Extracted from survival curves) Stage II: At 1 year: 55% At 2 years: 28% At 3 years: n/a At 5 years: n/a (Extracted from survival curves)

Across both stages: At 1 year: 74%

Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality At 2 years: 49%

Adverse events: ∙ Stricture: “most common complication”

Lovat LB, et al ∙Adenocarcinoma ∙ Case series Number of patients: 11 Drug: Metahydroxy‐ Tumour response: Tumour response: 4 (2005)91 ∙ Consecutive Number of tumours: 13 phenyl‐chlorin (mTHPC) Complete response (CR) PR : 6 patients (46%) Stage (number of ∙ Prospective Gender: Dosage: 0.15 mg/kg Partial response (PR) CR: 1 patient (8%) United Kingdom tumours): Male: 8 (73%) Route of administration: T1N0: 8 Number of sites: Female: 3 (27%) Intravenous Remission Remission: Note: T1NX: 1 1 centre Time to photoactivation: Disease free at study end 4 patients (33.3%) ∙ Included patients T1: 1 Age: 72 hours with high grade T2N0: 3 Length of follow‐up: Mean: 72.4 yrs Light source: 652 nm red Cause‐specific survival at 1 Cause‐specific survival at 1 year: dysplasia and 24 and 48 hours post Range: 40‐80 yrs light diode laser year 11 patients (100%) early esophageal PDT, every 3 months Total light dose: 7 J/cm cancer in the first year, every Tumour size: Treatment time: Not Overall survival at end of Overall survival at end of follow‐ ∙ Information 6 months in the Mean: 2.6 cm reported follow‐up up: extracted for early second year, and Range: 1‐6 cm Number of treatments: 8 patients (73%) esophageal cancer yearly thereafter Range: 1‐3 Overall survival at 1 year patients only Tumour location: Additional interventions: Overall survival at 1 year Mean: 24 months Not reported Chemoradiotherapy: 1 Adverse events 11 patients (100%) Range: 3 – 36 months patient (9%) Inclusion criteria: Chemotherapy: 1 patient Adverse events: ∙ Refused surgery (9%) ∙ Tracheoesophageal fistula: 1 ∙ Ineligible for surgery Esophagectomy: 1 patient patient (9%) (9%) ∙ Stricture: 1 patient (9%) Exclusion criteria: Chemoradiotherapy + ∙ T3/T4 lesions Endoscopic mucosal ∙ Nodal involvement resection: 1 patient (9%)

Previous treatment: Endoscopic mucosal resection: 1 patient (9%) Nd:YAG: 1 patient (9%) Esophagectomy: 2 patients (18%) 5‐aminolevulinic acid PDT: 4 patients (36%)

Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality Maunoury V, et al ∙Adenocarcinoma: 5 ∙ Case series Number of patients: 24 Drug: Porfimer sodium Tumour response: Tumour response: 4 (2005)92 patients (21%) Dosage: 2 mg/kg (assessed through endoscopy ∙ Overall Number of sites: Gender: Route of administration: and biopsy) CR: 18 patients (75%) ∙ Squamous cell 1 centre Male: 23 (96%) Intravenous Complete response (CR) France carcinoma: 19 patients Female: 1 (4%) Time to photoactivation: Recurrence: (79%) Length of follow‐up: 48 hours Recurrence 3 patients (17%) 2 months post PDT Age: Light source: 630 nm diode Stage: and every 3 months Mean 60 yrs laser Cause‐specific survival at end Cause‐specific survival at end of T1N0: 20 patients (83%) thereafter for 1 year Range: 46‐82 yrs Total light dose: 250‐300 of follow‐up follow‐up: T2N0: 4 patients (17%) Mean: 21 months J/cm 21 patients (88%) Range: 6‐45 months Tumour size: Treatment time: 600 Overall survival at end of Not reported seconds follow‐ip Overall survival at end of follow‐ Number of treatments: up: Tumour location: Range: 1‐3 Adverse events 18 patients (75%) Not specified Additional interventions: Radiation therapy: 2 Adverse events: Inclusion criteria: patients (8%) ∙ Chest pain: “some patients” ∙ Ineligible for surgery ∙ Stenosis: 6 patients (25%) ∙ Refused surgery ∙ Perforation into main left Previous treatment: bronchus causing death: 1 patient Radiation therapy: 13 (4%) patients (54%) McCaughan JS, et ∙Adenocarcinoma: 16 ∙ Case series Number of patients: 19 Drug: Tumour response: Tumour response: 4 al patients (84%) ∙ Prospective Hematoporphyrin (assessed through endoscopy Stage I: (1996)93 Gender: No stage specific deviative (1982‐84) or and biopsy) CR: 7 patients (88%) ∙ Squamous cell Number of sites: 1 information reported dihematoporphyrin ether Complete response (CR) United States carcinoma: 3 patients centre (1984‐1994) Stage II: (16%) Age: Not stage specific Dosage: Recurrence CR: Not reported Note: Length of follow‐up: information reported Hematoporphyrin ∙ Included patients Stage: 48‐72 hours post PDT, deviative: Overall survival at 1, 2, 3, and Recurrence with esophageal Stage I: 8 patients (42%) 1 month post‐PDT, Tumour size: Not reported 5 years Stage I: cancer stages I‐IV Stage II: 11 patients and “periodically” Not reported Dihematoporphyrin ether: 1 patient (14%) ∙ Information (68%) thereafter 60 mg/m² Adverse events: extracted for early Tumour location: Route of administration: No stage specific information Overall survival at 1, 2, 3, and 5 esophageal cancer Mean: Not reported Not reported Intravenous reported years patients only Range: Not reported Time to photoactivation: Stage I: Inclusion criteria: 24‐72 hours At 1 year: 100% ∙ Failed conventional Light source: 630 nm argon At 2 years: 66% treatment dye laser At 3 years 51%

Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality ∙ Ineligible for surgery Total light dose: 300 J/cm At 5 years: 51% ∙ Refused surgery Treatment time: Not (Extracted from survival curves) reported Stage II: Previous treatment: Number of treatments: At 1 year: 6 patients (54%) No stage specific Not reported At 2 years: 22% information reported Additional Interventions: At 3 years: 0% None At 5 years: 0% (Extracted from survival curves) Across both stages: At 1 year: 59% At 2 years: 41% At 3 years: 21% At 5 years: 21%

Messmann H, et al ∙ Squamous cell ∙ Case series Number of patients: 4 Drug: Porfimer sodium Tumour response: Tumour response: (1997) 94 carcinoma: ∙ Consecutive Dosage: 2 mg/kg (assessed through endoscopy CR: 4 patients (100%) ∙ Prospective Gender: Route of administration: and biopsy) Germany Stage: Male: (100%) Intravenous Complete response (CR) Recurrence: T1N0: 5 lesions (83.3%) Number of sites: 1 Time to photoactivation: 0 patients (0%) Note: T2N0: 1 lesion (16.7%) centre Age: 48 hours Recurrence ∙ Included patients Mean: 62.3 yrs Light source: 630 nm argon Adverse events: with esophageal Length of follow‐up: Range: 55‐78 yrs dye laser Adverse events ∙ Stenosis: 3 patients (75%) cancer stages I‐IV Endoscopy and biopsy Total light dose: 150 J/cm ∙ Fever: 1 patient (25%) ∙ Information 1 week after PDT, Tumour size: Treatment time: Not extracted for early then at 2, 3, 6, 9, 12, Not reported reported esophageal cancer 18, and 24 months Number of treatments: patients only thereafter Tumour location: 1 session: 2 patients Not reported 2 sessions: 1 patient Mean: 15 months 3 sessions: 1 patient Range: 7‐32 months Inclusion criteria: Additional interventions: ∙ Ineligible for surgery Radiotherapy: 1 patient

Previous treatment: None Moghissi K, Dixon ∙Adenocarcinoma ∙ Case series Number of patients: 18 Drug: Tumour response: Tumour response: 4 K (2003)95 ∙ Consecutive Porfimer Sodium (assessed through endoscopy CR: 17 patients (94%) ∙ Squamous cell ∙ Prospective Gender: Dosage: 2 mg/kg/bw and biopsy) PR: 1 patient (6%)

Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality United Kingdom carcinoma Male: 12 (66%) Route of administration: Complete response (CR) Number of sites: 1 Female: 6 (34%) Intravenous Partial response (PR) Mean survival: Note: Stage: centre Time to photoactivation: 60.5 months (SD 8.7) ∙ Included patients Tis/I: 18 patients (100%) Age: 24‐72 hours Mean survival with esophageal Length of follow‐up: Mean: 73.5 yrs Light source: Cause‐specific survival at 5 years cancer stages I‐IV 6‐8 weeks post PDT, Range: 62‐80 yrs 630 nm laser light Cause‐specific survival at 5 17 patients (94%) ∙ Information then at 3‐6 months Total light dose: years extracted for early intervals “until death” Tumour size: Not reported Overall survival at end of follow‐ esophageal cancer Not reported Treatment time: Overall survival at end of up: patients only Mean: 60.5 months Not reported follow‐up 15 patients (83%) Range: 1‐78 months Tumour location: Number of treatments: ‐ deaths unrelated to esophageal Upper and mid thoracic: 1 session: 17 patients Overall survival at 5 years cancer 2 patients (11%) 2 sessions: 1 patient Adverse events Overall survival at 5 years: 71% Lower thoracic and cardia Additional interventions: esophagus: None Adverse events: 16 patients (89%) Strictures: 2 patients (11%)

Inclusion criteria: ∙ Ineligible for surgery ∙ Refused surgery Nakamura T, et al ∙ Squamous cell ∙ Case series Number of patients: 7 Drug: Porfimer sodium Tumour response: Tumour response: 4 (2004)96 carcinoma ∙ Prospective Dosage: 2 mg/kg Complete response (CR) CR: 9 lesions (100%) Gender: Route of administration: Japan Stage: Number of sites: Male: 6 (86%) Intravenous Recurrence: Recurrence: Submucosal (T1): 4 1 centre Female: 1(14%) Time to photoactivation: Tumour recurrence (lesions) 0 tumours (0%) tumours (44%) 48 hours Mucosal (T2): 5 tumours Length of follow‐up: Age: Light source: 630 nm Cause‐specific survival at end Cause‐specific survival at end of (56%) 24 hours after PDT, Mean: 70.0 yrs excimer‐dye laser (with of follow‐up follow‐up: and periodically Range: 58‐81 yrs transparent hood around 7 patients (100%) thereafter light source) Overall survival at end of Tumour size: Total light dose: follow‐up Overall survival at end of follow‐ Mean: 17.4 months Mean: 1.7 cm Range: up: Range: 4‐51 months Range: 0.5‐3.0 cm 39.1‐193.5 J/cm Adverse events 7 patients (100%) Treatment time: Tumour location: 5‐20 minutes Adverse events: Middle esophagus: 7 Number of treatments: ∙ Fever, transient: 1 patient (14%) patients (78%) Range: 1‐2 ∙ Chest pain: 1 patient (14%) Proximal esophagus: 2 Additional interventions:

Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality patients (22%) None

Inclusion criteria: ∙ No nodal involvement

Previous treatment: Endoscopic mucosal resection: 1 patient (14%) Chemoradiotherapy: 1 patient (14%) Okunaka T, et al ∙ Squamous cell ∙ Case series Number of patients: 6 Drug: Porfimer sodium Tumour response: Tumour response: 4 (1990)97 carcinoma ∙ Prospective (Photofrin I or II) Complete response (CR) CR: 4 patients (67%) Gender: Dosage: Photofrin I: Partial response (≥ 60% PR: 2 patients (33%) Japan Stage: Number of sites: Male: 5 (83%) 3mg/kg reduction in tumour volume) “Early‐stage superficial”: 1 centre Female: 1 (17%) Photofrin II: 2 mg/kg Overall survival at end of follow‐ Note: 6 patients (100%) Route of administration: Overall survival at end of up: ∙ Included patients Length of follow‐up: Age: Intravenous follow‐up Mean: 27 months with esophageal 1 month after PDT Mean 65.8 yrs Time to photoactivation: Range: 13‐47 months cancer stages I‐IV Range: 53‐80 yrs 48‐72 hours Cause‐specific survival at 1 Alive at study end: 5 patients ∙ Information Mean: Not reported Light source: 630 nm argon year (83%) extracted for early Range: 4 – 47 months Tumour size: dye laser esophageal cancer Not reported Total light dose: 180‐360 Overall survival at 1 year Cause‐specific survival at 1 year: 6 patients only J/cm patients (100%) Tumour location: Treatment time: Not Adverse events: “Distance from teeth”: 12‐ reported No stage specific information Overall survival at 1 year: 32 cm Number of treatments: 1 reported 5 patients (83.3%)

Inclusion criteria: Additional interventions: ∙ Ineligible for surgery ∙ Radiation therapy: 2/6 (33%) Previous treatment: ∙ Surgery: Radiation therapy: 1 2/6 (33%) – 1 causing patient (17%) death Overholt BF, et al ∙Adenocarcinoma ∙ Case series Number of patients: 5 Drug: Porfimer Sodium Tumour response: Tumour response: 4 (1995)98 Dosage: 2 mg/kg (assessed through endoscopy CR: 5 patients (100%) Stage: Number of sites: Gender: Route of administration: and biopsy) United States Tis‐T1N0M0: 4 patients 1 centre Not reported Intravenous Complete response (CR) Recurrence: (80%) Time to photoactivation: 1 patient (20%) T2: 1 patient (20%) Length of follow‐up Age: 48 hours Recurrence

Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality (months): Not reported Light source: 630 nm red Adverse events: 48 hours post PDT and argon pumped dye laser Adverse events ∙ Chest pain: all patients (100%) at 1week, 3, 6, 9 and Tumour size: Total light dose: 200‐300 ∙ Stricture: 1 patient (20%) 12 months <1.5cm J/cm Treatment time: 180 Mean: Not reported Tumour location: seconds Range: 6‐54 months Distal, mid and proximal Number of treatments: esophagus Range: 1‐2

Inclusion criteria: ∙ Ineligible for surgery

Previous treatment: Not reported Overholt BF, ∙Adenocarcinoma ∙ Case series Number of patients: 1 Drug: Profimer sodium Tumour response: Tumour response: 4 Panjehpour M, ∙ Consecutive Dosage: 2 mg/kg (assessed through endoscopy CR: 1 patient (100%) Ayers M Stage: Gender: Route of administration: and biopsy) (1997)99 T1N0M0: 1 patient Number of sites: Male: 1 (100%) Intravenous Complete Response (CR) Adverse events: (100%) 1 centre Female: 0 (0%) Time to photoactivation: Atrial fibrillation: 1 patient (100%) United States 48 hours Adverse events Length of follow‐up: Age: 81 yrs Light source: 630 nm argon Note: 48 hours and 1 week pumped red light dye ∙ Included patients after PDT Lesion size: laser. with high grade Mean: No stage Not reported Total light dose: 250 J/cm dysplasia and specific information Treatment time: Not early esophageal reported Tumour location: reported cancer Range: No stage No stage specific Number of treatments: 1 ∙ Information specific information information reported extracted for early reported esophageal cancer Inclusion criteria: patients only Not reported

Exclusion criteria: Not reported

Previous treatment: Not reported Overholt BF, ∙Adenocarcinoma ∙ Case series Number of patients: 9 Drug: Porfimer sodium Tumour response: Tumour response: 4 Panjehpour M, Dosage: Not reported (assessed through endoscopy CR: 3 patients (33%)

Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality Halberg DL Stage: Number of sites: Gender: Route of administration: and biopsy) (2003)100 T1N0: 9 patients (100%) 1 centre Male: 8 (89%) Not reported Complete response (CR) Cause‐specific survival at end of Female: 1 (11%) Time to photoactivation: follow‐up United States Length of follow up: Not reported Cause‐specific survival at end 8 patients (89%) Mean: No stage Age: Light source: 630 nm of follow‐up Note: specific information Mean: 69 yrs (SD: 9.59) potassium tytanyl Overall survival at end of follow‐ ∙ Included patients reported Range: Not reported phosphate dye laser Overall survival at end of up: with high grade Range: No stage Total light dose: Not follow‐up 4 patients (44%) dysplasia and specific information Tumour size: reported early esophageal reported Not reported Treatment time: Not Overall survival at 1, 2, 3, 4, Overall survival at 1, 2, 3, and 5 cancer reported and 5 years years: ∙ Information Tumour location: Number of treatments: At 1 year: 78% extracted for early Not reported Not reported for cancer Adverse events At 2 years: 67% esophageal cancer patients only Not reported for cancer At 3 years: 56% patients only Inclusion criteria: patients only At 5 years: 44% ∙ Ineligible for surgery Additional interventions: (Extracted from survival curves) ∙ Refused surgery Thermal ablation: Not reported for cancer patients only Savoy AD, et al ∙ Adenocarcinoma ∙ Case series Number of patients: 17 Drug: Porfimer sodium Tumour response: Tumour response: 4 (2008)101 ∙ Retrospective Dosage: 2 mg/kg (assessed through endoscopy CR: 17 patients (100%) Stage: Gender: Route of administration: and biopsy) United States T1N0M0: 17 patients Number of sites: Not reported for cancer Intravenous Complete response (CR) (100%) 1 centre only Time to photoactivation: Note: 48‐72 hours Recurrence Recurrence: ∙ Included patients Length of follow‐up: Age: Not reported for Light source: 630 nm solid Tumour recurrence 0 patients 17 (0%) with high grade Every 3 months for cancer only state diode laser light dysplasia and first year, every 4 Total light dose: Range: Overall survival at end of Overall survival at end of follow‐ early esophageal months for second Tumour size: 150‐225 J/cm follow‐up up: cancer year, and Not reported Treatment time: Not 17 patients (100%) ∙ Information every 6 months reported Adverse events: extracted for early thereafter. Tumour location: Number of treatments: Not reported esophageal cancer Not reported 1 patients only T1N0M0 Group: Additional interventions: Mean: 14.5 months Inclusion criteria: Endoscopic mucosal Range: 6‐48 months ∙ Ineligible for surgery resection: 1 patient ∙ Refused surgery Esophagectomy: 1 patient

Exclusion criteria:

Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality ∙ Metastases ∙ Nodal involvement Shim C, et al ∙ Adenocarcinoma: 1 ∙ Case series Number of patients: 9 Drug: Hematoporphyrin Tumour response: Tumour response: 4 (2007)102 patient ∙ Prospective derivative (assessed through endoscopy CR: 8 patients (88.9%) Gender: Dosage: 2 mg/kg and biopsy) China ∙ Squamous cell Number of sites: Male: 8 (88.9%) Route of administration: Complete response (CR) Recurrence: carcinoma: 8 patients 1 centre Female: 1 (11.1) Intravenous 1 patient (12.5%) Time to photoactivation: Recurrence Stage: Length of follow‐up: Tumour size: 48 hours Tumour recurrence T1N0M0: 7 patients T1N0M0 Group: Not reported Light source: Not reported (77.8%) Mean: 13.5 months Total light dose: Adverse events: T2N0M0: 2 patients Range: 3.3‐34.3 Tumour location: Range: 120‐200 J/cm Not reported (22.2%) months Not reported Treatment time: Not reported Inclusion criteria: Number of treatments: ∙ Ineligible for surgery 1 session: 4 patients ∙ Refused surgery 2 sessions: 5 patients

Tan WC, et al ∙ Adenocarcinoma ∙ Case series Number of patients: 12 Drug: 5‐aminolaevulinic Tumour response: Tumour response: 4 (1999)103 Stage: ∙ Retrospective acid (5‐ALA) (assessed through endoscopy CR Tis: 2 patients (17%) Gender: Dosage: 75 mg/kg: 3 and biopsy) Tis: 1 patient (50%) T1‐T2N0M0: 10 patients Number of sites: Male: 7 (58%) patients (25%) or 60 Complete response (CR) by T1‐T2N0M0: 1 patient (10%) United States (83%) 1 centre Female: 5 (42%) mg/kg: 9 patients (75%) stage Route of administration: Cause ‐specific survival at end of Length of follow‐up: Age: Oral Cause ‐specific survival at end follow‐up: 1 to 7 days post PDT Mean 73 yrs Time to photoactivation: 4‐ of follow‐up 2 patients (17%) and monthly Range: 55‐88 yrs 6 hours thereafter Light source: 630 nm argon Overall survival at end of Overall survival at end of follow‐ Mean: Not reported Tumour size: pumped red light dye laser follow‐up up: Range: Not reported In situ: 2 patients (17%) or 630 nm KTP pumped 1 patient (9%) >1cm: 4 patients (33%) red light dye laser Adverse events <1cm: 6 patients (50%) Total light dose: Adverse events: Range: 100‐200 J/cm ∙ Nausea/vomiting and Inclusion criteria: Treatment time: Not retrosternal discomfort (chest ∙ Ineligible for surgery: 7 reported pain): 6 patients (50%) patients (58%) Number of treatments: ∙ Mild skin photosensitivity: ∙ Refused surgery: 1 session: 5 patients 1 patient (8.5%) 5 patients (42%) 2 sessions: 3 patients ∙ Elevated bilirubin/aspartate 3 sessions: 2 patients transaminase: 5 patients (42%)

Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality Previous treatment: 4 sessions: 2 patients None Mean 2.1 Range:1‐4 Yachimski P, ∙ Adenocarcinoma ∙ Case series Number of patients: 57 Drug: Profimer sodium Adverse events Adverse events: 4 Puricelli WP, ∙ Retrospective Dosage: 2 mg/kg Complications Stricture: 11 patients (19%) Nishioka NS Stage: Gender: Route of administration: (2008)104 Intramucosal cancer Number of sites: Not reported for cancer Intravenous T2: 57 patients (100%) 1 centre only Time to photoactivation: 48 hours United States Length of follow‐up: Age: Light source: 630 nm laser 96 hours and at 3 Not reported for cancer light Note: months only Total light dose: Range: ∙ Included patients 150‐300 J/cm with high grade Mean: Not reported Lesion size: Treatment time: Not dysplasia and for cancer only Not reported reported early esophageal Range: Not reported Number of treatments: cancer for cancer only Lesion location: Mean: Not reported for ∙ Information Not reported cancer only extracted for early Range:1‐4 esophageal cancer Inclusion criteria: Additional interventions: patients only ∙ Ineligible for surgery Proton Pump Inhibitors: All ∙ No metastases patients pre and post PDT

Previous treatment: EMR prior to PDT: Not reported for cancer only Esophagectomy: Not reported for cancer only Chemoradiatherapy: Not reported for cancer only Yano T, et al Cell type: ∙ Case series Total number of patients: Drug: Profimer sodium Tumour response: Tumour response: 4 (2006)105 Not reported ∙ Prospective 27 Dosage: 2 mg/kg Complete response (CR) T1N0M0: Gender: Route of administration: overall and by disease stage CR: 12/14 (86%) Stage: Number of sites: Not reported Intravenous T2N0M0: Japan T1N0M0: 14 patients 1 centre Time to photoactivation: Recurrence: CR: 6/13 (46%) (52%) Age: 48‐72 hours Not reported Overall: T2N0M0: 13 patients Length of follow‐up: Median: 64 yrs Light source: CR: 18/27 (67%)

Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality (48%) Median: 18 months Range: 50‐75 yrs 630 nm excimer dye laser Survival: Range: 7‐33 months Total light dose: Not 1 year overall survival Lesion size: reported Not reported Treatment time: Not 1 year survival by disease Survival: reported stage 1 year overall survival: 75% Lesion location: Number of treatments: Not specified Not reported Overall progression free 1 year survival by disease stage: Additional interventions: survival rates T1N0M0: 93% Inclusion criteria: Not reported T2N0M0: 52% Refused surgery Adverse events Overall progression free survival Exclusion criteria: rates: 44% ∙ Metastases ∙ Nodal involvement Adverse events Perforation: 2 patients (7%) Previous treatment: Esophageal stricture: Chemoradiotherapy: all 14/27 (52%) patients Yoshida K, et al Cell type: ∙ Case series Number of patients: 6 (8 Drug: Porfimer Sodium Tumour response: Tumour response: 4 (1998)106 Not reported ∙ Retrospective lesions) Dosage: 2.0 mg/kg (assessed through endoscopy CR: 8 tumours (100%) Route of administration: and biopsy) Stage: Number of sites: Gender: Intravenous Complete response (CR) Adverse events: Japan T1N0M0: 6 patients 6 centres Male: 5 (83%) Time to photoactivation: Anemia: 1 patient (17%) (100%) Female: 1 (17%) 48‐72 hours Adverse events Renal impairment: 2 patients Length of follow‐up Light source: (33%) T1(mucosa): 6 tumours (months): Age: 630 nm YAG‐OPO laser Fever: 1 patient (17%) T1(submucosa): 2 Mean 67.7 yrs Total light dose: Abdominal pain: 1 patient (17%) tumours Mean: Not reported Range: 41‐80 yrs Range: 60‐180 J/cm Diarrhea: 1 patient (17%) Range: Not reported Treatment time: Lesion size: Not reported <1.0 cm: 2 lesions (25%) Number of treatments: 1 1.1‐2.0 cm: 2 lesions (25%) Additional interventions: 2.2‐4.0 cm: 2 lesions (25%) None >4.1 cm: 2 lesions (25%)

Lesion location: Cervical Esophagus: 1 lesion (12.5%) Middle thoracic esophagus:

Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality 6 lesions (75%) Lower thoracic esophagus: 1 lesion (12.5%)

Inclusion criteria: ∙ Ineligible for surgery ∙ No metastases ∙ Tumour area <7 cm²

Exclusion criteria: Previous endoscopic treatment Comparative studies Pacifico RJ, et al ∙ Adenocarcinoma ∙ Cohort study Number of patients: 88 EMR + PDT group: Complete response Complete response: 2b (2003)107 ∙ Retrospective EMR + PDT: 24 patients ∙ EMR using variceal band ∙ EMR + PDT: 20 patients 83.3% Stage: ∙ Endoscopic mucosal Surgery: 64 patients ligation technique or Treatment failure ∙ Surgery: 63 patients (98%) United States Stage 0: 2 patients resection (EMR) and transparent cap technique Stage I: 86 patients photodynamic EMR + PDT group: ∙ Followed by PDT Cause‐specific survival at 1 Treatment failure therapy (PDT) vs. Gender performed a mean of 4.2 year ∙ EMR+PDT: 4 patients (16.6%) surgery Male: 21 weeks after EMR: ∙ Surgery: 1 patient (1.6%) Female: 3 Drug: Hematoporphyrin Overall survival at 1 year Number of sites: Stage I: 24 patients derivative or porfimer Cause‐specific survival at 1 year: 1 centre Age sodium Adverse events ∙ EMR+PDT: 24 patients (100%) Median (SD): 68 yrs (± 2 Dosage: 2 mg/kg ∙ Surgery: 63 patients (98%) Length of follow‐up: years) Route of administration: IV ∙ EMR + PDT: Time to photoactivation: Overall survival at 1 year Mean (SD): 12 months Surgery group: 48 hrs ∙ EMR+PDT: 22 patients (94%) (+ 2 months) Gender Light source: 630 nm laser ∙ Surgery: 63 patients (98%) ∙ Surgery: Male: 58 Total light dose: 300 J/cm Mean (SD): 19 months Female: 6 Energy density: 32 J/cm2 Adverse events (± 3 months) Stage 0: 2 patients Treatment time: Not EMR+PDT: Stage I: 62 patients reported ∙ Strictures: 2 patients (8.3%) Age Number of treatments: ∙ Photosensitivity, mild cutaneous: Median (SD): 67 yrs (± 1 Not reported 1 patient (4.2%) year) Surgery group: Surgery: Note: no statistically ∙ Esophagectomy ∙ Strictures: 10 patients (15.6%) significant differences ∙ Anastomotic leaks: 5 patients between groups except in (7.8%)

Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality pulmonary comorbidities ∙ Wound infections: 5 patients (p=0.03) (7.8%) ∙ Dumping syndrome: 3 patients Inclusion criteria (4.7%) ∙ Stages 0‐I ∙ Empyema: 2 patients (3.1%) adenocarcinoma ∙ Bleeding requiring transfusion: 2 ∙ No nodal involvement patients (3.1%) ∙ No metastases ∙ Atrial fibrillation: 2 patients ∙ Ineligible for surgery (3.1%) ∙ Refused surgery ∙ Death: 1 patient (1.6%)

Statistically significant differences between groups (p=0.01)

Table B 2. Studies of argon plasma coagulation (APC) for esophageal cancer Study authors Cancer / Cell Study (year published) Type Study Design Patients Intervention Outcome Measures Findings quality Non‐comparative studies Nomura T, et al ∙ Squamous cell ∙ Case series Number of patients: 8 Argon plasma coagulation Recurrence Recurrence: 4 (2007)108 carcinoma ∙ Prospective ∙ Argon gas and electrical (assessed through ∙ 2 patients (25%) ∙ Superficial ∙ Consecutive Gender: current applied uniformly in endoscopy and biopsy) Japan cancer Male: 7 horizontal and Overall survival (study end) ∙ Number of sites: 1 Female: 1 perpendicular directions to Overall survival (study 75% *Note: centre esophageal mucosa end) ∙Included Age: Disease specific survival patients with ∙ Length of follow‐ Mean: 70 yrs Number of treatment Disease specific survival (study end) high grade up: Range: 64 ‐74 yrs sessions: (study end) 100% dysplasia and 7 days and every 2 Mean: 1 sessions early to 3 months Previous interventions: Range: 1‐2 sessions Adverse events: esophageal thereafter ∙Endoscopic mucosal None reported cancer resection: 2 patients Additional interventions: ∙Information Mean: Not reported (25%) ∙Chemoradiotherapy: 1 extracted for for cancer only ∙Radiation: 3 patients patient (13%) early (38%) esophageal Range: 4 – 38 cancer patients months only

Van Laethem JL, ∙Adenocarcinoma ∙ Case series Number of patients: 3 Argon plasma coagulation Tumour response Tumour response 4 et al ∙ In situ ∙ Prospective ∙ Argon gas and electrical (assessed through CR: 3 patients (100%) (2001)109 ∙ Consecutive Gender: current applied uniformly in endoscopy and biopsy) Male: 2 a longitudinal or Complete response (CR) Recurrence: Belgium ∙ Number of sites: 1 Female: 1 circumferential mode to 0 patients (0%) centre esophageal mucosa Recurrence *Note: Age: (assessed through Cause‐specific survival at 1 year: ∙Included ∙ Length of follow‐ Mean: 78 yrs Number of treatment endoscopy) 3 patients (100%) patients with up: Range: 64‐88 yrs sessions: Cause‐ specific survival high grade 1 month and every 3 Mean: 4.3 sessions at 1 year dysplasia and months thereafter Inclusion criteria: Range: 3‐5 sessions early for a minimum of 12 ∙ Ineligible for surgery Adverse events: esophageal months ∙ Refused surgery None cancer Median: 24 months ∙Information Range: 12‐36 extracted for months early 98

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Table B 2. Studies of argon plasma coagulation (APC) for esophageal cancer Study authors Cancer / Cell Study (year published) Type Study Design Patients Intervention Outcome Measures Findings quality esophageal cancer patients only

Comparative studies None

Table B 3. Studies of cryoablation for esophageal cancer Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality Non‐comparative studies Dumot JA, et al ∙ Adenocarcinoma ∙ Case series Number of patients: 23 Cryoablation Tumour response: Tumour response 4 (2008)68 ∙ Squamous cell ∙ Prospective ∙ Low pressure liquid nitrogen Assessed through biopsy CR: 75% carcinoma ∙ Consecutive Gender: cryospray ∙Complete response (CR) United States Male: not reported for Adverse events: ∙ Intramucosal Number of sites: 1 cancer only Frequency of treatment: Overall Survival: ∙Perforation: 1 patient *Note: cancer: 13 patients Female: not reported for ∙ Every 6 weeks until ∙not reported for cancer only ∙Included ∙T1‐T2N0M0: 10 Length of follow‐up: cancer only endoscopic resolution patients with patients Mean: not reported Adverse events: high grade for cancer only Age: Number of treatment ∙complication dysplasia and Mean: not reported for sessions: early esophageal Range: 6‐30 months cancer only ∙Mean: 4 cancer Range: not reported for ∙Range: 1‐10 ∙Information cancer only extracted for early esophageal Previous interventions: cancer patients ∙APC: 1 patient only ∙PDT: 1 patient ∙EMR: 1 patient Comparative studies None found

100

Table B 4. Studies of radiofrequency ablation (RFA) for esophageal cancer Study authors Cancer / Cell Study (year published) Type Study Design Patients Intervention Outcome Measures Findings quality Non‐comparative studies Pouw RE, et al ∙ Not reported ∙ Case series Number of patients: 16 Radiofrequency ablation Tumour response Tumour response 4 (2008)110 for cancer only ∙ Prospective ∙ HALO ablation system (assessed through CR: 16 patients (100%) ∙ T1 ∙ Consecutive Gender: applied using HALO360 endoscopy and biopsy) Netherlands Male: not reported for circumferentially for primary Complete response (CR) ∙ Number of sites: cancer only ablation and HALO90 for *Note: Multicentre Female: not reported for secondary focal ablation of Tumour recurrence ∙ Included cancer only the esophageal mucosa Not reported for cancer patients with high ∙ Length of follow‐ only grade dysplasia up: Age: Number of treatment and early 2, 6 and 12 months Mean: not reported for sessions: Adverse events esophageal and annually cancer only Median: 1 Not reported for cancer cancer thereafter Range: not reported for Range: 1‐2 only ∙ Information Not reported for cancer only extracted for cancer only early esophageal Exclusion criteria: cancer patients ∙ Resection margins only positive for cancer ∙ Deep submucosal invading cancer ∙ Poorly or undifferentiated cancer ∙ Presence of lymphatic or vascular invasion ∙ Presence of esophageal stenosis at baseline ∙ Presence of invasive cancer at biopsy following endoscopic resection

Previous interventions: Endoscopic resection prior to radiofrequency ablation for all visible lesions and early cancers Comparative studies None

101

Table B 5. Studies of endoscopic mucosal resection (EMR) for esophageal cancer Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality Non‐comparative studies Conio M, et al ∙ Adenocarcinoma ∙ Case series Number of patients: 4 Endoscopic mucosal Tumour response Tumour response 4 (2005)111 ∙ Intramucosal ∙ Prospective resection (EMR) using cap (assessed through CR: 4 patients (100%) ∙ Consecutive Gender: method endoscopy – tumour Italy Could not be extracted free resection margins) Recurrence: ∙ Number of sites: 3 for cancer patients only Complete response (CR) 0 patients (0%) *Note: centres Information Age: Tumour recurrence Cause‐specific survival extracted for early ∙ Length of follow‐up: Could not be extracted (assessed through at end of follow‐up: esophageal cancer 3, 6, 9 & 12 months and for cancer patients only endoscopy) 4 patients (100%) patients only every 6 months thereafter up to 5 years Tumour diameter: Cause‐specific survival Median: 34.9 months Could not be extracted at end of follow‐up Range: 16.3‐72.1 for cancer patients only months Adverse events: Additional No cancer‐specific interventions: information reported Esophagectomy: 2 patients Ell C, et al ∙ Adenocarcinoma ∙ Case series Number of patients: Endoscopic mucosal Tumour response Tumour response 4 (2007)112 ∙ Retrospective 100 resection (EMR) by the (assessed through CR: 99 patients (99%) Clinical stage: ∙ Consecutive ”suck & cut” technique endoscopy – tumour Germany Lesions limited to the Gender: using ligation or cap free resection margins) Recurrence mucosa ∙ Number of sites: 1 Male: 89 method Complete response ∙ 11 patients (11%) (all had centre Female: 11 (CR): complete local repeat EMR and achieved Number of treatments: response complete local remission) ∙ Length of follow‐up: Age: ∙ 1 treatment: 70 patients 1, 2, 3, 6, 9 & 12 Mean: 62.1 yrs (70%) Tumour recurrence Cause‐specific survival at 5 months, then every 6 Range: 31‐86 yrs ∙ 2 treatments: 20 patients (assessed through years: months up to 5 yrs (20%) endoscopy) 100 patients (100%) Median: 33 months Tumour diameter: ∙ 3 treatments: 6 patients Cause‐specific survival Mean: 36.7 months < 20 mm (6%) at 5 years Overall survival at 5 years: Range: 2‐83 months ∙ 4 treatments: 1 patient ∙ 98 patients (98%) Exclusion criteria: (1%) Overall survival at 5 ∙ 2 patients died of other ∙ Evidence of tumour ∙ 5 treatments: 3 patients years causes stage > T1 (3%) ∙ Nodal involvement Adverse events Adverse events: ∙ Metastases ∙ Bleeding: 11 patients Giovannini M, et al ∙ Cancer type: Not ∙ Case series Number of patients: 9 Circumferential endoscopic Tumour response Tumour response 4 102

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Table B 5. Studies of endoscopic mucosal resection (EMR) for esophageal cancer Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality (2004)113 reported for cancer ∙ Prospective mucosal resection (EMR) (assessed through CR: 6 patients (67%) patients ∙ Consecutive Gender: by the “inject and cut” endoscopy – tumour France ∙ Mucosal carcinoma Male: 6 technique free resection margins) Adverse events ∙ Number of sites: 1 Female: 3 Complete response (CR) Bleeding: 1 patient (11%) *Note: Clinical stage: centre Number of treatments: 2 ∙Included patients TisN0M0 : 9 patients Age: Adverse events with high grade ∙ Length of follow‐up: Mean: 65.7 yrs Additional treatments: dysplasia and early 1 month then every 4 Range: 51‐75 yrs ∙ Chemoradiotherapy: esophageal cancer months thereafter 2 patients (22%) ∙Information Mean: 16 months Tumour diameter: ∙ Esophagectomy: extracted for early Range: 6‐24 months Not reported for cancer 1 patient (11%) esophageal cancer patients patients only Katada C, et al ∙ Squamous cell ∙ Case series Number of patients: Endoscopic mucosal Tumour recurrence Tumour recurrence: 4 (2007)114 carcinoma ∙ Retrospective 104 patients with 111 resection (EMR) by 1 of the (assessed through ∙ 23 lesions (20.7%) ∙ Invaded muscularis ∙ Consecutive lesions following methods: endoscopy) ∙ Time to recurrence: mucosa ∙ Strip biopsy: 81.1% Median: 8 months ∙ Number of sites: 8 Gender: ∙ EMR tube: 12.6% Cause‐specific survival Range: 1‐65 months Clinical stage: centres Male: 94 ∙ EMR ligation: 4.5% at 3 and 5 years with no 0/I: 1 patients (0.9%) Female: 10 ∙ EMR cap: 1.8% additional treatments Cause‐specific survival at 3 0/IIa: 5 patients (4.5%) ∙ Length of follow‐up: and 5 years: 0/IIb: 1 patient (0.9%) Median: 43 months Age: Additional treatments: Overall survival at 3 and 3 years: 99% 0/IIc: 104 patients Range: 8‐134 months Mean (SD): 64 yrs ∙ None, 86 patients (82.7%) 5 years 5 years: 95% (93.7%) (± 9.3 yrs) ∙ Radiotherapy: 7 patients Range: 38‐81 yrs (6.7%) Overall survival at 3 Overall survival at 3 and 5 ∙ Chemoradiotherapy: years without additional years: Tumour diameter: 6 patients (5.8%) treatment 3 years: 89% ∙ Mean: 24 mm ∙ Chemotherapy: 2 patients 5 years: 80% < 20 mm: 44 (40%) (1.9%) Adverse events 20 to < 30 mm: 30 ∙ Esophagectomy: Adverse events: (27%) 3 patients (2.9%) ∙ Bleeding: 11 patients ≥ 30 mm: 37 (33%) (10.6%) ∙ Stenosis: 13 patients Inclusion criteria: (11.7%) ∙ Newly diagnosed ∙ Tumour invasion of the muscularis mucosa ∙ No lymph node involvement or metastases

103

Inclusion criteria: ∙ Newly diagnosed Manner H, et al ∙ Adenocarcinoma ∙ Case series Number of patients: 19 Definitive endoscopic Tumour response Tumour response 4 (2008)116 ∙ Prospective mucosal resection (EMR) (assessed through CR: 18 patients (94.7%) Clinical stage: ∙ Consecutive Gender: by the ”suck & cut” biopsy – tumour free F: 1 patient (5.3%) Germany T1a‐T1b Male: 18 technique deep and lateral Note: 1 patient was ∙ Number of sites: Female: 1 margins) referred for 1 centre Number of treatment Complete response (CR) esophagectomy after Age: sessions: Failed (F) if treatment initiation assessment and 1 ∙ Length of follow‐up: Mean: 61.6 yrs Mean: 2.9 ± 2.7 strategy had to be patient was lost to follow‐ Every 1, 3, 6, 9, 12, 18 (±9.1 yrs) Range: 1‐9 changed to surgery up and 24 months and Range: 47‐78 yrs Note: of the 19 patients every 6 months who underwent Tumour recurrence Tumour recurrence thereafter for 5 years Tumour diameter: completion of therapy (assessed through ∙ 5 patients (27.8%) ≥2 cm: 7 patients endoscopy) Mean: 61.9 (±11.1) ≤2 cm: 14 patients Additional treatments Cause‐specifc survival at 5 months ∙ Argon plasma Cause‐specifc survival at years: Range: 45‐89 months Inclusion criteria: coagulation: 14 patients 5 years ∙19 patients (100%) ∙ Lesion limited to upper third of Overall survival at 5 Overall survival at 5 years submucosal layer years 15 patients (79%) ∙ Histological grade G1‐ 2 Adverse events Adverse events ∙ Macroscopic type I‐II ∙Upper GI bleed: 1 patient (5.3%)

104

Seewald S, et al ∙ Squamous cell ∙ Case series Number of patients: 4 ∙Circumferential Tumour recurrence: Tumour recurrence: 4 (2003) 118 carcinoma ∙ Retrospective endoscopic mucosal Number of recurrent Number of recurrent Stage: ∙ Consecutive Gender: resection (EMR) lesions obtained on lesions: 0 (0%) T1N0M0: 4 patients Male: 4 follow‐up biopsy Germany ∙ Number of sites: Female: 0 Number of treatment Adverse events: 1 centre sessions: Adverse events: ∙ Stricture: 2 patients Age: Mean: 3.75 *Note: ∙ Length of follow‐up: Mean: 71 yrs Range: 1 – 5 Information Every 3, 6 and 12 Range: 62 ‐ 88 yrs extracted for early months and every 6 esophageal cancer months thereafter Tumour diameter: patients only Not reported for early Mean: 7.5 months cancer only

105

Exclusion criteria: ∙ node positive disease ∙ advanced cancer stage ≥ T1b(submucosal) Shimizu Y, et al ∙ Squamous cell ∙ Case series Number of patients: 16 Endoscopic mucosal Cause‐specific survival Cause‐specific survival at 3 4 (2006)119 carcinoma ∙ Prospective resection (EMR) (technique at 3 years years ∙ Consecutive Gender: not specified) ∙ 16 patients (100%) Japan Male: 14 Overall survival at 3 ∙ Number of sites: 1 Female: 2 years Overall survival at 3 years centre ∙ 16 patients (100%) Age: Adverse events ∙ Length of follow‐up: Mean: 64.6 yrs Adverse events Every 3‐6 months for Range: 53 ‐ 79 yrs No complications the first year and 6‐12 months thereafter Tumour diameter: ∙ Mean: 15 mm (range 5‐35 mm)

Tumour location: ∙ Upper: 3 patients ∙ Middle: 10 patients ∙ Lower: 3 patients Tanabe S, et al ∙ Squamous cell ∙ Case series Number of patients: 85 ∙ Endoscopic oblique Tumour response Tumour response 4 (2008)120 carcinoma ∙ Retrospective aspiration mucosectomy Complete response (CR) CR: 70 patients (82.5%) ∙ Superficial Gender: (EOAM) (Patients considered to Japan ∙ Number of sites: 1 Male: 73 have incompletely Recurrence: ∙ Depth of invasion: centre Female: 12 Additional treatments resected tumours if the ∙ 5 patients (7%) m1: 41 patients Some patients received lesion could not be ∙ Among remaining 80 m2: 14 patients ∙ Length of follow‐up: Age: radiotherapy or reconstructed patients no recurrence at: m3: 18 patients At 2, 6 & 12 months and Mean: 68 yrs chemotherapy 2 months accurately) 1 year: 96.4% sm1: 9 patients every 6 months Range 45‐86 yrs after treatment 2 years: 95.0% sm2: 3 patients thereafter Recurrence 3 years: 93.4% Median: 36 months Tumour diameter: Range: 6‐72 months Median: 15 mm Need for additional Need for additional Range: 2‐72 mm treatments treatments

106

Adverse events ∙ Stenosis: 8 patients (9%) ∙ Hematoma: 2 patients (3%) ∙ Bleeding: 1 patient (1%) Comparative studies Ishihara R, et al ∙ Squamous cell ∙ Cohort study Number of patients: 70 EMR: Recurrence Recurrence 2b (2008)121 carcinoma ∙ Retrospective (78 lesions) ∙ EMR using strip biopsy or EMR group: 11 lesions (24%) ∙ Endoscopic mucosal EMR group: 44 patients cap method Adverse events ESD group: 1 lesion (3%) Japan ∙ Depth of invasion: resection (EMR) vs. ESD group: 26 patients Not reported by Statistically significant ∙ m1: 40/78 (51%) Endoscopic submucosal ESD: treatment group difference between groups ∙ m2: 17/78 (22%) dissection (ESD) Gender: ∙ ESD using a hook‐knife ∙ m3: 16/78 (21%) Male: 56 Cause‐specific survival Cause‐specific survival at ∙ sm1: 5/78 (6%) ∙ Number of sites: Female: 14 at end of follow‐up: end of follow‐up: 1 centre Not reported by 70 patients (100%) Age: treatment group Mean: 65 yrs Overall survival at end of ∙ Length of follow‐up: Range: 48‐87 yrs Overall survival at end follow‐up: Median: 32 months of follow‐up: Not 67 patients (96%) Range: 12‐121 months Tumour diameter: reported by treatment ∙ Median: 30 mm group Note: no association found ∙ Range 20‐70 mm between local recurrence and: Inclusion criteria: ∙ Patient age ∙ Histologically proven ∙ Patient gender superficial esophageal ∙ Coexistence of head & neck SCC cancer ∙ Tumour diameter ≥ 20 ∙ Tumour size mm ∙ Tumour location

107

Tanabe S, et al ∙ Squamous cell ∙ Cohort study Number of patients: 66 Strip biopsy group Tumour response Tumour response 2b (2004)122 carcinoma ∙ Retrospective ∙ Strip biopsy: 27 ∙ Saline solution injected Complete response CR: ∙ Superficial ∙ Consecutive patients into submucosa; snare (CR) Strip biopsy: 19 patients Japan ∙ Non‐concurrent ∙ EOAM: 39 patients placed around elevated (Patients considered to (70.4%) ∙ Strip biopsy vs. region and closed have incompletely EOAM: 29 patients (74.4%) endoscopic oblique ∙ Statistically significant resected tumours if No statistically significant aspiration differences in lesion EOAM group the lesion could not be difference between groups mucosectomy length and depth ∙ Saline solution injected reconstructed (p=0.793) (EOAM) between groups into submucosa; lesion accurately) aspirated into hood; lesion Adverse events: ∙ Number of sites: 1 Strip biopsy group ensnared and resected Adverse events ∙ Bleeding centre Gender: electrosurgically Strip biopsy: 2 patients Male: 24 (7.4%) ∙ Length of follow‐up: Female: 3 EOAM: 1 patient (2.6%) Not reported ∙ Stenosis Age: EOAM: 3 patients Mean (SD): 66.8 yrs (± (7.7%) 10.1 yrs) ∙ Hematoma EOAM: 1 patient (2.6%) Tumour diameter: ∙ < 10 mm: 11 patients (41%) ∙ 10‐19.9 mm: 14 patients (52%) ∙ 20‐29.9 mm: 2 patients (7%)

EOAM group Gender: Male: 36 patients Female: 3 patients Age: Mean (SD): 66.1 years (± 7.7 yrs)

Tumour diameter: ∙ < 10 mm: 8 patients

108

109

Table B 6. Studies of chemotherapy (CT) for esophageal cancer

Study authors Cancer / Cell Study (year published) Type Study Design Patients Intervention Outcome Measures Findings quality Non‐comparative studies None Comparative studies Heroor A, et al ∙ Squamous cell ∙ Cohort study Number of patients: Surgery group Overall survival: Overall survival: 2b (2003)123 carcinoma ∙ Retrospective 75 ∙ Transthoracic esophagectomy At 5 years and 10 Surgery: ∙ Surgery followed CT + surgery: 15 procedure with either 2 or 3 field years 5 years: 88% Stage: by chemotherapy Surgery: 60 lymphadenectomy (TTE) 10 years: 79% Japan Surgery (Surgery + CT) vs. Adverse events: Stage I: 32 Surgery Gender: No stage Surgery + CT group No stage specific Surgery + CT *Note: patients (53%) specific information ∙ TTE information 5 years: 82%% Information Stage IIa: 28 Number of sites: 1 reported ∙ Followed by chemotherapy reported 10 years: 69% extracted for patients (47%) centre (either cisplatin 70 mg/m² and early esophageal Age: No stage vindesine 3 mg/m² on day 1 or Difference between groups: not cancer patients Surgery + CT Length of follow‐ specific information cisplatin 70 mg/m² and 5‐FU 700 statistically significant (p= 0.704) only Stage I: 5 up: reported mg/m² from days 1 to 5 patients (33%) No stage specific Stage IIa: 10 information Tumour location: patients (67%) reported Thoracic esophagus

Tumour size: No stage specific information reported Malaisrie SC, et al ∙ ∙ Cohort study Number of patients: CT + CRT + surgery group: Median overall Median overall survival 2b (2006)124 Adenocarcinoma ∙ Retrospective 118 ∙ Induction chemotherapy: Either survival CT + CRT + surgery group: 59 ∙ Induction CT + CRT + surgery: 1‐2 courses of 5‐fluorouracil (5‐ Overall survival at 3 months United States Stage: chemotherapy 56 patients FU), cisplatin & paclitaxel or 1‐2 years CRT + surgery group: 37 months Stage II: 118 followed by CRT + surgery: 62 courses of irinotecan, docetaxel & Adverse events: Difference between groups: not *Note: patients chemoradiotherap patients 5‐FU No stage specific statistically significant (p=0.61) Information y followed by ∙ Followed by radiotherapy at 45 information extracted for surgery (CT + CRT Gender: No stage Gy in 25 fractions concurrent with reported Survival at 3 years early esophageal + surgery) vs. specific information 5‐FU & CT + CRT + surgery group: 60% cancer patients chemoradiotherap reported cisplatin or radiotherapy at 50.4 CRT + surgery group: 54% only y and surgery (CRT Gy in 28 fractions concurrent with Difference between groups: not + surgery) Age: No stage irinotecan, statistically significant specific information docetaxel & 5‐FU Number of sites: reported ∙ Followed by surgery 3‐6 weeks 1 centre later

110

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Table B 6. Studies of chemotherapy (CT) for esophageal cancer

Study authors Cancer / Cell Study (year published) Type Study Design Patients Intervention Outcome Measures Findings quality Tumour location: No (Ivor‐Lewis, transthoracic, or Length of follow‐ stage specific McKeown esophagectomy) up: information reported At 1, 3, 6 & 12 CRT & surgery group: months, and every ∙ Radiotherapy up to 50.4 Gy and 6 months concurrent chemotherapy with thereafter either cisplatin and 5‐FU or taxol Median: 50 and carboplatin months Range: 19‐ ∙ Followed by surgery 3‐6 103 months weeks later (Ivor‐Lewis, transthoracic, or McKeown esophagectomy) Nemoto K, et al ∙ Squamous cell ∙ Cohort study Number of patients: RT group Overall survival at Overall survival 2b (2006)125 carcinoma ∙ Prospective 141 ∙ EBRT to a total dose of 60‐70 Gy end of follow‐up According to disease stage: ∙ Superficial ∙ RT: 57 patients AND/OR ∙ mucosal: Japan ∙ Radiotherapy ∙ RT + CT: 84 patients ∙ High (8‐35 Gy) or low (12 Gy) Adverse events 1 year: 95% Stage: (RT) vs. dose intraluminal BT 2 years: 90% ∙ T1aN0M0 chemotherapy Gender 3 years: 90% (mucosal): 41 (CT) and RT Male: 123 RT + CT group ∙ submucosal patients (29%) [external beam Female: 18 ∙ Cisplatin and/or 5‐Fluorouracil 1 year: 90% ∙ T1bN0M0 radiotherapy 2 years: 81% (submucosal): (EBRT) and/or Age 3 years: 70% 100 patients brachytherapy Median: 68 yrs Difference was not statistically (71%) (BT)] Range: 46‐82 yrs significant

Number of sites: Exclusion criteria: According to treatment group: 24 centres ∙ No nodal 3 years: involvement RT: 72% Length of follow‐ ∙ No metastases RT + CT: 78% up: Median: 28 Difference was not statistically months Range: 14‐ significant 48 months Adverse events: No treatment specific information provided ∙ Pneumonitis: 2 patients (1.4%)

111

Table B 7. Studies of external beam radiotherapy (EBRT) or intraluminal brachytherapy for esophageal cancer Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality Noncomparative studies Kawashima M, et ∙ Squamous cell ∙ Case series Number of patients: External beam Complete response Complete response: 4 al (2006)126 carcinoma ∙ Prospective 51 radiotherapy (at 4 weeks post‐treatment as ∙ Overall: 31 patients (61%) ∙ Superficial ∙ Dose of 66 Gy over 6.5 assessed through physical ∙ Stage I (T1N0): 15 patients (83%) Japan Number of sites: 22 Gender weeks using once‐daily exam, chest X‐ray, barium ∙ Stage IIa (T2N0): 3 patients (50%) Stage: centres Male: 35 2‐Gy doses swallow, endoscopy, and CT) ∙ Stage IIa (T3N0): 13 patients (48%) ∙ Stage I (T1N0): Female: 16 18 patients (35%) Length of follow‐up: ∙ Details of treatment Overall survival at 1, 3, and 5 Overall survival: ∙ Stage IIa (T2N0): 6 ∙ Endoscopy Age (including planning) years ∙ 1 year: 71% (95%CI: 58‐83%) patients (12%) ∙ Every 6 months Median: 83 yrs varied across 22 ∙ 2 years: 53% (95%CI: 39‐67%) ∙ Stage IIa (T3N0): 27 ∙ All patients Range: 80‐91 yrs institutions ∙ 3 years: 39% (95%CI: 24‐52%) patients (53%) followed for > 2 Disease‐free survival at 3 years Tumour size ∙ No other treatment years At follow‐up: ∙ Length allowed unless ∙Alive without disease: 13 patients Median: 5 cm recurrence developed – Adverse events (25%) Range: 2‐11 cm “recurrence” not ∙Alive with disease: 1 patient (2%) defined ∙Died of cancer: 31 patients (61%) Tumour location ∙Died of other causes: 6 patients (12%) Upper 1/3: 2 patients (4%) Disease‐free survival at 3 years: Middle 1/3: 32 ∙ Stage I: 52% (95%CI=28‐77%) patients (63%) ∙ Stage IIa: 12% (95%CI=1‐23%) Lower 1/3: 17 patients (33%) Adverse events ∙ Treatment‐related death: 3 patients Comorbidities (Acute respiratory distress: 2 patients; ∙ None: 24 (47%) pneumonia: 1 patient) ∙ Single: 16 (31%) ∙ Angina: 1 patient (2%) ∙ ≥ 2: 11 (22%) ∙ Fatigue: 1 patient (2%) ∙ Pain on swallowing: 2 patients (4%) Inclusion criteria: ∙ Age ≥ 80 yrs ∙ No previous treatment ∙ No nodal involvement ∙ No metastases Kodaira T, et al ∙ Squamous cell ∙ Case series Number of patients: External beam Tumour response: Overall survival at 2 years: 4 (2003)127 carcinoma ∙ Retrospective 33 radiotherapy (EBRT): ∙ Not reported for early 73.9% ∙ Consecutive ∙ Daily dose of 1.8 to 2 cancer only 112

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Table B 7. Studies of external beam radiotherapy (EBRT) or intraluminal brachytherapy for esophageal cancer Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality Japan Stage: Gender Gy 5 times per week Adverse events: Stage I: 33 patients Number of sites: 1 Male: not reported for Recurrence: Esophageal fistula: 1 patient (3%) (100%) centre early cancer only Intraluminal ∙ Not reported for early Perforation after ICBT: 1 patient (3%) *Note: Female: not reported brachytherapy (BT): cancer only ∙Included patients Length of follow‐up: for early cancer only ∙ If excellent response to with advanced ∙ Endoscopy, EBRT Overall survival at 2 years: and early scanning, histology Age ∙ 4 to 20 Gy 1 to 2 weeks (Univariate survival rate) esophageal cancer and physical exam Mean: not reported for after EBRT ∙Information ∙ 1 to 2 month early cancer only ∙ Not reported for early Adverse events extracted for early intervals fro the first Range: not reported cancer only esophageal cancer 2 years and 3 to 4 for early cancer only patients only month intervals thereafter Tumour size Additional treatments ∙ Not reported for early ∙ Concurrent Not reported for cancer only chemotherapy: not early cancer only reported for early Tumour location cancer only ∙ Not reported for early ∙ Neoadjunctive cancer only chemotherapy: not reported for early Inclusion criteria: cancer only ∙ Ineligible for surgery

Exclusion criteria: ∙ Distant metastasis Sugahara S, et al ∙ Squamous cell ∙ Case series Number of patients: 23 External bean Tumour response Tumour response 4 (2005)128 carcinoma ∙ Prospective radiotherapy (assessed through endoscopy) CR: 23 patients (100%) ∙ Adenocarcinoma Gender ∙ Proton beam therapy Complete response (CR) Japan Number of sites: 1 No stage specific with 250‐MeV proton centre information reported beams degraded from Tumour recurrence Tumour recurrence: Note: Stage: 500 MeV generated by a 5 patients (23%) ∙ Included patients ∙ T1: 23 patients Length of follow‐up: Age sub‐atomic particle with advanced ∙ Endoscopy No stage specific accelerator (Median Actuarial survival at 5 years Overall survival at 5 years: and early ∙ 1 month after information reported total dose: 82 Gy) 13 patients (56%) esophageal cancer treatment and every ∙ Information 3 months thereafter ∙ Respiration‐gated RT Disease specific survival at 5 5 year disease‐specific survival: extracted for early for 2 years was used as needed in years 22 patients (95%) esophageal cancer ∙ Median: not last 1/3 of study patients only reported for T1 Adverse events Adverse events patients only ∙ Majority of patients ∙ No patient had treatment

113

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Table B 7. Studies of external beam radiotherapy (EBRT) or intraluminal brachytherapy for esophageal cancer Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality received a combination interruptions due to radiation‐induced of 10‐MV X‐rays and esophagitis or hematologic toxicity protons due to the limited availability of proton beams (median total combined X‐ray and proton radiotherapy dose: 76 Gy) Zhao K‐L, et al ∙ Squamous cell ∙ Case series Number of patients: 54 External beam Tumour recurrence Tumour recurrence 4 (2004)129 carcinoma ∙ Prospective radiotherapy ∙Overall ∙Overall: 33 patients (61%) Gender ∙ 1.8 Gy/fraction 5/week ∙Local first failure ∙Local: 14 patients (26%) China Stage: Number of sites: 1 No stage specific to a dose of 41.4 Gy in ∙Distant metastasesas as first ∙Metastases: 19 patients (35%) ∙T1N0M0: 1 patient centre information reported 23 fractions in 4‐5 weeks failure∙ Note: Information ∙T2N0M0: ∙ Followed by late course Overall survival: extracted for early 53 patients Length of follow‐up: Age accelerated Overall survival rate at 1, 3 1 year: 49 patients (91%) esophageal cancer ∙ Every 4 months for No stage specific hyperfractionated and 5 years 3 years: 31 patients (58%) patients only the first year, then information reported radiotherapy using 5 years: 25 patients (47%) every 6 months for reduced fields twice the next 4 years, and Inclusion criteria daily, 1.5 Gy/fraction to Adverse events: annually thereafter ∙ No previous a total of 27 Gy ∙ No stage specific treatment information reported ∙ Median: Not ∙ No nodal involvement ∙ Total radiotherapy reported for early ∙ No metastases dose given to tumour: cancer only ∙ No evidence of 68.4 Gy (in 41 fractions ∙ Range: Not perforation in 44 days) reported for early ∙ No evidence of cancer only bleeding Additional treatments ∙ Patients with treatment failure received chemotherapy

Comparative studies Ishikawa H, et al ∙ Squamous cell ∙ Cohort study Number of patients: EBRT group Tumour response Tumour response 2b (2006)130 carcinoma ∙ Retrospective 68 External beam (at 1 month post‐treatment as CR: 60 patients (88%) ∙ Superficial ∙ Consecutive ∙ EBRT: 32 radiotherapy (EBRT) assessed through endoscopy ∙ mucosal: 18 patients (100%) Japan ∙ EBRT + LDBT: 19 alone: and esophagography) ∙ submucosal: 42 patients (84%) Stage: ∙ External beam ∙ EBRT + HDBT: 17 Total dose: Complete response (CR) T1N0M0 radiotherapy (EBRT) Median: 66 Gy (Range: ∙ T1AN0M0 (mucosal): vs. EBRT + low dose Gender 60‐72 Gy) Tumour recurrence Tumour recurrence: 18 patients (27%) intraluminal Male: 54 ∙ mucosal: 0 patients (0%)

114

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Table B 7. Studies of external beam radiotherapy (EBRT) or intraluminal brachytherapy for esophageal cancer Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality ∙ T1BN0M0 brachytherapy Female: 14 EBRT + LDBT group ∙ submucosal: 14 patients (28%) (submucosal): (LDBT) vs. EBRT + ∙ EBRT (total dose of 56 50 patients (73%) high dose Age Gy for mucosal and 60 Local recurrence at 5 years Local recurrence at 5 years: intraluminal Median: 70 yrs Gy for submucosal) 10 patients (15%) brachytherapy Range: 50‐86 yrs followed by low dose (HDBT) rate intraluminal Overall survival at 5 years Overall survival at 5 years: 59% Tumour size brachytherapy to a total Number of sites: 2 ∙ Length dose of 10 Gy Cause‐specific survival at 5 Cause‐specific survival at 5 years: centres < 5 cm: 51 patients years: ∙ According to treatment group: (75%) EBRT + HDBT group EBRT: 58% Length of follow‐up: > 5 cm: 17 patients ∙ EBRT (total dose of 56 Adverse events EBRT+ (LDBT or HDBT): 81% ∙ Endoscopy at 1 (25%) Gy for mucosal and 60 Difference was not statistically month, then every 3 Gy for submucosal) significant months for the first Tumour location followed by high dose year, and every 6 Upper 1/3: 11 patients rate intraluminal Adverse events months thereafter (16%) brachytherapy to a total EBRT (across all three groups): ∙ CT every 6 months Middle 1/3: 38 dose of 9 Gy ∙ Esophagitis: 10 patients (14.7%) ∙ Median: 51 months patients (56%) ∙ Pneumonitis: 2 patients (2.9%) ∙ Range: 11‐145 Lower 1/3: 19 patients Additional treatments EBRT + LDBT: months (28%) for local recurrence ∙ Esophageal ulcer: 4 patients (21.1%) ∙ Surgery: 3 patients ∙ Death: 1 patient (5.3%) ∙ Radiotherapy: 3 EBRT + HDBT: Inclusion criteria patients ∙ Esophageal ulcer: 1 patient (5.9%) ∙ Considered to be ∙ Chemotherapy: 2 ∙ Death: 1 patient (5.9%) ineligible for surgery: patients 46 patients (68%) ∙ Refused surgery: 15 patients (21%) ∙ Positive margin after endoscopic mucosal resection: 7 patients (11%)

Sai H, et al ∙ Squamous cell ∙ Cohort study Number of patients: 34 EBRT group Recurrence Recurrence 2b (2005)131 carcinoma ∙ Retrospective ∙ EBRT: 7 External beam 9 patients (26.5%) (values for each ∙ Superficial ∙ Consecutive ∙ EBRT + HDBT: 27 radiotherapy (EBRT) Overall survival at 2, 3 and 5 group not reported) Japan alone: years Stage: ∙ External beam Age Total dose: Overall survival at 2, 3 and 5 years T1N0M0 radiotherapy (EBRT) Median: 68 yrs Median: 66 Gy (Range: Cause‐specific survival at 2, 3 ∙ 2 years: 69.5% (95%CI: 53.6‐85.3%) ∙ mucosal: 3 patients vs. EBRT + high dose Range: 53‐83 yrs 60‐69 Gy) and 5 years ∙ 3 years: 66.3% (95%CI: 50.0‐82.6%)

115

EBRT + HDBT group Gender Male: 24 patients Female: 3 Patients

Inclusion criteria ∙ Considered to be ineligible for surgery ∙ Refused surgery

116

Table B 8. Studies of chemoradiotherapy (CRT) for esophageal cancer Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality Non‐comparative studies Czito BG, et al ∙ Squamous cell ∙ Case series Number of patients: 2 ∙ Capecitabine 825 Tumour response: Tumour response: 4 (2007)132 carcinoma: 1 patient . Prospective mg/m2 twice daily on (Assessed through endoscopy CR: 1 patient (50%) ∙ Adenocarcinoma: 1 Gender: radiation therapy days and tomography at 4 weeks) SD: 1 patient (50%) United States patient Number of sites: ∙ Not reported for early ∙ Carboplatin area under Complete response (CR): 1 centre cancer only the curve weekly days 2, complete disappearance of all Adverse events: *Note: Stage: 9, 16, 23 and 30. tumours Ulcer: 1 patient (50%) ∙Included patients Stage IIA: 2 patients Length of follow‐up: Age: ∙ Paclitaxel 60 mg/m2 Partial response (PR): primary Esophagitis: 1 patient (50%) with advanced ∙ Not reported for ∙ Not reported for early weekly days 2, 9, 16, 23 tumour reduction of 50% and early early cancer only cancer only and 30. Stable disease (SD): tumour esophageal cancer ∙ Concurrent size increase > 25% or ∙Information Tumour size: radiotherapy at dose of appearance of new tumour extracted for early ∙ Not reported for early 36 – 50.4 Gy in 1.8Gy esophageal cancer cancer only fractions Overall survival: patients only No stage specific information Tumour location: Additional Interventions: reported ∙ Not reported for early ∙ Transhiatal cancer only esophagectomy: 2 Adverse events patients Inclusion criteria: ∙ No previous treatment ∙ Histologically confirmed adenocarcinoma or squamous cell carcinoma ∙ Age ≥ 18 years

Exclusion criteria: ∙ Serious comorbidities ∙ Distant metastases ∙ Evidence of esophageal perforation ∙ Prior chemotherapy or radiation ∙ Tumour extension beyond the thoracic inlet

117

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Table B 8. Studies of chemoradiotherapy (CRT) for esophageal cancer Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality Sato Y, et al ∙ Squamous cell ∙ Case series Number of patients: 7 ∙ Nedaplatin: 2 cycles on Tumour response: Tumuor response: 4 (2006)133 carcinoma days 1 and 8 at 40‐60 (Assessed through endoscopy CR: Number of sites: Gender: mg/m2 and biopsy at 4 weeks) Stage I: 4 patients (100%) 1 centre No stage specific ∙ 5‐Fluorouracil (5‐FU): Complete response (CR) Stage II: 2 patients (67%) Japan Stage: information reported continuous infusion days Stage I: 4 patients Length of follow‐up: 1‐5 and 8‐12 at 400 Partial response (PR): primary PR: *Note: (57%) Every 2 months for Age: mg/m2/day tumour reduction of ≥ 50% Stage II: 1 patients (33%) ∙Included patients Stage II: 3 patients the first 2 years and No stage specific AND with advanced (43%) twice a year information reported ∙ Concurrent Progressive disease (PD): PD: and early thereafter radiotherapy at dose of tumour size increase ≥ 25% Stage I: 0 patients (0%) esophageal cancer Tumour size: 60 Gy 30 fractions over 6 Stage II: 0 patients (0%) Information No stage specific weeks Overall survival: extracted for early information reported No stage specific information Adverse events: esophageal cancer Additional Interventions: reported ∙ Nausea: 3 patients (43%) patients only Tumour location: Not reported ∙ Esophagitis: 3 patients (43%) No stage specific Adverse events ∙ Neutropenia leading to treatment information reported interruption: 1 patient (14%)

Inclusion criteria: ∙ No previous treatment ∙ Healthy enough to tolerate chemoradiation ∙ Life expectancy ≥ 2 months

Exclusion criteria: ∙ Serious comorbidities ∙ Concomitant malignancies ∙ Pregnant or lactating Wang S, et al ∙ Squamous cell ∙ Case series Number of patients: 11 ∙Combinations of 5‐FU Tumour response: Tumour response: 4 (2006) carcinoma ∙ Retrospective plus or minus cisplatin, (Assessed through endoscopy CR: 9 patients (82%) 134 ∙ Adenocarcinoma Gender: paciltaxel, carboplatin, with or without biopsy) Number of sites: 1 Not reported for irinotecan at various Complete response (CR): Stage: centre cancer only doasages and visible tumour disappearance China T1‐T2N0M0: 11 frequencies. for more than weeks patients Length of follow‐up: Age: *Note: Every 3 months for 2 Not reported for ∙Radiotherpay dose of Recurrence:

118

Previous treatments: None Yamada K, et al ∙ Squamous cell ∙ Case series Number of patients: 63 ∙ Cisplatin: 60 mg/m² on Tumour response Tumour response 4 (2006)71 carcinoma ∙ Prospective day 1 Treatment failure: Treatment failure: 22 patients (35%) ∙ Superficial Gender: ∙ 5‐FU 400 mg/m² on Radiologic and endoscopic Number of sites: 1 Male: 57 days 1 through 4 evidence of tumour growth in Cause‐specific survival at 5 years: Japan Stage: centre Female: 6 the esophageal tumor Stage T1a: 85.2% . 0 ‐ IIa 1 course: 11 patients Stage T1b: 70.0% T1a: 23 patients Length of follow‐up: Age: (18%) Cause‐specific survival at 5 T1b: 40 patients Every 3‐4 months Mean: 67 yrs 2 courses: 28 patients years Overall survival at 5 years: and CT scan every 6 Range: 48‐83 yrs (44%) 66.4% months 3 courses: 24 patients Overall survival at 5 years Tumour size (38%) Adverse events: Mean: 45 months Median: 3.6 cm AND Adverse events Anemia: 10 patients (16%) Range: 7‐122 Range: 1‐14 cm ∙ Concurrent Leukopenia: 42 patients (67%) months radiotherapy to mean Thrombocytopenia: 4 patients (6%) Tumour location dose of 59.8 Gy Acute esophagitis: 18 patients (29%) Cervical esophagus: AND Renal toxicity: 9 patients (14%) 5/63 (8%) ∙ High dose intraluminal Esophageal ulcers: 13 patients (21%) Upper thoracic: 8/63 brachytherapy (BT) Esophageal fistula: 2 patients (3%) (13%) Esophageal stricture: 2 patients (3%) Middle thoracic: 29/63 Additional Interventions: Pericardial effusion: 3 patients (5%)

119

Inclusion criteria: ∙ Normal renal and liver function

Previous treatments: EMR: 3 patients (5%) Comparative studies De Manzoni G, et ∙ Squamous cell ∙ Cohort study Number of patients: 79 Low dose CRT + surgery Overall survival at 5 years Note: stage‐specific survival rates by 2b al (2005)135 carcinoma ∙ Retrospective patients group: treatment group were not presented ∙ Non‐concurrent Low dose CRT + ∙ Chemotherapy (2 Adverse events: Italy Stage: ∙ 2 courses of surgery: 47 patients courses of cisplatin at No stage specific information Overall survival at 5 years (across all I (T1N0): 7 patients chemotherapy and High dose CRT + 100 mg/m2 on days 1 & reported stages): IIa (T2N0): 26 patients concurrent surgery: 32 patients 29 & 5‐FU at 1000 Low dose CRT + surgery: 7.5% *Note: IIa (T3N0): 46 patients radiotherapy, mg/m2/ day on days 1‐4 High dose CRT + surgery: 30.6% ∙ Included patients followed by surgery ∙ Gender: Not reported & 29‐32) and concurrent Difference between groups: statistically with advanced (Low dose CRT+ for Stages I and II radiotherapy (daily significant (p=0.017) and early surgery) vs. 3 patients only fraction of 200 cGy esophageal cancer courses of totalling 3000 cGy) ∙ Information chemotherapy and ∙ Age: Not reported for ∙ Followed by surgery 3 extracted for early concurrent Stages I and II patients weeks later (various esophageal cancer radiotherapy, only techniques used) patients only followed by surgery (High dose CRT + ∙ Tumour location: Not High dose CRT + surgery surgery) reported group: ∙ Chemotherapy (3 Number of sites: 1 Inclusion criteria: courses of cisplatin at centre ∙ Histologically proven 100 mg/m2 on days 1, 22 Squamous cell & 53 & 5‐FU at 1000 Length of follow‐up: carcinoma mg/m2/ day on days 1‐4, At 4 months and 22‐25, & 53‐56) and every 6 months Exclusion criteria: concurrent radiotherapy thereafter ∙ History of secondary (daily fraction of 200 Mean: 74 months malignancies cGy totalling 5000 cGy) Range: 32‐117 ∙ Low dose CRT + ∙ Followed by surgery 4‐

120

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Table B 8. Studies of chemoradiotherapy (CRT) for esophageal cancer Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality months surgery: 5 weeks later (various > 70 yrs techniques used) ∙ High dose CRT + surgery: > 75 yrs Hironaka S, et al ∙ Squamous cell ∙ Cohort study Number of patients: 53 Surgery group: Tumour recurrence: Overall survival at 5 years: 2b (2003)136 carcinoma ∙ Retrospective Surgery group: 31 ∙ Total or subtotal ∙ Not reported for early Surgery group: 19 patients (62%) ∙ Surgery vs. patients thoracic esophagectomy cancer only CRT group: 10 patients (45%) Japan Stage: chemoradiotherapy CRT group: 22 IIa (T2N0): 53 patients (CRT) patients CRT group: Overall survival at 5 years: (Data extracted from survival curve) ∙ Chemotherapy with (Overall survival by treatment Number of sites: Gender protracted infusion of 5‐ type) Adverse events: *Note: 1 centre ∙Not reported for early FU (400 mg/m2/day) ∙ Treatment‐related death ∙Included patients cancer only days 1‐5 and 8‐12 & Adverse events Surgery group: 2 patients (4%) with advanced Length of follow‐up: infusion of cisplatin (40 CRT group: 0 patients (0%) and early ∙ Surgery group: Age mg/m2/day) on days 1 ∙ Leukopenia esophageal cancer every 6 months and ∙Not reported for early and 8, repeated twice Surgery group: 0 patients (0%) ∙Information every 12 months cancer only every 5 weeks CRT group: 6 patients (27%) extracted for early thereafter ∙ Concurrent radiation at ∙ Esophagitis esophageal cancer Not reported for Inclusion criteria: 2 Gy/day, 5 days/week Surgery group: 0 patients (0%) patients only cancer only ∙ Histologically proven to a total of 60 Gy; a 2 CRT group: 11 patients (50%) Squamous cell week break after 30 Gy. ∙ Pneumonitis ∙ CRT group: carcinoma ∙ For objective response: Surgery group: 0 patients (0%) every 3 months in ∙ Age ≤75 years protracted infusion of 5‐ CRT group: 2 patients (9%) the first year and ∙ Eastern Cooperative FU (800 mg/m2/day) every 6 months Oncology Group days 1‐5 & infusion of thereafter performance status of cisplatin (80 mg/m2/day) Not reported for 0‐2 on days 1, repeated cancer only Range: ∙ T2‐T3 disease every 4 weeks not reported for ∙ Positive or negative cancer only nodal status ∙ No distant metastasis

Exclusion criteria: ∙ Serious comorbidities ∙ Secondary cancers beyond early stages

121

Table B 9. Studies of chemoradiotherapy (CRT) and surgery (esophagectomy) for esophageal cancer Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality Non‐comparative studies Donahue JM, et al ∙ Squamous cell ∙ Case series Number of patients: Chemoradiotherapy Tumour recurrence Overall survival at 5 years (%) 4 (2009)137 carcinoma ∙ Retrospective 12 ∙ 5‐fluorouracil 1,000 ∙ Not reported for early 64% ∙ Adenocarcinoma ∙ Consecutive mg/m2 per day for 96‐ cancer only (Data extracted from survival United States Gender: hours continuous infusion curve) Stage Number of sites: 1 ∙ Not reported for on the first and last for Overall Survival at 5 *Note: Stage IIa: 12 patients centre early cancer only days of radiotherapy years ∙Included patients ∙ Cisplatin 75 mg/m2 per with high grade Length of follow‐up: Age: day days on the first and Adverse events dysplasia and early Mean: not reported ∙ Not reported for last for days of ∙ Not reported for early esophageal cancer for cancer only early cancer only radiotherapy cancer only ∙Information Range: not reported ∙ Concomitant extracted for early for cancer only Tumour location: radiotherapy at 28 esophageal cancer ∙ Not reported for fractions 5 days per week patients only early cancer only for total of 50.4 Gy in 1.8Gy fractions Previous Surgery interventions: ∙ Esophagogastrectomy: ∙Endoscopic mucosal one of Ivor Lewis, resection: 2 patients McKeown, transhiatal or (25%) thoracoabdominal ∙Radiation: 3 patients techniques (38%) Comparative studies De Manzoni G, et ∙ Squamous cell ∙ Cohort study Number of patients: Low dose CRT + surgery Overall survival at 5 Note: stage‐specific survival 2b al (2005)135 carcinoma ∙ Retrospective 79 patients group: years rates by treatment group ∙ Non‐concurrent Low dose CRT + ∙ Chemotherapy (2 were not presented Italy Stage: ∙ 2 courses of surgery: 47 patients courses of cisplatin at 100 Adverse events: I (T1N0): 7 patients chemotherapy and High dose CRT + mg/m2 on days 1 & 29 & No stage specific Overall survival at 5 years IIa (T2N0): 26 patients concurrent surgery: 32 patients 5‐FU at 1000 mg/m2/ day information reported (across all stages): *Note: IIa (T3N0): 46 patients radiotherapy, on days 1‐4 & 29‐32) and Low dose CRT + surgery: ∙ Included patients followed by surgery ∙ Gender: Not concurrent radiotherapy 7.5% with advanced and (Low dose CRT+ reported for Stages I (daily fraction of 200 cGy High dose CRT + surgery: early esophageal surgery) vs. 3 courses and II patients only totalling 3000 cGy) 30.6% cancer of chemotherapy and ∙ Followed by surgery 3 Difference between groups: ∙ Information concurrent ∙ Age: Not reported weeks later (various statistically significant extracted for early radiotherapy, for Stages I and II techniques used) (p=0.017) esophageal cancer followed by surgery patients only patients only (High dose CRT + High dose CRT + surgery 122

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Table B 9. Studies of chemoradiotherapy (CRT) and surgery (esophagectomy) for esophageal cancer Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality surgery) ∙ Tumour location: group: Not reported ∙ Chemotherapy (3 Number of sites: 1 courses of cisplatin at 100 centre Inclusion criteria: mg/m2 on days 1, 22 & 53 ∙ Histologically & 5‐FU at 1000 mg/m2/ Length of follow‐up: proven Squamous day on days 1‐4, 22‐25, & At 4 months and cell carcinoma 53‐56) and concurrent every 6 months radiotherapy (daily thereafter Exclusion criteria: fraction of 200 cGy Mean: 74 months ∙ History of totalling 5000 cGy) Range: 32‐117 secondary ∙ Followed by surgery 4‐5 months malignancies weeks later (various ∙ Low dose CRT + techniques used) surgery: > 70 yrs ∙ High dose CRT + surgery: > 75 yrs

123

Table B 10. Studies of surgery (esophagectomy) for esophageal cancer Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality Non‐comparative studies Alexiou C, et al ∙ Adenocarcinoma ∙ Case series Number of patients: Type of surgical approach: Overall survival at 5 years Overall survival at 5 years: 4 (2006)138 132 patients 212 Left thoracotomy & Adenocaracinoma Number of sites: 1 phrenotomy, left Median survival in months Stage I: 55 % England ∙ Squamous cell centre Gender: thoracolaparotomy, Stage IIa: 32 % carcinoma No stage specific Ivor Lewis, transhiatal, or Adverse events: Pooled across stages: 36% *Note: 80 patients Length of follow‐up: information reported McKeown No stage specific Information Every 3 months for information reported Squamous cell carcinoma extracted for early Stage: the first year, every 6 Age: Stage I: 66 % esophageal cancer Stage I: 38 patients months for the next 4 No stage specific Stage IIa: 52 % patients only† (19%) years, and yearly information reported Pooled across stages: 54% Stage IIa: 174 patients thereafter (81%) Tumour size: Median survival: Mean: Not reported No stage specific Adenocarcinoma Range: Not reported information reported Stage I: 94 months (95% CI: 32‐155) Stage IIa: 33 months (95% CI: 26‐40) Tumour location: No stage specific Squamous cell carcinoma information reported Stage I: 72 months (95% CI: 14‐129) Stage IIa: 64 months (95% CI: 34‐93) Inclusion criteria: Not reported

Exclusion criteria: Prior chemotherapy of radiation therapy Egberts JH, et al ∙ Adenocarcinoma ∙ Case series Number of patients: 41 Type of surgical approach: Median survival: Median survival: 4 (2008)139 13 patients (32%) ∙ Consecutive Left thoracotomy & 76 months Gender: phrenotomy, left Germany ∙ Squamous cell Number of sites: 1 No stage specific thoracolaparotomy, Kaplan‐Meier 5 year Kaplan‐Meier 5 year survival: carcinoma centre information reported Ivor Lewis, transhiatal, or survival 5 year survival: ≈ 61% *Note: 26 patients (63%) McKeown (extracted from survival curve) Information Length of follow‐up: Age: Adverse events: extracted for early ∙ Other: 2 patients (5%) No stage specific No stage specific Additional interventions: Not reported esophageal cancer information reported information reported Radiation therapy and/or patients only† Stage: chemotherapy (details not Stage I or II Tumour size: provided No stage specific information reported 124

Tumour location: No stage specific information reported

Exclusion criteria: ∙ Infiltrating tumor ∙ Metastases

Previous treatment: Radiotherapy and/or chemotherapy (details not provided) Mariette C, et al ∙ Adenocarcinoma ∙ Case series Number of patients: Type of surgical approach: Overall survival at 1, 3, and Overall survival: (2004)140 ∙ Retrospective 139 Transthoracic en bloc 5 years At 1 year: ∙ Squamous cell esophagectomy with Stage 0: 100% carcinoma Number of sites: 1 Gender: abdominal/mediastinal Adverse events: Stage I: 99% France centre No stage specific lymphadenectomy (mid and No stage specific Stage IIa: 98% Stage: information reported lower 1/3 esophagus information reported Pooled across stages: 98.6% *Note: Stage 0: 4 patients (3%) Length of follow‐up: tumors) (TTE) or transhiatal Information Stage I: 71 patients At 1 month, then esophagectomy without At 3 years: extracted for early (51%) every 6 months for Age: thoracotomy with Stage 0: 100% esophageal cancer Stage IIa: 64 patients first and second years, No stage specific abdominal/extended Stage I: 92% patients only†† (46%) and annually information reported mediastinal inferor Stage IIa: 59% thereafter lymphadenectomy (THE) Pooled across stages: 77.0%

No stage specific Tumour size: Type of surgical approach by At 5 years: information reported No stage specific stage: Stage 0: 100% information reported TTE: Stage I: 84% Stage 0: 3 patients Stage IIa: 50% Tumour location: Stage 1: 40 patients Pooled across stages: 68.3% No stage specific Stage IIa: 53 patients information reported THE: Exclusion criteria: Stage 0: 1 patient ∙ Rare tumors Stage I: 31 patients ∙ Adenocarcinoma of Stage IIa: 11 patients the esogastric junction ∙ Tumors of the upper esophageal sphincter

125

Tumour location: Not reported for cancer only Nguyen N, et al ∙ Adenocarcinoma ∙ Case series Number of patients: 26 Type of surgical approach: Overall survival at 2 years: Overall survival at 2 years: 4 (2003)142 ∙ Consecutive Combined thoracoscopic 2‐year survival rates by stage: ∙ Squamous cell Gender: and laparoscopic Stage 0: 100% carcinoma Number of sites: 1 Not reported for esphagectomy, Stage I: 100% United States centre cancer only thoracoscopic and Stage II: 54% Stage: laparoscopic Ivor Lewis Pooled across stages: 71.7% *Note: Stage 0: 7 patients (27%) Length of follow‐up: Age: resection, abdominal only Information At 1, 3, 6, 9 and 12 Not reported for laparoscopic Recurrence Recurrence : extracted for early Stage I: 3 patients (11%) months and yearly cancer only esophagogastrectomy, or (at 1 and 2 year follow‐up At 1 year esophageal cancer thereafter hand‐assisted laparoscopic by stage and overall) Stage 0: 1 patient (14%) patients only†††† Stage II: 16 patients Tumour size: transhiatal esophagectomy Stage I: 2 patients (66%) (62%) Not reported Not reported for Stage II: 5 patients (31%) for cancer only cancer only Overall: 8 patients (31%)

Tumour location: At 2 years Not reported for Stage 0: 3 patients (43%) cancer only Stage I: 3 patients (100%) Stage II: 9 patients (56%) Exclusion criteria: Overall: 15 patients (58%) ∙ Metastases Adverse events: ∙ Ineligible for surgery Not reported for cancer *extracted from survival curves ∙ Morbid obesity only

126

Previous treatment: Some received chemoradiotherapy Thomson BNJ, ∙ Adenocarcinoma ∙ Case series Number of patients: 12 Type of surgical approach: Overall survival at end of Overall survival at end of follow‐up: 4 Cade RJ ∙ Prospective Esophagectomy (no details follow‐up (study end) 9 patients (75%) (2003)143 Stage: Gender: provided) T1N0M0: 12 patients Number of sites: 1 Not reported Disease specific survival at Disease specific survival at end of Australia (100%) centre end of follow‐up (study follow‐up: Age: end) 92% Length of follow‐up: Mean: 64.7 yrs *Note: Mean: 34.7 months Range: 48‐80 yrs Adverse events: Adverse events: Information Range: 7 to 79 months Complications ∙ Respiratory: 6 patients (50%) extracted for early Tumour size: ∙ Cardiac: 4 patients (33%) esophageal cancer Not reported ∙ DVT: 1 patient (8%) patients only††††† ∙ Leak: 1 patient (8%) Tumour location: ∙ Nerve palsy: 1 patient (8%) Not reported

Exclusion criteria: ∙ Ineligible for surgery Udagawa H, et al ∙ Adenocarcinoma ∙ Case series Number of patients: Type of surgical approach: Tumour response: Overall survival: 4 (2007)144 187 Esophagectomy with 2 field No stage specific At 1 year: ∙ Squamous cell Number of sites: 1 dissection or information reported Stage 0/I: ≈ 97% carcinoma centre Gender: esophagectomy with 3 field Japan No stage specific dissection (3FD) Recurrence: At 2 years: Stage: Length of follow‐up: information reported No stage specific Stage 0/I: ≈ 95% *Note: Stage 0: 22 patients Mean: Not reported Type of surgical approach by information reported Information (12%) Range: Not reported Age: procedure: At 3 years: extracted for early Stage I: 165 patients No stage specific 2FD Overall survival at 1, 2, 3, 4 Stage 0/I: ≈ 91% esophageal cancer (88%) information reported Stage 0: 15 patients (68%) and 5 years patients only† Stage I: 39 patients (24%) At 4 years: Tumour size: Adverse events: Stage 0/I: ≈ 87% Not reported 3FD No stage specific Stage 0: 7 patients (32%) information reported 5 years: Tumour location: Stage I: 126 patients (76%) Stage 0/I: ≈ 82% Not reported (Extracted from survival curves)

Exclusion criteria: ∙ Previous treatments

127

Tumour location: Upper thoracic esophagus

Inclusion criteria: ∙Surgical curative intent Wang GQ, et al Cell type: ∙ Case series Number of patients: 76 Type of surgical approach: Overall survival at 5 and 25 Overall survival: 4 (2004)146 ∙Squamous cell Left posterolateral years carcinoma Number of sites: Not Gender: No stage thoracotomy with At 5 years: 74 patients (97%) reported specific information esophagogastrostomy with Adverse events: At 25 years: 65 patients (85%) China Stage: reported routine lymph node No stage specific TisN0M0: 76 patients Length of follow‐up dissection information reported *Note: No stage specific Age: No stage specific Information information reported information reported extracted for early esophageal cancer Tumour size: patients only†† No stage specific information reported

Tumour location: No stage specific information reported Westerterp M, et ∙ Adenocarcinoma ∙ Case series Number of patients: 66 Type of surgical approach: Recurrence Recurrence 4 al Transhiatal esophagctomy ∙ after 5 years ∙At 5 years: 4%

128

Exclusion criteria: ∙ Previous treatment Wolfsen HC, ∙ Adenocarcinoma ∙ Case series Number of patients: 6 Type of surgical approach: Tumour response Tumour response: 4 Hemminger LL, ∙ Non‐consecutive Open transthoracic Tumour downgrade Tumour downgrade: DeVault KR Stage: Gender: esophagectomy (Ivor Lewis Barrett’s metaplasia: 1 patient (16.5%) (2004)148 Stage IIa: 6 patients Number of sites: 1 Male: 3 (50%) procedure) with Recurrence HGD: 1 patient (16.5%) (100%) centre Female: 3 (50%) pyloroplasty LGD: 2 patients (33%) Adverse events: Recurrence: United States Length of follow‐up: Age: Additional Interventions: Not reported 2 patients (33%) Mean: 35.7 months Mean: 68.8 years Following esophagectomy Range: 7‐88 months Range: 58‐80 years Surgery: 1 patient *Note: PDT: 1 patient Information Tumour size: Proton pump inhibitors extracted for early Not reported twice daily: 3 patients esophageal cancer patients only†††† Tumour location: Not reported Yamamoto S, et al ∙ Adenocarcinoma ∙ Case series Number of patients: 47 Type of surgical approach: Tumour response: Overall survival: 4 (2005)149 Thoracoscopic and video No stage specific 4 year survival: ∙ Squamous cell Number of sites: 1 Gender: No stage assisted esophagectomy, information reported Stage 0: 100% carcinoma centre specific information thoracoscopic Japan reported esophagectomy, or Recurrence: 5 year survival by stage: Stage: Length of follow‐up: video‐assisted No stage specific Stage I: 87% *Note: Stage 0: 3 patients (6%) Mean: Not reported Age: No stage specific esophagectomy information reported Stage IIa: 70% Information Stage I: 23 patients Range: Not reported information reported

129

Tumour location: 5 year survival for Stage No stage specific I/IIa disease information reported 5 year survival all stages Exclusion criteria: ∙ History of right side Adverse events: thoracic surgery No stage specific information reported

Comparative studies Benzoni E, et al ∙ Adenocarcinoma ∙ Non‐ randomized Number of patients: 10 Type of surgical approach: Kaplan‐Meier 1, 2, 3, and 4 Kaplan‐Meier 1, 2, 3 and 4 year overall 2b (2007)150 control trial THE Group: year overall survival survival: ∙ Squamous cell ∙ Transhiatal Gender: Transhiatal laparoscopic (by stage and overall) Italy carcinoma laparoscopic No stage specific esophagectomy Stage 0: esophagectomy (THE) information reported Adverse events: At 1 year: 100% *Note: Stage: vs. laparoscopic and TT/LE Group No stage specific At 2 years: 100% Information THE Group: right transthoracic Age: Laparoscopic information reported At 3 years: 100% extracted for early Stage 0: 1 patient (17%) esophagectomy No stage specific esophagectomy with right At 4 years: 100% esophageal cancer Stage I: 1 patient (17%) (TT/LE) information reported transthoracic approach patients only† Stage IIa: 4 patients Stage I: (66%) Number of sites: 1 Tumour size: At 1 year: 100% centre No stage specific At 2 years: 100% TT/LE Group: information reported At 3 years: 0% Stage 0: 2 patients (50%) Length of follow‐up: At 4 years: 0% Stage I: 0 patients (0%) No stage specific Tumour location: Stage IIa: 2 patients information reported No stage specific Stage IIa: (50%) information reported At 1 year: 100% At 2 years: 80% Inclusion criteria: At 3 years: 80% Not reported At 4 years: 80%

Exclusion criteria: Overall: Not reported At 1 year: 100% At 2 years: 90% Previous treatment: At 3 years: 80%

130

Stage I: 16 patients Stage IIa: 10 patients

Additional Interventions: Some stage II patients received chemoradiotherapy following surgery Heroor A, et al ∙ Squamous cell ∙ Cohort study Number of patients: 75 Type of surgical approach: Overall survival: Overall survival: 2b (2003)123 carcinoma ∙ Retrospective CT + surgery: 15 Surgery group At 5 years and 10 years Surgery: ∙ Surgery followed by Surgery: 60 ∙ Transthoracic At 5 years: 88% Stage: chemotherapy esophagectomy procedure Adverse events: At 10 years: 79% Japan Surgery (Surgery + CT) vs. Gender: No stage with either 2 or 3 field No stage specific Stage I: 32 patients Surgery specific information lymphadenectomy (TTE) information reported Surgery + CT *Note: (53%) reported At 5 years: 82%% Information Stage IIa: 28 patients Number of sites: 1 Surgery + CT group At 10 years: 69% extracted for early (47%) centre Age: No stage specific ∙ TTE esophageal cancer information reported ∙ Followed by chemotherapy Difference between groups: not patients only† Surgery + CT Length of follow‐up: (either cisplatin 70 mg/m² statistically significant (p= 0.704)

131

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Table B 10. Studies of surgery (esophagectomy) for esophageal cancer Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality Stage I: 5 patients (33%) No stage specific Tumour location: and vindesine 3 mg/m² on Stage IIa: 10 patients information reported Thoracic esophagus day 1 or cisplatin 70 mg/m² (67%) and 5‐FU 700 mg/m² from Tumour size: days 1 to 5 No stage specific information reported Hironaka S, et al ∙ Squamous cell ∙ Cohort study Number of patients: 53 Type of surgical approach: Tumour recurrence: 2b (2003)136 carcinoma ∙ Retrospective Surgery group: 31 Surgery group: ∙Not reported for early ∙ Surgery vs. patients ∙ Total or subtotal thoracic cancer only Japan Stage: chemoradiotherapy CRT group: 22 esophagectomy IIa (T2N0): 53 patients (CRT) patients Median survival: Median survival: CRT group: (Median survival by Surgery group: not reached Number of sites: Gender ∙ Chemotherapy with treatment type) CRT group: 37 months *Note: 1 centre ∙Not reported for early protracted infusion of 5‐FU ∙Included patients cancer only (400 mg/m2/day) days 1‐5 Overall survival at 5 years: Overall survival at 5 years: with advanced Length of follow‐up: and 8‐12 & infusion of (Overall survival by Surgery group: 19 patients (62%) and early ∙ Surgery group: every Age cisplatin (40 mg/m2/day) on treatment type) CRT group: 10 patients (45%) esophageal cancer 6 months and every ∙Not reported for early days 1 and 8, repeated twice ∙Information 12 months thereafter cancer only every 5 weeks (Data extracted from survival curve) extracted for early ∙ Concurrent radiation at 2 Adverse events: esophageal cancer Not reported for Inclusion criteria: Gy/day, 5 days/week to a ∙Not reported for early patients only cancer only ∙ Histologically proven total of 60 Gy; a 2 week cancer only Squamous cell break after 30 Gy. ∙ CRT group: carcinoma ∙ For objective response: every 3 months in the ∙ Age ≤75 years protracted infusion of 5‐FU first year and every 6 ∙ Eastern Cooperative (800 mg/m2/day) days 1‐5 & months thereafter Oncology Group infusion of cisplatin (80 performance status of mg/m2/day) on days 1, Not reported for 0‐2 repeated every 4 weeks cancer only ∙ T2‐T3 disease ∙ Positive or negative nodal status ∙ No distant metastasis

Exclusion criteria: ∙ Serious comorbidities ∙ Secondary cancers beyond early stages Javle MM, et al ∙ Squamous cell ∙ Cohort study Number of patients: 72 Type of surgical approach: Median survival Median survival 2b (2006)152 carcinoma ∙ Retrospective Surgery: 25 patients Surgery group: Surgery: 75.0 months

132

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Table B 10. Studies of surgery (esophagectomy) for esophageal cancer Study authors Study (year published) Cancer / Cell Type Study Design Patients Intervention Outcome Measures Findings quality ∙ Adenocarcinoma ∙ Surgery vs. CT + RT + Surgery: 17 ∙ Transthoracic CT + RT + surgery: 35.7 months United States chemotherapy and patients esophagectomy (Ivor Lewis) CT + RT: 19.1 months Stage: radiotherapy and CT + RT: 30 patients *Note: In situ or stages I to IIa surgery (CT + RT + CT + RT + Surgery group: No statistically significant difference Information surgery) vs. Gender ∙ Cisplatin based between surgery group and CT + RT + extracted for early chemotherapy and No stage specific chemotherapy surgery group (p=0.097) esophageal cancer radiotherapy (CT + RT) information reported ∙ No further details patients only† provided Statistically significant difference Number of sites: 1 Age ∙ Followed by transthoracic between surgery group and CT + RT centre No stage specific esophagectomy (Ivor Lewis) group, favouring surgery group information reported Length of follow‐up: CT + RT group: Adverse events: Adverse events: Not reported ∙ Cisplatin based Not reported, except for Treatment‐related death: 0 patients chemotherapy death ∙ No further details provided Pacifico RJ, et al ∙ Adenocarcinoma ∙ Cohort study Number of patients: 88 Type of surgical approach: Complete response Complete response: 2b (2003)107 ∙ Retrospective EMR + PDT: 24 EMR + PDT group: ∙ EMR + PDT: 20 patients 83.3% Stage: ∙ Endoscopic mucosal patients ∙ EMR using variceal band ∙ Surgery: 63 patients (100%) United States Stage 0: 2 patients resection (EMR) and Surgery: 64 patients ligation technique or Stage I: 86 patients photodynamic transparent cap technique therapy (PDT) vs. EMR + PDT group: ∙ Followed by PDT Treatment failure Treatment failure surgery Gender performed a mean of 4.2 ∙ EMR+PDT: 4 patients (16.6%) Male: 21 weeks after EMR: ∙ Surgery: 1 patient (1.6%) Number of sites: Female: 3 Drug: Hematoporphyrin 1 centre derivative or porfimer Adverse events Adverse events Age sodium EMR+PDT: Length of follow‐up: Median (SD): 68 yrs (± Dosage: 2 mg/kg ∙ Strictures: 2 patients (8.3%) ∙ EMR + PDT: 2 yrs) Route of administration: IV ∙ Cutaneous photosensitivity, mild: 1 Mean (SD): 12 months Time to photoactivation: 48 patient (4.2%) (+ 2 months) Surgery group: hrs ∙ Surgery: Gender Light source: 630 nm laser Surgery: Mean (SD): 19 months Male: 58 Total light dose: 300 J/cm ∙ Strictures: 10 patients (15.6%) (± 3 months) Female: 6 Energy density: 32 J/cm2 ∙ Anastomotic leaks: 5 patients (7.8%) Treatment time: Not ∙ Wound infections: 5 patients (7.8%) Age reported ∙ Dumping syndrome: 3 patients (4.7%) Median (SD): 67 yrs (± Number of treatments: Not ∙ Empyema: 2 patients (3.1%) 1 yr) reported ∙ Bleeding requiring transfusion: 2 patients (3.1%) Note: no statistically Surgery group: ∙ Atrial fibrillation: 2 patients (3.1%)

133

Inclusion criteria ∙ Stages 0‐I adenocarcinoma ∙ No nodal involvement ∙ No metastases Peyre CG, et al ∙ Adenocarcinoma ∙ Cohort study Number of patients: 85 Type of surgical approach: Recurrence Recurrence 2b (2007)153 ∙ Retrospective THE: 35 patients THE group: THE: 0 patients Stage: ∙ Transhiatal VSE: 29 patients ∙ Transhiatal esophagectomy VSE: 0 patients United States T1‐2N0M0 esophagectomy (THE) En bloc: 21 patients with midline laparotomy En bloc: 1 patient vs. En bloc resection ( and left neck incision *Note: En bloc) vs. vagal‐ Gender: No stage Overall survival at 5 years Overall survival at 5 years: Information sparing specific information VSE group: THE: 65% extracted for early esophagectomy (VSE) reported ∙ Vagal‐sparing VSE: 89% esophageal cancer esophagectomy through En bloc: 95% patients only††† Number of sites: Age: No stage specific abdominal left neck 1 centre information reported approach either via Statistically significant difference laparotomy or as a between THE and VSE groups (p‐value Length of follow‐up): Tumour size: No stage laparoscopic procedure = 0.0063) Every 3 months for specific information first 3 years, every 6 reported En bloc group No statistically significant difference months up to 5 years, ∙ En bloc esophagectomy between En bloc and VSE groups (p and annually Tumour location: No involving right thoracotomy, value = 0.91) thereafter stage specific midline laparotomy, and left Adverse events: information reported neck incision Not reported for cancer No stage specific patients only information reported Smithers BM, et al ∙ Squamous cell ∙ Cohort study Number of patients: Type of surgical approach: Median survival Median survival (months) 2b (2007)154 carcinoma ∙ Prospective 170 Open TTE group: (Stage IIA only by surgery Open TTE: ∙ Adenocarcinoma ∙ Consecutive ∙ Open transthoracic type) Stage IIa: 32 months Australia TTE group: 25 patients esophagectomy TA: Stage: ∙ Open TTE vs TA group: 139 patients Overall 3 years survival Stage IIa: 35 months *Note: Stage 0 ‐IIa Thoracoscopic MIE group: 6 patients Thoracoscopic‐ Assisted (Stage I and IIA only by Information assisted vs group (TA): surgery type) MIE: extracted for early MIE surgery Gender ∙ Thoracoscopic and Stage IIa: 22 months

134

Overall survival at 5 years (%): Open TTE: Stage I: 67% Stage IIa: 34%

TA: Stage I: 85% Stage IIa: 33%

Total MIE: Stage I: 100% Stage IIa: 50% †Study included patients with all stages of esophageal cancer (0 through IV (i.e., early to advanced)) ††Study included patients with early (stages 0 – IIa) and locally advanced cancer (stage IIb (nodal involvement) cancer †††Study included patients with high grade dysplasia in Barrett’s Esophagus and early esophageal cancer (stages 0 – IIa) ††††Study included patients with high grade dysplasia in Barrett’s Esophagus and those with all stages of esophageal cancer (stages 0 through IV) †††††Study included patients with low grade dysplasia in Barrett’s Esophagus and those with stages I through III of esophageal cancer

135

Table C 1. Excluded studies Study authors (year published) Main reason for exclusion Agranovich A, et al (2008)155 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Ajani JA, et al (2008)156 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Alsabahi HNA, et al (2006)157 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Ancona E, et al (2008)158 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Ando N, et al (2003)159 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Benzoni E, et al (2008)160 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Bergquist H, et al (2007)161 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Bernabe KQ, et al (2005)162 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Blackmon SH, et al (2007)163 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Bresadola V, et al (2006)164 Study did not include outcomes of interest Chang AC, et al (2008)165 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Chiu PWY, et al (2005)166 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Chou S, et al (2005)167 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Clocirlan M, et al (2008)168 Study presented a single case report Conio M, et al (2005)111 Study did not include outcomes of interest Dabrowski A, et al (2006)169 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Dan HL, et al (2003)170 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Dapri G, et al (2008)171 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Darnton SJ, et al (2003)172 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Das A, et al (2008)173 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only De Boer AG, et al (2004)174 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Di Fiore F, et al (2006)175 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Di Franco F, et al (2008)176 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Doki Y, et al (2008)177 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Donington JS, et al (2003)178 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Dunkin BJ, et al (2006)179 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Ell C, et al (2000)180 Study included patients with Barrett’s esophagus and early esophageal cancer, and it was not possible to extract information for those with early esophageal cancer only El‐Rayes BF, et al (2004)181 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Ertan A, et al (1995)182 Study presented a single case report Farran L, et al (2007)183 Study did not include outcomes of interest Ferahkose Z, et al (2008)184 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Frechette E, et al (2004)185 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Go JT, et al (2006)186 Study included patients with Barrett’s esophagus and early esophageal cancer, and it was not possible to extract information for those with early esophageal cancer only Gockel I, et al (2007)187 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Goldberg M, et al (2003)188 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Gossner L, et al (1998)189 Patients already included in study by “Gossner L, et al (1999)87” Gossner L, et al (1998)190 Patients already included in study by “Gossner L, et al (1999)87” 137

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Table C 1. Excluded studies Study authors (year published) Main reason for exclusion Govindan R, et al (2004)191 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Gradauskas P, et al (2006)192 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Greenwald BD, et al (2008)193 Study included patients with Barrett’s esophagus and early esophageal cancer, and it was not possible to extract information for those with early esophageal cancer only Grosjean P, et al (1996)194 Patients already included in study by “Radu A, et al (1999)195” Hainsworth JD, et al (2007)196 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Halliday BP, et al (2007)197 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Heath EI, et al (2006)198 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Herman LL, et al (1993)199 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Higuchi A, et al (2006)200 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Higuchi K, et al (2007)201 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Imdahl A, et al (2004)202 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Ishikawa H, et al (2005)203 Patients already included in study by “Ishikawa H, et al (2006)130” Jamieson NF, et al (2003)204 Patients already included in study by “Jamieson N, et al (2003)205” Jin J, et al (2004)206 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Jo WM, et al (200)207 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Junginger T, et al (2006)208 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Kashtan H, et al (1999)209 Patients already included in study by “Kashtan J, et al (2001)210” Katada C, et al (2003)211 Study did not include outcomes of interest Kelsen DP, et al (2007)212 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Kelsey CR, et al (2007)213 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Keresztes RS, et al (2003)214 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Kim JH, et al (2007)215 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Kleinberg L, et al (2003)216 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Kodaira T, et al (2006)217 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Kunisaki C, et al (2007)218 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Lee JL, et al (2004)219 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Lew RJ, et al (2002)220 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Li JH, et al (1990)221 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Lovat LB, et al (2000)222 Patients already included in study by “Jamieson N, et al (2002)223” Luechakiettisak P, et al (2008)224 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Luu TD, et al (2008)225 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Ma JY, et al (2006)226 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Maish MS, et al (2004)227 Study did not include outcomes of interest Malhi‐Chowla N, et al (2001)228 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only May A, et al (2003)229 Patients already included in study by “Pech O, et al (2004)230” Meerten E, et al (2006)231 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Michel P, et al (2006)232 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Miyashita M, et al (2003)233 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Monnier P, et al (1990)234 Study did not include outcomes of interest

138

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Table C 1. Excluded studies Study authors (year published) Main reason for exclusion Monnier P, et al (1994)235 Study did not include outcomes of interest Moorjani N, et al (2007)236 Study did not include outcomes of interest Morgan MA, et al (2007)237 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Morita M, et al (2008)238 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Murakami Y, et al (2007)239 Study did not include outcomes of interest Natsugoe S, et al (2006)240 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Nemoto K, et al (2005)241 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Oh DS, et al (2006)242 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Ohana M, et al (2005)243 Study did not include outcomes of interest Ohana M, et al (2005)244 Patients already included in study by “Ohana M, et al (2005)243” Ohana M, et al (2005)245 Patients already included in study by “Ohana M, et al (2005)243” Okuyama M, et al (2007)246 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Omloo JMT, et al (2007)247 Patients already included in study by “Westerterp M, et al (2005)147” Overholt B, et al (1993)248 Study presented a single case report Overholt BF, et al (1996)249 Patients already included in study by “Overholt BF, et al (1997)99” Oyama T, et al (2005)250 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Patrice T, et al (1990)251 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Pech O, et al (2004)230 Patients already included in study by “May A, et al (2003)229” Peters F, et al (2004)252 Patients already included in study by “Peters FP, et al (2005)253” Peters FP, et al (2005)253 Study included patients with Barrett’s esophagus and early esophageal cancer, and it was not possible to extract information for those with early esophageal cancer only Peters FP, et al (2005)254 Patients already included in study by “Peters FP, et al (2005)253” Peyre CG, et al (2007)153 Study included patients with Barrett’s esophagus and early esophageal cancer, and it was not possible to extract information for those with early esophageal cancer only Polee MB, et al (2003)255 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Portale G, et al (2006)256 Study did not include outcomes of interest Pouw RE, et al (2008)257 Study presented a single case report Pouw RE, et al (2008)258 Patients already included in study by “”Pouw RE, et al (2008)110” Pouw RE, et al (2008)259 Patients already included in study by “”Pouw RE, et al (2008)110” Pouw RE, et al (2008)260 Patients already included in study by “”Pouw RE, et al (2008)110” Pouw RE, et al (2008)261 Patients already included in study by “”Pouw RE, et al (2008)110” Rahmani EY, et al (2004)262 Study included patients with Barrett’s esophagus and early esophageal cancer, and it was not possible to extract information for those with early esophageal cancer only Rentz J, et al (2003)263 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Reynolds JV, et al (2006)264 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Rizzetto C, et al (2008)265 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Rohatgi PR, et al (2005)266 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Rutegard M, et al (2008)267 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Sanfilippo NJ, et al (2001)268 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Schaffer M, et al (1997)269 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only

139

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Table C 1. Excluded studies Study authors (year published) Main reason for exclusion Schembre DB, et al (2008)270 Study did not include outcomes of interest Seruga B, et al (2006)271 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Seung SK, et al (2004)272 Study did not include outcomes of interest Shimoyama S, et al (2006)273 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Smith BR, et al (2008)274 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Sonnenberg A, et al (2003)275 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Stahl M, et al (2008)276 Study did not include outcomes of interest Stein HJ, et al (2005)277 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Sun SP, et al (2006)278 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Tachibana M, et al (2003)279 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Tachibana M, et al (2007)280 Study did not include outcomes of interest Tajiri H, et al (1987)281 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Terrosu G, et al (2003)282 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Tetzlaff ED, et al (2008)283 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Tsuji N, et al (2003)205 Patients already included in study by “Lovat LB, et al (2005)91” Urba SG, et al (2003)284 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Van Heijl M, et al (2008)285 Study did not include outcomes of interest Van Meerten E, et al (2008)72 Patients already included in study by “Van Meerten E, et al (2006)231” Vuong T, et al (2005)286 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Walther B, et al (2003)287 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Wang KK (2002)288 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Wang H, et al (2007)289 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Wang S, et al (2008)290 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Wang SJ, et al (2008)291 Study presented a single case report Wolfsen HC, et al (2000)292 Patients already included in study by “Savoy AD, et al (2008)101” Wolfsen HC, et al (2002)293 Patients already included in study by “Savoy AD, et al (2008)101” Wolfsen HC, et al (2004)294” Patients already included in study by “Savoy AD, et al (2008)101” Wolfsen HC, et al (2004)295 Patients already included in study by “Wolfsen HC, et al (2004)294” Wolfsen HC, et al (2006)296 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Wood D, et al (1999)297 Study presented a single case report Yano T, et al (2005) 298 Patients already included in study by “Yano T, et al (2006) 101” Yoshinaga S, et al (2008) 299 Study included patients with cancer of the esophagogastric junction and did not include outcomes of interest Zingg U, et al (2007)300 Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only Possible reasons for exclusion: 1. Patients already included in study by “‐‐‐‐‐‐‐‐‐‐‐“ 2. Study included patients with all stages of cancer, and it was not possible to extract information for stages 0‐IIa only 3. Study did not include outcomes of interest 4. Study presented a single case report 5. Study included patients with several types of cancer, and it was not possible to extract information for those with esophageal cancer only

140

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta 6. Study included patients with Barrett’s esophagus and early esophageal cancer, and it was not possible to extract information for those with early esophageal cancer only

Please note: Review articles and other references used for background information have not been listed in the excluded studies table. Health technology assessments and guidance from other agencies are discussed separately and these reports are also not listed in the table.

141

Appendix D Safety (adverse events)

142

Table D 1. Adverse events/complications reported in studies of photodynamic therapy (PDT) for esophageal cancer Reported adverse events/complications (% of study sample) Tracheo‐ Treat‐ Pleural esophag Atrial Anast Abdominal ment Study authors No. of Photo‐ Steno Chest effusio eal Perforati Fever/ fibrilla Nausea/ Bleedi Renal omoti pain / related (year published) patients sensitivity Stricture sis pain n fistula on infection tion vomiting ng toxicity c leak diarrhoea death Comparative studies Pacifico RJ, et al 88 (2003)107 EMR + photodynamic 24 4% 8% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% therapy (PDT) vs 64 0% 16% 0% 0% 0% 0% 0% 8% 3% 0% 3% 0% 8% 5% 2% Esophagectomy Pooled total n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a Non‐comparative studies Corti L, et al 62 8% 0% 5% 0% 0% 2% 0% 0% 0% 0% 0% 0% 0% 0% 0% (2000)82 Craig C, et al 28 Not “majority” Not “most” Not Not Not Not Not Not Not Not Not Not Not (2007)83 eported reported reported reported reported reporte repo reported reported reporte reporte reporte reporte d rted d d d d DuVall GA, et al 5 0% 40% 0% 0% 20% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% (1996)84 Etienne J, et al 7 14% 14% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% (2004)85 Foroulis C, et al 6 Not 33% 0% 0% 16% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% (2006)86 reported Gossner L, et al 58 Not Not Not Not Not Not Not Not Not Not Not Not Not Not Not (1999)87 reported reported reported reported reported reported reported reporte repo reported reported reporte reporte reporte reporte d rted d d d d Gossner L, et al 18 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% (1999)88 Jamieson NF, et al 4 Not Not Not Not Not Not Not Not Not Not Not Not Not Not Not (2002)89 reported reported reported reported reported reported reported reporte repo reported reported reporte reporte reporte reporte d rted d d d d Keeley SB, et al 36 Not “Most Not Not Not Not Not Not Not Not Not Not Not Not 0% (2007)90 reported common” reported reported reported reported reported reporte repo reported reported reporte reporte reporte d rted d d d Lovat LB, et al 11 0% 9% 0% 0% 0% 9% 0% 0% 0% 0% 0% 0% 0% 0% 0% (2005)91 Maunoury V, et al 24 0% 0% 25% “some” 0% 0% 4% 0% 0% 0% 0% 0% 0% 0% 4%# (2005)92

143

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta McCaughan JS, et al 19 Not Not Not Not Not Not Not Not Not Not Not Not Not Not Not * (1996)93 reported reported reported reported reported reported reported reporte repo reported reported reporte reporte reporte reporte d rted d d d d Messmann H, et al 4 0% 0% 75% 0% 0% 0% 0% 25% 0% 0% 0% 0% 0% 0% 0% (1997)94 Moghissi K, Dixon K 18 0% 11% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% (2003)95 Nakamura T, et al 7 0% 0% 0% 14% 0% 0% 0% 14% 0% 0% 0% 0% 0% 0% 0% (2004)96 Okunaka T, et al * 6 Not Not Not Not Not Not Not Not Not Not Not Not Not Not Not (1990)97 reported reported reported reported reported reported reported reporte repo reported reported reporte reporte reporte reporte d rted d d d d Overholt BF, et al 5 0% 20% 0% 100% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% (1995)98 Overholt BF, et al 1 Not Not Not Not Not Not Not Not 100 Not Not Not Not Not Not (1997)99 reported reported reported reported reported reported reported reporte % reported reported reporte reporte reporte reporte d d d d d Overholt BF, et al* 9 Not Not Not Not Not Not Not Not Not Not Not Not Not Not Not (2003)100 reported reported reported reported reported reported reported reporte repo reported reported reporte reporte reporte reporte d rted d d d d Savoy AD, et al 17 Not Not Not Not Not Not Not Not Not Not Not Not Not Not Not (2008)101 reported reported reported reported reported reported reported reporte repo reported reported reporte reporte reporte reporte d rted d d d d Shim C, et al 9 Not Not Not Not Not Not Not Not Not Not Not Not Not Not Not (2007)102 reported reported reported reported reported reported reported reporte repo reported reported reporte reporte reporte reporte d rted d d d d Tan WC, et al 12 9% 0% 0% 50% 0% 0% 0% 0% 0% 50% 0% 0% 0% 0% 0% (1999)103 Yachimski P, et al 57 Not 19% Not Not Not Not Not Not Not Not Not Not Not Not Not (2008)104 reported reported reported reported reported reported reporte repo reported reported reporte reporte reporte reporte d rted d d d d Yano T, et al 27 0% 52% 0% 0% 0% 0% 7% 0% 0% 0% 0% 0% 0% 0% 0% (2006)105 Yoshida K, et al 6 0% 0% 0% 0% 0% 0% 0% 17% 0% 0% 17% 33% 17% 33% 0% (1998)106 Pooled total 456 3% 13% 6% 7% 0.5% 1% 1% 2% 0.5% 1% 0.5% 1% 1% 1% 0.5% *No information was reported on adverse events for early esophageal cancer patients (i.e., Stages 0, I, II, and IIA) only # Patient had extrinsic compression of the esophagus and died from a perforation due to the PDT procedure

144

Table D 2. Adverse events/complications reported in studies of argon plasma coagulation (APC) for esophageal cancer Reported adverse events/complications (% of study sample) Treatmen Study authors Esophageal Esophageal Hematolog Pain on Pneumoniti Respirator Stenosi t related (year published) No. of patients Angina Esophagitis fistula ulcer Fatigue ic toxicity swallowing s y distress s death Other Non‐comparative studies Nomura T, et al Not Not Not Not Not Not Not Not Not Not Not Not (2007)108 8 reporte reporte reporte reporte reported reported reported reported reported reported reported reported d d d d Van Laethem JL, et al (2001) 3 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0%

Pooled total 11 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a Comparative studies None

145

Table D 3. Adverse events/complications reported in studies of cryoablation for esophageal cancer Reported adverse events/complications (% of study sample) Treatmen Study authors Esophageal Esophageal Hematolog Pain on Pneumoniti Respirator Stenosi t related (year published) No. of patients Perforation Esophagitis fistula ulcer Fatigue ic toxicity swallowing s y distress s death Other Non‐comparative studies Dumot JA, et al Not Not Not Not Not Not Not Not Not Not Not Not (2008)68 23 reporte reporte reporte reporte reported reported reported reported reported reported reported reported d d d d Pooled total n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a Comparative studies None

146

Table D 4. Adverse events/complications reported in studies of radiofrequency ablation (RFA) for esophageal cancer Reported adverse events/complications (% of study sample) Treatmen Study authors Esophageal Esophageal Hematolog Pain on Pneumoniti Respirator Stenosi t related (year published) No. of patients Dysphagia Esophagitis fistula ulcer Fatigue ic toxicity swallowing s y distress s death Other Non‐comparative studies Pouw RE, et al Not Not Not Not Not Not Not Not Not Not Not Not (2008)110 16 reporte reporte reporte reporte reported reported reported reported reported reported reported reported d d d d Pooled total n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a Comparative studies None

147

Table D 5. Adverse events/complications reported in studies of endoscopic mucosal resection (EMR) for esophageal cancer Reported adverse events/complications (% of study sample) Study authors (year published) No. of patients Bleeding Hematoma Stenosis Strictures Comparative studies Ishihara R, et al (2008)121 70

EMR 44 Not Not Not Not vs reported reported reported reported Endoscopic submucosal dissection (ESD) 26 Tanabe S, et al (2004)122 66

Endoscopic Oblique Aspiration 39 3% 3% 8% 0% Mucosectomy (EOAM) vs Strip biopsy 27 7% 0% 0% 0% Pooled total 136 n/a n/a n/a n/a Non‐comparative studies Not Not Not Not Conio M, et al (2005)*111 4 reported reported reported reported Ell C, et al (2007)112 100 11% 0% 0% 0% Giovannini M, et al (2004)113 9 11% 0% 0% 0% Katada C, et al (2007)114 104 11% 0% 9% 0% Not Not Not Not Lopes CV, et al (2007)*115 23 reported reported reported reported Manner H, et al (2007)116 19 5% 0% 0% 0% Not Not Not Not Pech O, et al (2007) 117 53 reported reported reported reported Seewald S, et al (2003)*118 4 0% 0% 0% 50% Shimizu Y, et al (2006)119 15 0% 0% 0% 0% Tanabe S, et al (2008)120 85 1% 3% 9% 0% Pooled total 4174 7% 1% 6% 0.5% *No information was reported on adverse events for early esophageal cancer patients (Stages 0, I, II, and IIA) only

148

Table D 6. Adverse events/complications reported in studies of chemotherapy for esophageal cancer Reported adverse events/complications (% of study sample) Treat‐ ment Study authors No. of Esophageal Esophage Hematologic Pain on Respiratory related (year published) patients Angina Esophagitis fistula al ulcer Fatigue toxicity swallowing Pneumonitis distress Stenosis death Other Comparative studies Heroor K, et al* 75 (2003)123

Not Not Not Not Not Not Not Not Not Not Not Not Surgery + 15 reported reported reported reported reported reported reported reported reported reported reported reported Chemotherapy (CT) vs 60 Surgery Malaisrie SC, et al* 118 (2006)124

CT + 56 Not Not Not Not Not Not Not Not Not Not Not Not chemoradiotherapy reported reported reported reported reported reported reported reported reported reported reported reported (CRT) + surgery vs CRT + surgery 62 Nemoto K, et al 141 (2006)125 Not Not Not Not Not Not Not Not r Not Not Not 2%† Radiotherapy (RT) 57 reported reported reported reported reported reported reported eported reported reported reported vs RT + CT 84 Pooled total 3 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a 34 Non‐comparative studies None *No information was reported on adverse events for early esophageal cancer patients (i.e., Stages 0, I, II, and IIA) only

149

Table D 7. Adverse events/complications reported in studies of external beam radiotherapy (EBRT) and/or brachytherapy (BT) for esophageal cancer Reported adverse events/complications (% of study sample) Pain on Treatmen Study authors No. of Esophageal Esophageal swallowin Fatigu Respirator Perforatio t related (year published) patients Esophagitis ulcer fistula Stenosis Pneumonitis Angina g e y distress n death Other Comparative studies Ishikawa H, et al 68 15%† 0% 3%† None (2006)130

EBRT 32 vs 0% 0% 0% 0% 0% 0% 0% 0% 0% EBRT + low dose BT vs 19 EBRT + high dose BT 21% 5% 0% 0% 0% 0% 0% 0% 5%

17 6% 6% 0% 0% 0% 0% 0% 0% 6% Sai H, et al (2005)131 34

EBRT 7 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% None vs EBRT + high dose BT 27 0% 0% 4% 4% 0% 0% 0% 0% 0% 0% 4% Pooled total 243 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a Non‐comparative studies Kawashima M, et al 51 0% 0% 0% 0% 2% 2% 4% 2% 4% 0% 6% None (2006)126 Kodaira T, et al (2003)127 33 0% 0% 3% 0% 0% 0% 0% 0% 0% 3% 0% None Sugahara S, et al (2005)128 23 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% None

Zhao K‐L, et al (2004)129 Not Not Not 54 Not Not Not Not Not Not Not Not Not reporte reporte reporte reported reported reported reported reported reported reported reported reported d d d Pooled total 161 0% 0% 1% 0% 1% 1% 2% 1% 2% 1% 3% n/a *No information was reported on adverse events for early esophageal cancer patients (Stages 0, I, II, and IIA) only † Summary value across study groups – no treatment specific values presented

150

Table D 8. Adverse events/complications reported in studies of chemoradiotherapy (CRT) for esophageal cancer Reported adverse events/complications (% of study sample) Acute hematologic toxicity (e.g., anemia, Treatment Study authors No. of Esophageal Esophageal Pericardial Renal leukopenia, related (year published) patients Esophagitis ulcer fistula Stricture Effusion Toxicity Hypothyroidism thrombocytopenia, etc.) deaths Other Comparative studies De Manzoni G, et al* 79 (2005)135,135 Low dose CRT + Surgery 47 Not Not Not Not Not Not Not Not Not None vs reported reported reported reported reported reported reported reported reported High dose CRT + 32 Surgery Hironaka S, et al 53 Pneumonitis: (2003)136 31 0% 0% 0% 0% 0% 0% 0% 0% 7% 0% Surgery vs 22 50% 0% 0% 0% 0% 0% 0% 27% 0% 9% CRT Pooled total 132 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a Non‐comparative studies Czito BG, et al 2 50% 50% 0% 0% 0% 0% 0% 0% 0% None (2007) 132 Sato Y, et al* Not Not Not Not Not Not Not Not 7 0% None (2006)133 reported reported reported reported reported reported reported reported Wang S, et al (2006)134 Not Not Not Not Not Not Not Not Not 11 None reported reported reported reported reported reported reported reported reported Yamada K, et al Anemia: 16% (2006)71 63 29% 21% 3% 3% 5% 14% 8% Leukopenia: 67% 2% None

Thrombocytopenia: 6% Pooled total 83 30% 22% 3% 3% 5% 14% 8% 61% 1% n/a *No information was reported on adverse events for early esophageal cancer patients (Stages 0, I, II, and IIA) only

151

Table D 9. Adverse events/complications reported in studies of chemoradiotherapy (CRT) and surgery (esophagectomy) for esophageal cancer Reported adverse events/complications (% of study sample) Acute hematologic toxicity Treatment Study authors No. of Esophageal Esophageal Pericardial Renal (e.g., anemia, leukopenia, related (year published) patients Esophagitis ulcer fistula Stricture Effusion Toxicity Hypothyroidism thrombocytopenia, etc.) deaths Other Comparative studies De Manzoni G, et al* 79 (2005)135,135 Not Not Not Not Not Not Not Not Not Low dose CRT + Surgery 47 None reported reported reported reported reported reported reported reported reported vs High dose CRT + Surgery 32 Pooled total n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a Non‐comparative studies Donahue JM, et al Not Not Not Not Not Not Not Not Not 12 None (2009)74 reported reported reported reported reported reported reported reported reported Pooled total n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a

152

Table D 10. Adverse events/complications reported in studies of surgery (esophagectomy) for esophageal cancer Reported adverse events / complications (% of study sample) Pulmo‐ Respira‐ nary Treat‐ Diaphrag‐ Cardiac tory Deep vein thrombo ment‐ Study authors No. of Anastom‐ Atrial Bleed‐ matic Dumping Emphy‐ complic‐ Nerve Pleural compli‐ thrombo‐ embol‐ Wound related (year published) patients otic leak fibrillation ing hernia syndrome sema ations palsy effusion cations sis ism Stricture infection death Comparative studies Benzoni E, et al* 10 (2007)150 Transhiatal laparoscopic 6 esophagectomy Not Not Not Not Not Not Not Not Not Not Not Not Not Not Not vs reported reported reported reported reported reported reported reported reported reported reported reported reported reported reported Laparoscopic esophagectomy 4 with right transthoracic approach Braghetto I, et al* 38 (2006)151 Open 12 Not Not Not Not Not Not Not Not Not Not Not Not Not Not Not esophagectomy reported reported reported reported reported reported reported reported reported reported reported reported reported reported reported vs Minimally invasive 26 esophagectomy Heroor A, et al* 75 (2003)123 Chemotherapy Not Not Not Not Not Not Not Not Not Not Not Not Not Not Not (CT) + 15 reported reported reported reported reported reported reported reported reported reported reported reported reported reported reported Esophagectomy vs 60 Esophagectomy Hironaka S, et al 53 (2003)136 Not Not Not Not Not Not Not Not Not Not Not Not Not Not Not Surgery 31 reported reported reported reported reported reported reported reported reported reported reported reported reported reported reported vs CRT 22 Javle MM, et al* 72 (2006)152 Esophagectomy 25 vs CT + radiotherapy 17 Not Not Not Not Not Not Not Not Not Not Not Not Not Not Not (RT) + reported reported reported reported reported reported reported reported reported reported reported reported reported reported reported esophagectomy vs 30 CT + radiotherapy (RT)

153

Transhiatal 35 esophagectomy vs 29

Vagal sparing esophagectomy Not Not Not Not Not Not Not Not Not Not Not Not Not Not Not vs 21 reported reported reported reported reported reported reported reported reported reported reported reported reported reported reported En bloc Smithers BM, et 170 al* (2007)154 Open transthoracic 25 esophagectomy vs Thoracoscopic 139 assisted esophagectomy vs Laparoscopic 6 Not Not Not Not Not Not Not Not Not Not Not Not Not Not Not esophagectomy reported reported reported reported reported reported reported reported reported reported reported reported reported reported reported Pooled total 570 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a Non‐comparative studies Alexiou C, et al* Not Not Not Not Not Not Not Not Not Not Not Not Not Not 212 None (2006)138 reported reported reported reported reported reported reported reported reported reported reported reported reported reported Egberts JH, et al Not Not Not Not Not Not Not Not Not Not Not Not Not Not Not 41 (2008)139 reported reported reported reported reported reported reported reported reported reported reported reported reported reported reported Mariette C, et Not Not Not Not Not Not Not Not Not Not Not Not Not Not 139 None al* (2004)140 reported reported reported reported reported reported reported reported reported reported reported reported reported reported Moraca RJ, Low Not Not Not Not Not Not Not Not Not Not Not Not Not Not Not 25 DE* (2006)141 reported reported reported reported reported reported reported reported reported reported reported reported reported reported reported Nguyen N, et al* Not Not Not Not Not Not Not Not Not Not Not Not Not Not 26 None (2003)142 reported reported reported reported reported reported reported reported reported reported reported reported reported reported Thomson BNJ, 12 Not Not Not Not Not Not 36% 9% Not 55% 9% Not Not Not None 154

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Table D 10. Adverse events/complications reported in studies of surgery (esophagectomy) for esophageal cancer Reported adverse events / complications (% of study sample) Pulmo‐ Respira‐ nary Treat‐ Diaphrag‐ Cardiac tory Deep vein thrombo ment‐ Study authors No. of Anastom‐ Atrial Bleed‐ matic Dumping Emphy‐ complic‐ Nerve Pleural compli‐ thrombo‐ embol‐ Wound related (year published) patients otic leak fibrillation ing hernia syndrome sema ations palsy effusion cations sis ism Stricture infection death Cade RJ* reported reported reported reported reported reported reported reported reported reported (2003)143 Udagawa H, et Not Not Not Not Not Not Not Not Not Not Not Not Not Not Not al* 187 reported reported reported reported reported reported reported reported reported reported reported reported reported reported reported (2007)144 Wang H‐W, et Not Not Not Not Not Not Not Not Not Not Not Not Not Not Not 42 al*(2004)145 reported reported reported reported reported reported reported reported reported reported reported reported reported reported reported Wang GQ, et 76 Not Not Not Not Not Not Not Not Not Not Not Not Not Not Not Al (2004)146 reported reported reported reported reported reported reported reported reported reported reported reported reported reported reported Westerterp M, Not Not Not Not Not Not Not Not Not Not Not Not Not Not Not 66 et al* (2005)147 reported reported reported reported reported reported reported reported reported reported reported reported reported reported reported Wolfsen HC, Hemminger LL, Not Not Not Not Not Not Not Not Not Not Not Not Not Not Not 6 DeVault RR* reported reported reported reported reported reported reported reported reported reported reported reported reported reported reported (2004)148 Yamamoto S, et Not Not Not Not Not Not Not Not Not Not Not Not Not Not Not 47 al* (2005)149 reported reported reported reported reported reported reported reported reported reported reported reported reported reported reported Pooled total 879 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a *No information was reported on adverse events for early esophageal cancer patients (Stages 0, I, II, and IIA) only

155

Appendix E Efficacy / effectiveness tables

156

Table E 1. Treatment response and tumour recurrence in patients receiving photodynamic therapy (PDT) for esophageal cancer Treatment Response (% of study sample) Recurrence groups/ (% of patients with response) Favors Study / Cell type No. of patients Complete Partial Minimal/none Favors PDT comparator Comparative studies Pacifico RJ, et al (2003)107 PDT 24 83%

Esophagectom 100% Not reported Not reported 0% Neither y 64 Pooled total n/a n/a n/a n/a Non‐comparative studies Corti L, et al (2000)82 ∙ Adenocarcinoma 62 37% 48% 15% Not reported n/a ∙ Squamous cell carcinoma

Craig C, et al (2007)83 ∙ Adenocarcinoma 28 64% Not reported Not reported 61% n/a ∙ Squamous cell carcinoma

DuVall GA, et al (1996)84 ∙ Adenocarcinoma 5 Not reported Not reported Not reported 40% n/a ∙ Squamous cell carcinoma

Etienne J, et al (2004)85 ∙ Adenocarcinoma 7 100% Not reported Not reported 0% n/a

Foroulis C, et al (2006)86 ∙ Adenocarcinoma 6 33% 50% 17% Not reported n/a

Gossner L, et al (1999)87 58 74% Not reported Not reported 23% n/a ∙ Squamous cell carcinoma

Gossner L, et al (1999)88 ∙ Squamous cell carcinoma 18 53% 47% Not reported 10% n/a

Jamieson NF, et al (2002)89 ∙ Adenocarcinoma 4 75% Not reported Not reported Not reported n/a

Keeley SB, et al (2007)90 ∙ Adenocarcinoma 36 28%† Not reported 64%† 58%* n/a ∙ Squamous cell carcinoma

Lovat LB, et al (2005)91 11 9% 46% Not reported Not reported n/a 157

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Table E 1. Treatment response and tumour recurrence in patients receiving photodynamic therapy (PDT) for esophageal cancer Treatment Response (% of study sample) Recurrence groups/ (% of patients with response) Favors Study / Cell type No. of patients Complete Partial Minimal/none Favors PDT comparator ∙ Adenocarcinoma

Maunoury V, et al (2005)92 ∙ Adenocarcinoma 24 75% Not reported Not reported 17% n/a ∙ Squamous cell carcinoma

McCaughan JS, et al (1996) 93 ∙ Adenocarcinoma 19 88% Not reported Not reported 14% n/a ∙ Squamous cell carcinoma

Messmann H, et al (1997)94 4 100% Not reported Not reported 0% n/a ∙ Squamous cell carcinoma Moghissi K, Dixon K (2003)95 ∙ Adenocarcinoma 18 94% 6% Not reported Not reported n/a ∙ Squamous cell carcinoma

Nakamura T, et al (2004)96 ∙ Adenocarcinoma 7 100% Not reported Not reported 0% n/a ∙ Squamous cell carcinoma

Okunaka T, et al (1990)97 ∙ Squamous cell carcinoma 6 67% 33% Not reported Not reported n/a

Overholt BF, et al (1995)98 ∙ Adenocarcinoma 5 100% Not reported Not reported 20% n/a

Overholt BF, Panjehpour M, Ayers M (1997)99 1 100% Not reported Not reported Not reported n/a ∙ Adenocarcinoma

Overholt BF, Panjehpour M, Halberg DL (2003)100 9 33% Not reported Not reported Not reported n/a ∙ Adenocarcinoma

Savoy AD, et al (2008)101 ∙ Adenocarcinoma 17 100% Not reported Not reported 0% n/a

Shim C, et al (2007)102 ∙ Adenocarcinoma 9 89% Not reported Not reported 13% n/a ∙ Squamous cell carcinoma

158

Yachimski P, Puricelli WP, Nishioka NS (2008)104 57 Not reported Not reported Not reported Not reported n/a ∙ Adenocarcinoma

Yano T, et al (2006)105 T1: 86% ∙ Cell type not reported 27 Not reported Not reported Not reported n/a T2: 46%

Yoshida K, et al (1998)106 ∙ Cell type not reported 6 100%† Not reported Not reported Not reported n/a

Pooled total 456 n/a n/a Studies of adenocarcinoma: 54% 3% Studies of squamous cell carcinoma: 71% 19% Studies including both: 69% 28% * Study reported pooled values across treatment groups only, since differences between groups were not statistically significant † Reported as % of tumours

159

Table E 2. Treatment response and tumour recurrence in patients who received argon plasma coagulation (APC) for esophageal cancer Treatment groups/ Response (% of study sample) Recurrence (% of patients with Favors Study / Cell type No. of patients Complete Partial None response) APC Favors comparator Non‐comparative studies Nomura T, et al (2007)108

8 Not reported Not reported Not reported 25% n/a Squamous cell carcimoma

Van Leethem JL, et al (2001)109 3 100% Not reported Not reported 0% n/a Adenocarcinoma

Pooled total n/a n/a n/a 18% n/a Comparative studies None * No information was reported for early esophageal cancer patients (Stages 0, I, II, and IIA) only

160

Table E 3. Treatment response and tumour recurrence in patients who received cryoablation for esophageal cancer Treatment groups/ Response (% of study sample) Recurrence (% of patients Favors Study / Cell type No. of patients Complete Partial Minimal/none with response) Cryoablation Favors comparator Non‐comparative studies Dumot JA, et al (2008)68

23 75% Not reported Not reported 0% n/a ∙ Adenocarcinoma ∙ Squamous cell carcinoma Pooled total n/a n/a n/a n/a Comparative studies None

161

Table E 4. Treatment response and tumour recurrence in patients who received radiofrequency ablation (RFA) for esophageal cancer Treatment groups/ Response (% of study sample) Recurrence (% of patients Study / Cell type No. of patients Complete Partial None with response) Favors RFA Favors comparator Non‐comparative studies Pouw RE, et al (2008)110 ∙ Adenocarcinoma 16 100% Not reported Not reported 0% n/a ∙ Squamous cell carcinoma Pooled total n/a n/a n/a n/a n/a Comparative studies None

162

Table E 5. Treatment response and tumour recurrence in patients receiving endoscopic mucosal resection (EMR) for esophageal cancer Treatment groups/ Response (% of study sample) Recurrence Favors Study / Cell type no. of patients Complete Partial None (% of patients with response) Favors EMR comparator Comparative studies Ishihara R, et al ∙ EMR / 44 (2008)121 24% Squamous cell carcinoma ∙ Endoscopic Not reported Not reported Not reported submucosal  3% dissection (ESD) / 26

Tanabe S, et al ∙ Endoscopic Oblique (2004)122 Aspiration 74% Mucosectomy Not reported Not reported Not reported Squamous cell carcinoma (EOAM) / 39 Neither 70% ∙ Strip biopsy/27 Pooled total n/a n/a n/a n/a Non‐comparative studies Conio M, et al (2005)*111 Adenocarcinoma 4 100% Not reported Not reported 0% n/a

Ell C, et al (2007)112 Adenocarcinoma 100 99% Not reported Not reported 11% n/a

Giovannini M, et al (2004)113 9 67% Not reported Not reported Not reported n/a Cell type not reported Katada C, et al (2007)114 104 Not reported Not reported Not reported 21%† n/a Squamous cell carcinoma Lopes CV, et al (2007)*115 23 Not reported Not reported Not reported 9% n/a Adenocarcinoma Manner H, et al (2008)116 Adenocarcinoma 19 95% Not reported Not reported 28% n/a

Pech O, et al (2007) 117 53 96% Not reported Not reported 28% n/a Squamous cell carcinoma Seewald S, et al (2003)118 4 Not reported Not reported Not reported 0%† n/a Adenocarcinoma Shimizu Y, et al (2006)119 n/a Squamous cell carcinoma 16 Not reported Not reported Not reported Not reported

Tanabe S, et al (2008)120 85 83% Not reported Not reported 7% n/a Squamous cell carcinoma

163

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Table E 5. Treatment response and tumour recurrence in patients receiving endoscopic mucosal resection (EMR) for esophageal cancer Treatment groups/ Response (% of study sample) Recurrence Favors Study / Cell type no. of patients Complete Partial None (% of patients with response) Favors EMR comparator

Pooled total 417 93% n/a n/a Studies of adenocarcinoma: Studies of squamous cell 98% 13% n/a carcinoma: Studies including both: 88% 16% 67% Not reported * Study reported pooled values across treatment groups only, since differences between groups were not statistically significant † Reported as % of tumours

164

Table E 6. Treatment response and tumour recurrence in patients who received chemotherapy (CT) for esophageal cancer Response (% of study sample) Recurrence Favors Study / Cell type Treatment groups Complete Partial None (% of patients with response) Favors CT comparator Comparative studies Heroor K, et al ∙ Surgery + Chemotherapy (2003)123 (CT) Not reported Not reported Not reported Not reported n/a

∙ Surgery Malaisrie SC, et al ∙ CT + chemoradiotherapy (2006)124 (CRT) + surgery Not reported Not reported Not reported Not reported n/a ∙ CRT + surgery

Nemoto K, et al ∙ Radiotherapy (RT) (2006)125 ∙ RT + CT Not reported Not reported Not reported Not reported n/a

Pooled total n/a n/a n/a n/a Non‐comparative studies None

165

Table E 7. Treatment response and tumour recurrence in patients receiving external beam radiotherapy (EBRT) or brachytherapy (BT) for esophageal cancer Treatment groups/ Response (% of study sample) Recurrence Favors Favors Study / Cell type no. of patients Complete Partial None (% of patients with response) radiotherapy comparator Comparative studies Ishikawa H, et al ∙ EBRT (2006)130 ∙ EBRT + low dose 80%* 21%* BT Not reported Not reported Neither Squamous cell carcinoma ∙ EBRT + high dose BT

Sai H, et al (2005)131 ∙ EBRT ∙ EBRT + high dose Not reported Not reported Not reported 27%* Neither Squamous cell carcinoma BT

Pooled total n/a n/a n/a n/a Non‐comparative studies Kawashima M, et al T1: 83% (2006)126 51 T2: 50% Not reported Not reported Squamous cell carcinoma Not reported T3: 48%

Kodaira T, et al

(2003)127 Not reported 33 Not reported Not reported Squamous cell carcinoma Not reported

Sugahara S, et al (2005)128 Squamous cell carcinoma 23 100% Not reported Not reported 23% Adenocarcinoma Zhao K‐L, et al (2004)129 54 100% 59% Squamous cell carcinoma Not reported Not reported Pooled total 161 n/a n/a Studies of adenocarcinoma: Not reported Not reported Studies of squamous cell carcinoma: 81% 59% Studies including both: 100% 23% * Study reported pooled values across treatment groups only, since differences between groups were not statistically significant

166

Table E 8. Treatment response and tumour recurrence in patients receiving chemoradiotherapy (CRT) for esophageal cancer Treatment groups/ Response (% of study sample) Recurrence Favors Study / Cell type no. of patients Complete Partial Minimal/none (% of patients with response) Favors CRT comparator Comparative studies De Manzoni G, et al* (2005)72 ∙ Low dose CRT + Squamous cell carcinoma Surgery Not reported Not reported Not reported Not reported n/a ∙ High dose CRT + Surgery Hironaka S, et al (2003)136 ∙ Surgery Not reported Not reported Not reported Not reported n/a Squamous cell carcinoma ∙ CRT Pooled total n/a n/a n/a n/a n/a Non‐comparative studies Czito BG, et al (2007) 132 Adenocarcinoma 2 50% ‐ 50% Not reported n/a Squamous cell carcinoma Sato Y, et al* (2006)133 Stage I: 100% 7 Not reported Not reported Not reported n/a Squamous cell carcinoma Stage II: 67% Wang S, et al (2006)134 Adenocarcinoma 11 82% Not reported Not reported Not reported n/a Squamous cell carcinoma Yamada K, et al (2006)71 63 Not reported Not reported 35% Not reported n/a Squamous cell carcinoma Pooled total 161 Studies of adenocarcinoma: Not reported Studies of squamous cell n/a n/a n/a n/a carcinoma: 86% Studies including both: 77%

167

Table E 9. Treatment response and tumour recurrence in patients receiving chemoradiotherapy (CRT) and surgery (esophagectomy) for esophageal cancer Treatment groups/ Response (% of study sample) Recurrence Favors CRT + Favors Study / Cell type no. of patients Complete Partial None (% of patients with response) surgery comparator Comparative studies ∙ Low dose CRT + Surgery De Manzoni G, et al* (2005)72 ∙ High dose CRT + Not reported Not reported Not reported Not reported n/a

Surgery Pooled total 79 n/a n/a n/a n/a n/a Non‐comparative studies Donahue JM, et al 12 Not reported Not reported Not reported Not reported n/a (2009)74 Pooled total n/a n/a n/a n/a n/a

168

Table E 10. Treatment response and tumour recurrence in patients who underwent surgery (esophagectomy) for esophageal cancer Response (% of study sample) Recurrence Treatment groups/ (% of patients with Study / Cell type no. of patients Complete Partial None response) Favors surgery Favors comparator Comparative studies Benzoni E, et al (2007)150 ∙ Transhiatal Adenocarcinoma laparoscopic Squamous cell carcinoma esophagectomy ∙ Laparopscopic esophagectomy Not reported Not reported Not reported Not reported n/a with right transthoracic approach

Braghetto I, et al (2006)151 ∙ Minimally Adenocarcinoma invasive Squamous cell carcinoma esophagectomy (MIE) ∙ Transthoracic or Not reported Not reported Not reported Not reported n/a transhiatal esophagectomy (Open)

Heroor A, et al (2003)123 ∙ Esophagectomy Squamous cell carcinoma ∙ Esophagectomy Not reported Not reported Not reported Not reported n/a + CT Hironaka S, et al (2003)136 ∙ Surgery Squamous cell carcinoma ∙ CRT Not reported Not reported Not reported Not reported n/a

Javle MM, et al (2006)152 ∙ Esophagectomy Adenocarcinoma ∙ Chemotherapy + Squamous cell carcinoma radiotherapy + Not reported Not reported Not reported Not reported n/a esophagectomy ∙ Chemotherapy + radiotherapy Pacifico RJ, et al * ∙ Endoscopic (2003)107 mucosal resection Adenocarcinoma (EMR) and 83% Not reported Not reported Not reported Neither photodynamic therapy (PDT) 100% ∙ Esophagectomy Peyre CG, et al ∙ Transhiatal Not reported Not reported Not reported Neither (2007)153 esophagectomy 0%

169

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Table E 10. Treatment response and tumour recurrence in patients who underwent surgery (esophagectomy) for esophageal cancer Response (% of study sample) Recurrence Treatment groups/ (% of patients with Study / Cell type no. of patients Complete Partial None response) Favors surgery Favors comparator Adenocarcinoma (THE) ∙ En bloc resection 5% (En bloc) ∙ Vagal‐sparing 0% esophagectomy (VSE)

Smithers BM, et al ∙ Open (2007)154 transthoracic Adenocarcinoma esophagectomy Squamous cell carcinoma ∙ Thoracoscopic assisted Not reported Not reported Not reported Not reported n/a esophagectomy ∙ Laparoscopic esophagectomy

Pooled total n/a n/a n/a n/a n/a Non‐comparative studies Alexiou C, et al (2006)138 Adenocarcinoma 212 Not reported Not reported Not reported Not reported n/a Squamous cell carcinoma

Egberts JH, et al (2008)139 Adenocarcinoma 41 Not reported Not reported Not reported Not reported n/a Squamous cell carcinoma

Mariette C, et al (2004)140 Adenocarcinoma 139 Not reported Not reported Not reported Not reported n/a Squamous cell carcinoma

Moraca RJ, Low DE* (2006)141 Adenocarcinoma 25 Not reported Not reported Not reported 8% n/a Squamous cell carcinoma

Nguyen N, et al (2003)142 Adenocarcinoma 26 Not reported Not reported Not reported 31% n/a Squamous cell carcinoma

Thomson BNJ, Cade RJ 12 Not reported Not reported Not reported Not reported n/a (2003)143

170

Udagawa H, et al (2007)144 Adenocarcinoma 187 Not reported Not reported Not reported Not reported n/a Squamous cell carcinoma

Wang H‐W, et al (2004)145 Squamous cell carcinoma 42 Not reported Not reported Not reported Not reported n/a

Wang GQ, et al (2004)146 Not reported 76 Not reported Not reported Not reported Not reported n/a

Westerterp M, et al (2005)147 66 Not reported Not reported Not reported 0% n/a Adenocarcinoma

Wolfsen HC, Hemminger LL, DeVault KR* (2004)148 6 Not reported Not reported Not reported 33% n/a Adenocarcinoma

Yamamoto S, et al (2005)149 47 Not reported Not reported Not reported Not reported n/a Adenocarcinoma Squamous cell carcinoma Pooled total Studies of adenocarcinoma: 3% Studies of squamous cell n/a n/a n/a Not reported n/a carcinoma: 20% Studies including both: * No information was reported for early esophageal cancer patients (Stages 0, I, II, and IIA) only

171

Appendix F Evidence tables: survival

172

Table F 1. Survival rates in studies of photodynamic therapy (PDT) for esophageal cancer Overall Overall survival / Cause‐specific survival (% of study sample) Median survival at Cause‐specific survival at end of survival at end Treatment end of follow‐up (% of follow‐up groups/ follow‐up of study (% of study Favors Favors Study / Cell type No. of patients (months) sample) sample) 1 year 2 years 3 years 4 years 5 years 10 years PDT comparator Comparative studies Pacifico RJ, et al ∙ PDT / 24 Not Not Not Not Not Not Not Not Not (2003)107 ∙ Esophagectomy reported reported reported eported reported reported reported reported reported / 64 Pooled value n/a n/a n/a n/a n/a n/a n/a n/a n/a Non‐comparative studies Corti L, et al * (2000)82 Not Not Not Not Not Not Not Not 62 37 months n/a reported reported reported reported reported reported reported reported ∙ Adenocarcinoma ∙ Squamous cell carcinoma Craig C, et al (2007)83 68% 79% Not Not Not Not Not Not 28 25 (2‐56 (2‐56 n/a ∙ Adenocarcinoma reported reported reported reported reported reported months) months) ∙ Squamous cell carcinoma DuVall GA, et al* (1996)84 Not Not Not Not Not Not Not Not Not 5 n/a reported reported reported reported reported reported reported reported reported ∙ Adenocarcinoma ∙ Squamous cell carcinoma Etienne J, et al (2004)85 57% 100% Not 100% / Not Not Not Not Not 7 (12‐68 (12‐68 n/a reported 100% reported reported reported reported reported ∙ Adenocarcinoma months) months) Foroulis C, et al (2006)86 Not Not Not Not Not Not 6 100% 83% 67% n/a reported reported reported reported reported reported ∙ Adenocarcinoma Gossner L, et al* (1999)88 Not Not Not Not Not Not Not Not Not 18 n/a reported reported reported eported reported reported reported reported reported ∙ Squamous cell carcinoma Jamieson NF, et al* (2002)89 Not Not Not Not Not Not Not Not Not 4 n/a reported reported reported eported reported reported reported reported reported ∙ Adenocarcinoma Keeley SB, et al (2007)90 36 Not Not Not 74% 49% Not Not 10% Not n/a 173

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Table F 1. Survival rates in studies of photodynamic therapy (PDT) for esophageal cancer Overall Overall survival / Cause‐specific survival (% of study sample) Median survival at Cause‐specific survival at end of survival at end Treatment end of follow‐up (% of follow‐up groups/ follow‐up of study (% of study Favors Favors Study / Cell type No. of patients (months) sample) sample) 1 year 2 years 3 years 4 years 5 years 10 years PDT comparator reported reported reported reported reported reported ∙ Adenocarcinoma ∙ Squamous cell carcinoma Lovat LB, et al (2005)91 73% 100% Not Not Not Not Not Not Not ∙ Adenocarcinoma 11 (3‐36 (3‐36 n/a reported reported reported reported reported reported reported months) months) Maunoury V, et al* 75% 88% (2005)92 Not Not Not Not Not Not Not 24 (6‐45 (6‐45 n/a ∙ Adenocarcinoma reported reported reported reported reported reported reported months) months) ∙ Squamous cell carcinoma McCaughan JS, et al (1996)93 Not Not Not Not Not ∙ Adenocarcinoma 19 59% 41% 21% 21% n/a reported reported reported reported reported ∙ Squamous cell carcinoma Messmann H, et al* Not Not Not Not Not Not Not Not Not (1997)94 4 n/a reported reported reported reported reported reported reported reported reported ∙ Squamous cell carcinoma Moghissi K, Dixon K (2003)95 Not Not Not Not Not Not Not 71%/ Not ∙ Adenocarcinoma 18 n/a reported reported reported reported reported reported reported 94% reported ∙ Squamous cell carcinoma Nakamura T, et al* 100% (2004)96 Not Not Not Not Not Not Not Not 7 (5‐51 n/a ∙ Adenocarcinoma reported reported reported reported reported reported reported reported months) ∙ Squamous cell carcinoma 27 Okunaka T, et al (1990)97 Not Not 83% / Not Not Not Not Not 6 (4‐47 n/a ∙ Squamous cell carcinoma reported reported 100% reported reported reported reported reported months) Overholt BF, et al* Not Not Not Not Not Not Not Not Not (1995)98 5 n/a reported reported reported eported reported reported reported reported reported ∙ Adenocarcinoma Overholt BF, Panjehpour M, Not Ayers M * Not Not Not Not Not Not Not Not 1 n/a (1997)99 reported reported reported reported reported reported reported reported reported ∙ Adenocarcinoma Overholt BF, Panjehpour M, Not Not Not Not 44% / Not Halberg DL (2003)100 9 78% 67% 56% n/a reported reported reported reported 89% reported ∙ Adenocarcinoma

174

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Table F 1. Survival rates in studies of photodynamic therapy (PDT) for esophageal cancer Overall Overall survival / Cause‐specific survival (% of study sample) Median survival at Cause‐specific survival at end of survival at end Treatment end of follow‐up (% of follow‐up groups/ follow‐up of study (% of study Favors Favors Study / Cell type No. of patients (months) sample) sample) 1 year 2 years 3 years 4 years 5 years 10 years PDT comparator Savoy AD, et al* 100% Not Not Not Not Not Not Not Not (2008)101 17 (6‐48 n/a reported reported eported reported reported reported reported reported ∙ Adenocarcinoma months) Shim C, et al * Not (2007)102 Not Not Not Not Not Not Not Not 9 n/a ∙ Adenocarcinoma reported reported reported reported reported reported reported reported reported ∙ Squamous cell carcinoma Tan WC, et al* Not Not Not Not Not Not Not Not Not (1999)103 12 n/a reported reported reported reported reported reported reported reported ∙ Adenocarcinoma reported Yachimski P, Puricelli WP, Nishioka NS* Not Not Not Not Not Not Not Not Not 57 n/a (2008)104 reported reported reported eported reported reported reported reported reported ∙ Adenocarcinoma Yano T, et al Not Not Not Not Not Not Not Not (2006)105 27 75% n/a reported reported reported reported reported reported reported reported ∙ Cell type not reported Yoshida K, et al* Not Not Not Not Not Not Not Not Not (1998)106 6 n/a reported reported reported reported reported reported reported reported reported ∙ Cell type not reported Pooled total n/a n/a Overall: Overall: Overall: n/a Overall: Studies of adenocarcinoma: 100% 87% 73% 56% 28% Studies of squamous cell 100% 83% Not Not Not carcinoma: 91% 71% reported reported reported Studies including both: 47% 21% 28% *No survival information was reported for early esophageal cancer patients (Stages 0, I, II, and IIA) only

175

Table F 2. Survival rates in studies of argon plasma coagulation (APC) for esophageal cancer Cause‐ Overall survival / cause‐specific survival (% of study sample) Overall specific survival at Median survival at end of Treatment survival at end of follow‐up (% groups/ end of follow‐up of study No. of follow‐up (% of study Favors Favors sample) Study / Cell type patients (months) sample) 1 year 2 years 3 years 5 years 10 years APC comparator Non‐comparative studies Nomura T, et al (2007)108 75% 100% Not Not Not Not Not 8 (4‐38 (4‐38 Not reported n/a Squamous cell reported reported reported reported reported months) months) carcimoma

Van Leethem JL, et al (2001)109 Not Not Not Not Not Not 3 100% Not reported n/a reported reported reported reported reported reported Adenocarcinoma

Pooled total n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a Comparative studies None

176

Table F 3. Survival rates in studies of cryoablation for esophageal cancer Cause‐ Overall survival / cause‐specific survival (% of study sample) Overall specific survival at Median survival at end of Treatment survival at end of follow‐up (% groups/ end of follow‐up Favors of study No. of follow‐up (% of study Cryo‐ Favors sample) Study / Cell type patients (months) sample) 1 year 2 years 3 years 5 years 10 years therapy comparator Non‐comparative studies Dumot JA, et al (2008)68 100% Not Not Not Not Not Not Not Adenocarcinoma 23 (6‐30 n/a reported reported reported reported reported reported reported Squamous cell months) carcimoma

Pooled total n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a Comparative studies None

177

Table F 4. Survival rates in studies of radiofrequency ablation (RFA) for esophageal cancer Overall Overall survival / cause‐specific survival (% of study sample) Median survival at Cause‐specific Treatment survival at end of survival at end groups/ end of follow‐up (% of follow‐up No. of follow‐up of study (% of study Favors Favors Study / Cell type patients (months) sample) sample) 1 year 2 years 3 years 5 years 10 years RFA comparator Non‐comparative studies Pouw RE, et al (2008)110 Adenocarcinoma 100% Not Not Not Not Not Not Not Squamous cell 16 (10‐27 n/a reported reported reported reported reported reported reported carcimoma months)

Pooled total n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a Comparative studies None

178

Table F 5. Survival rates in studies of endoscopic mucosal resection (EMR) for esophageal cancer Overall Cause‐specific Overall survival / Cause‐specific survival (% of study sample) survival at survival at Median survival end of end of follow‐ at end of follow‐ follow‐up (% up Treatment groups/ up of study (% of study Favors Favors Study / Cell type No. of patients (months) sample) sample) 1 year 2 years 3 years 5 years 10 years EMR comparator Comparative studies Ishihara R, et al ∙ EMR (2008)121 ∙ Endoscopic Not Not Not 96%* / Not Not Not Not

submucosal reported reported reported 100%* reported reported reported reported Squamous cell carcinoma dissection (ESD Tanabe S, et al ∙ Endoscopic (2004)122 Oblique Aspiration Not Not Not Not Not Not Not Not Mucosectomy reported reported reported reported reported reported reported reported Squamous cell carcinoma (EOAM) ∙ Strip biopsy Pooled total n/a n/a n/a n/a n/a n/a n/a n/a Non‐comparative studies Conio M, et al (2005)*111 Not Not Not Not Not Not Not 4 / 100% n/a reported reported reported reported reported reported reported Adenocarcinoma Ell C, et al (2007)112 Not Not Not Not Not Not 98% / Not 100 n/a reported reported reported reported reported reported 100% reported Adenocarcinoma Giovannini M, et al* Not Not Not Not Not Not Not Not (2004)113 9 n/a reported reported reported reported reported reported reported reported Cell type not reported Katada C, et al (2007)114 Not Not Not Not Not 99% / 80% / Not 104 n/a Squamous cell carcinoma reported reported reported reported reported 89% 95% reported Lopes CV, et al (2007)*115 Not Not Not Not Not Not Not Not 23 n/a reported reported reported reported reported reported reported reported Adenocarcinoma Manner H, et al (2008)116 Not Not Not Not Not Not 79%/ Not 19 n/a reported reported reported reported reported reported 100% reported Adenocarcinoma Pech O, et al 87% 96% Not Not Not Not Not (2007) 117 53 (16‐62 (16‐62 n/a reported reported reported reported reported Squamous cell carcinoma months) months) Seewald S, et al (2003)118 Not Not Not Not Not Not Not Not 4 n/a reported reported reported reported reported reported reported reported Adenocarcinoma Shimizu Y, et al (2006)119 16 Not Not Not Not Not 100% / Not Not n/a 179

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Table F 5. Survival rates in studies of endoscopic mucosal resection (EMR) for esophageal cancer Overall Cause‐specific Overall survival / Cause‐specific survival (% of study sample) survival at survival at Median survival end of end of follow‐ at end of follow‐ follow‐up (% up Treatment groups/ up of study (% of study Favors Favors Study / Cell type No. of patients (months) sample) sample) 1 year 2 years 3 years 5 years 10 years EMR comparator reported reported reported reported reported 100% reported reported Squamous cell carcinoma Tanabe S, et al (2008)120 Not Not Not Not Not Not Not Not 85 n/a reported reported reported reported reported reported reported reported Squamous cell carcinoma Pooled total 417 n/a n/a n/a n/a n/a Overall survival: Studies of Not 95% adenocarcinoma: reported Studies of squamous cell 90% 80% carcinoma: Not Not Studies including both: reported Reported

Cause‐specific survival: Studies of Not 100% adenocarcinoma: reported Studies of squamous cell 98% 95% carcinoma: Not Not Studies including both: reported reported * Study reported pooled values across treatment groups reported only, since differences between treatment groups were not statistically significant

180

Table F 6. Survival rates in studies of chemotherapy (CT) for esophageal cancer Cause‐specific Overall survival / Cause‐specific survival (% of study sample) Median survival Overall survival survival at end of at end of follow‐ at end of follow‐up Treatment groups/ up follow‐up (% of (% of study Favors Favors Study / Cell type No. of patients (months) study sample) sample) 1 year 2 years 3 years 5 years 10 years CT comparator Comparative studies Heroor A, et al ∙ CT + surgery Not Not Not Not Not Not 82.0% 69.0% (2003)123 ∙ Surgery reported reported reported reported reported reported 88.0% 79.0%

Squamous cell No No carcinoma statistically statistically significant significant Neither difference difference between between groups groups (p>0.5) (p>0.5)

Malaisrie SC, et al ∙ CT + CRT + 59 months Not Not Not Not 60% Not n/a (2006)124 surgery 37 months reported reported reported reported 54% reported ∙ CRT + surgery Adenocarcinoma No statistically No significant statistically difference between significant Neither groups (p=0.61) difference between groups (p>0.5)

Nemoto K, et al ∙ RT* Not Not Not Not Not 72.0% Not Not (2006)125 ∙ RT* + CT reported reported reported reported reported 78.0% reported reported

Squamous cell No carcinoma statistically Neither significant difference between groups (p>0.5) Pooled total n/a n/a n/a n/a n/a n/a n/a n/a Non‐comparative studies None *Patients received external beam radiotherapy and/or intraluminal brachytherapy

181

Table F 7. Survival rates in studies of external beam radiotherapy (EBRT) and/or intraluminal brachytherapy (BT) for esophageal cancer Cause‐specific Overall survival / Cause‐specific survival (% of study sample) survival at Median survival Overall survival end of follow‐ at end of follow‐ at end of up Favors Treatment groups/ up follow‐up (% of (% of study 3 RT or Favors Study / Cell type No. of patients (months) study sample) sample) 1 year 2 years years 5 years 10 years BT comparator Comparative studies Ishikawa H, et al ∙ EBRT Not Not Not Not Not Not 58% (2006)130 ∙ EBRT + low dose reported reported reported reported reported reported 81%δ Squamous cell carcinoma BT ∙ EBRT + high dose No Neither BT statistically significant difference across groups Sai H, et al (2005)131 Not Not Not Squamous cell carcinoma ∙ EBRT reported reported 62% reported 70%* 66%* 59%* n/a ∙ EBRT + high dose 78% BT Neither No statistically significant difference across groups Pooled total n/a n/a n/a n/a n/a n/a n/a n/a Non‐comparative studies Kawashima M, et al ∙ EBRT / 51 Not Not Not reported 71% 53% 39% n/a n/a (2006)126 reported reported n/a Squamous cell carcinoma

Kodaira T, et al ∙ EBRT + BT / Not Not Not Not 74% n/a n/a n/a (2003)127 33 reported reported reported reporte n/a Squamous cell carcinoma d

Sugahara S, et al (2005)128 ∙ EBRT / 23 Not Not Not reported Not Not Not 56% / 95% n/a Squamous cell carcinoma reported reported reporte reported reported n/a Adenocarcinoma d

Zhao K‐L, et al (2004)129 ∙ EBRT / 54 Not Not Not 91% Not 58% 47% n/a reported reported reported reported n/a Squamous cell carcinoma Pooled total Overall: n/a n/a n/a n/a n/a n/a n/a n/a Studies of adenocarcinoma: Not

182

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Table F 7. Survival rates in studies of external beam radiotherapy (EBRT) and/or intraluminal brachytherapy (BT) for esophageal cancer Cause‐specific Overall survival / Cause‐specific survival (% of study sample) survival at Median survival Overall survival end of follow‐ at end of follow‐ at end of up Favors Treatment groups/ up follow‐up (% of (% of study 3 RT or Favors Study / Cell type No. of patients (months) study sample) sample) 1 year 2 years years 5 years 10 years BT comparator Studies of squamous cell reported carcinoma: 61% Studies including both: Not reported * Study reported pooled values across treatment groups reported only, since differences between treatment groups were not statistically significant; δ Only pooled survival information for the 2 groups receiving BT was reported

183

Table F 8. Survival rates in studies of chemoradiotherapy (CRT) for esophageal cancer Cause‐ Overall survival / Cause‐specific survival (% of study sample) Overall specific Median survival at survival at Treatment survival at end of end of follow‐ groups/ end of follow‐up (% up Favors No. of follow‐up of study (% of study Favors comparat Study / Cell type patients (months) sample) sample) 1 year 2 years 3 years 5 years 10 years CRT or Comparative studies De Manzoni G, et al ∙ Low dose Not Not Not Not Not Not 8% n/a (2005)135 CRT + reported reported reported reported reported reported 31% surgery Squamous cell carcinoma ∙ High dose Statistically  CRT + significant surgery difference (p=0.02) Hironaka S, et al (2003)136 ∙ Surgery Not Not Not Not Not Not 62% ∙ CRT reported reported reported reported reported reported 45% Squamous cell carcinoma Neither Difference not statistically significant Pooled total n/a n/a n/a n/a n/a n/a n/a n/a Non‐comparative studies Czito BG, et al (2007)132 Not Not Not Not Not Not Not 2 Not reported n/a Adenocarcinoma reported reported reported reported reported reported reported Squamous cell carcinoma

Sato Y, et al (2006)*133 Not Not Not Not Not Not Not 7 Not reported n/a reported reported reported reported reported reported reported Squamous cell carcnoma Yamada K, et al (2006)71 Not Not Not Not Not Not 11 Not reported 66% n/a reported reported reported reported reported reported Squamous cell carcinoma Pooled total 20 n/a n/a n/a n/a n/a n/a n/a n/a

184

Table F 9. Survival rates in studies of chemoradiotherapy (CRT) and surgery (esophagectomy) for esophageal cancer Median Cause‐specific Overall survival / Cause‐specific survival (% of study sample) survival at Overall survival survival at end end of follow‐ at end of of follow‐up Favors Treatment groups/ up follow‐up (% of (% of study CRT + Favors Study / Cell type No. of patients (months) study sample) sample) 1 year 2 years 3 years 5 years 10 years surgery comparator Comparative studies De Manzoni G, et ∙ Low dose CRT + Not Not Not Not Not Not 8% n/a al (2005)135 surgery reported reported reported reported reported reported 31% ∙ High dose CRT + Squamous cell surgery Statistically  carcinoma significant difference (p=0.02) Pooled total n/a n/a n/a n/a n/a n/a n/a n/a Non‐comparative studies Donahue JM, et al (2009)74

Not Not Not Not Not Not Not Adenocarcinoma 79 64% n/a reported reported reported reported reported reported reported Squamous cell carcinoma

Pooled total n/a n/a n/a n/a n/a n/a n/a n/a

185

Table F 10. Survival rates in studies of surgery (esophagectomy) for esophageal cancer Overall Cause‐ Overall survival / Cause‐specific survival (% of study sample) survival at specific Median end of survival at Treatment survival at follow‐up end of groups/ end of (% of follow‐up Favors No. of follow‐up study (% of study surger Favors Study / Cell type patients (months) sample) sample) 1 year 2 years 3 years 4 years 5 years 10 years y comparator Comparative studies Benzoni E, et al ∙ Transhiatal Not Not Not Stage 0: Stage 0: 100% Stage 0: Stage 0: Not Not (2007)150 laparoscopic reported reported reported 100% Stage I: 100% 100% 100% reported reported esophagectomy Stage I: Stage IIa: 80% Stage I: 0% Stage I: 0% Adenocarcinoma 100% Stage IIa: Stage IIa: Squamous cell ∙ Laparopscopic Stage IIa: Note: no 80% 80% carcinoma esophagectomy 100% treatment with right specific Note: no Note: no transthoracic Note: no results treatment treatment approach treatment reported specific specific specific results results results reported reported reported

Braghetto I, et al ∙ Minimally Not Not Not Not Not 67% Not Not Not (2006)151 invasive reported reported reported reported reported reported reported reported esophagectomy Adenocarcinoma (MIE) 73% Squamous cell carcinoma ∙ Transthoracic or No Neither transhiatal statistically esophagectomy significant (Open) difference between groups Heroor A, et al (2003)123 ∙ Not Not Not Not Not Not Not 88% 79% Esophagectomy reported reported reported reported reported reported reported Squamous cell 82% 69% carcinoma ∙ Esophagectomy No No Neither + Chemotherapy statistically statistically significant significant difference difference between between groups groups

186

Pacifico RJ, et al * ∙ Endoscopic (2003)107 mucosal resection

(EMR) and

Adenocarcinoma photodynamic

therapy (PDT) Not Not Not Not Not Not Not Not Not reported reported reported reported reported reported reported reported reported ∙ Esophagectomy

Peyre CG, et al ∙ Transhiatal Not Not Not reported Not Not Not Not 65% Not  (2007)153 esophagectomy reported reported reported reported reported reported reported (VSE) (THE) 187

∙ Vagal‐sparing Statistically esophagectomy significant (VSE difference between THE and VSE groups

Smithers BM, et al ∙ Open Not Not Not reported Not Not Not Not 56% (2007)154 transthoracic reported reported reported reported reported reported esophagectomy Adenocarcinoma Squamous cell ∙ Thoracoscopic 66% Neither carcinoma assisted esophagectomy

∙ Laparoscopic 83% esophagectomy

Pooled total† n/a n/a n/a n/a n/a n/a n/a n/a n/a

Non‐comparative studies Alexiou C, et al ACC (2006)138 Stage I: 55% Stage IIa: 32% Not Not Not Not Not Not Not Not Adenocarcinoma (ACC) 212 SCC reporte n/a reported reported reported reported reported reported reported Squamous cell carcinoma Stage I: 66% d Stage IIa: 52%

Egberts JH, et al Not (2008)139 Not Not Not Not Not Not 41 76 months 61% reporte n/a reported reported reported reported reported reported d Adenocarcinoma

188

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta Table F 10. Survival rates in studies of surgery (esophagectomy) for esophageal cancer Overall Cause‐ Overall survival / Cause‐specific survival (% of study sample) survival at specific Median end of survival at Treatment survival at follow‐up end of groups/ end of (% of follow‐up Favors No. of follow‐up study (% of study surger Favors Study / Cell type patients (months) sample) sample) 1 year 2 years 3 years 4 years 5 years 10 years y comparator Squamous cell carcinoma Mariette C, et al Stage 0: Stage 0: (2004)140 Stage 0: 100% Not Not Not Not 100% Not 100% Not 139 Stage I: 84% reporte n/a reported reported reported Stage I: 99% reported Stage I: 92% reported Adenocarcinoma Stage II: 50% d Stage II: 98% Stage II: 59% Squamous cell carcinoma Moraca RJ, Low DE* (2006)141 Not Not Not Not Not Not Not Not 25 96% reporte n/a reported reported reported reported reported reported reported Adenocarcinoma d Squamous cell carcinoma Nguyen N, et al Stage 0: (2003)142 100% Not Not Not Not Not Not Not 26 Stage I: n/a n/a reported reported reported reported reported reported reported Adenocarcinoma 100% Squamous cell carcinoma Stage II: 54% Thomson BNJ, Cade RJ (2003)143 Not Not Not Not Not Not Not 12 75% n/a n/a reported reported reported reported reported reported reported Adenocarcinoma Udagawa H, et al (2007)144 Not Not Not 187 97% 95% 91% 87% 82% n/a n/a reported reported reported Adenocarcinoma Squamous cell carcinoma Wang H‐W, et al Stage 0/I: Stage 0/I: Stage 0/I: Stage 0/I: (2004)145 Not Not Stage 0/I: 83% 42 60.1 months 83% 83% 83% 83% n/a n/a reported reported Stage II: 27% Stage II: 58% Stage II: 43% Stage II: 30% Stage II: 27% Squamous cell carcinoma Wang GQ, et al Not Not Not Not Not Not Not (2004)146 76 97% n/a n/a reported reported reported reported reported reported reported Not reported Westerterp M, et al Not (2005)301 Not Not Not Not Not Not Not 66 96% reporte n/a reported reported reported reported reported reported reported d Adenocarcinoma

189

190

Level of Evidence Level Study design 1a Systematic review with homogeneity of RCTs 1b Individual RCT with narrow confidence interval All or none studies (where all patients died before the treatment became 1c available) 2a Systematic review with homogeneity of cohort studies 2b Individual cohort study or low quality RCT ( e.g., <80% follow‐up) 2c "Outcomes" research; ecological studies 3a Systematic review with homogeneity of case‐control studies 3b Individual case‐control study 4 Case‐series or poor quality cohort or case‐control studies Expert opinion without explicit critical appraisal, or based on physiology, bench 5 research or "first principles"

Grades of recommendation Grade Levels of evidence A (excellent) Consistent level 1 studies B (good) Consistent level 2 or 3 studies or extrapolations from level 1 studies C (fair) Level 4 studies or extrapolations from level 2 or 3 studies D (poor) Level 5 evidence or troublingly inconsistent or inconclusive studies of any level Adapted from the Oxford Centre for Evidence‐based Medicine levels of evidence and grades of recommendation for studies of therapy. Oxford: Centre for Evidence‐based Medicine; 2009. Available: http://www.cebm.net/index.aspx?o=1047

References

1. American Cancer Society. What is cancer of the esophagus? American Cancer Society; 2009. Available: http://www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_is_esophagus_cancer_12.asp.

2. Fisichella PM, Patti MG. Esophageal cancer. In: EMedicine: Medscape.com; 2009. Available: http://emedicine.medscape.com/article/277930‐overview.

3. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55(2):74‐108.

4. Reynolds JV, McLaughlin R, Moore J, Rowley S, Ravi N, Byrne PJ. Prospective evaluation of quality of life in patients with localized oesophageal cancer treated by multimodality therapy or surgery alone. Br J Surg 2006;93(9):1084‐90.

5. National Comprehensive Cancer Network. Esophageal cancer. National Comprehensive Cancer Network (NCCN); 2009. v.1.2009. Available: http://www.nccn.org/professionals/physician_gls/PDF/esophageal.pdf.

6. National Cancer Institute. What you need to know about cancer of the esophagus [NIH Publication No. 08‐ 1557]. Bethesda, MD: US National Institutes of Health, National Cancer Institute; 2009. Available: http://www.cancer.gov/cancertopics/wyntk/esophagus.pdf.

7. Eslick GD. Epidemiology of esophageal cancer. Gastroenterol Clin North Am 2009;38:17‐25.

8. Enzinger PC, Mayer RJ. Esophageal cancer. N Eng J Med 2003;349(23):2241‐52.

9. Absi A, Adelstein DJ, Rice T. Esophageal cancer [Disease Management Project]. Beachwood, OH: The Cleveland Clinic Center for Continuing Education; 2008. Available: http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/hematology‐ oncology/esophageal‐cancer/.

10. Yao PF, Li GC, Li J, Xia HS, Yang XL, Huang HY, et al. Evidence of human papilloma virus infection and its epidemiology in esophageal squamous cell carcinoma. World J Gastroenterol 2006;12(9):1352‐5.

11. Morgan MA. Influence of socio‐economic deprivation on outcomes for patients diagnosed with oesophageal cancer. Scandinavian Journal of Gastroenterology 2007;42(10):1230‐7.

12. Brown LM, Hoover R, Silverman D, Baris D, Hayes R, Swanson GM, et al. Excess incidence of squamous cell esophageal cancer among US Black men: role of social class and other risk factors. Am J Epidemiol 2001;153(2):114‐22.

13. Lagergren J, Bergstrom R, Lindgren A, Nyren O. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Eng J Med 1999;340(11):825‐31.

14. Merry AH, Schouten LJ, Goldbohm RA, van den Brandt PA. Body mass index, height and risk of adenocarcinoma of the oesophagus and gastric cardia: a prospective cohort study. Gut 2007;56(11):1503‐ 11.

192

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta 15. Blot WJ, Devesa SS, Kneller RW, Fraumeni JF, Jr. Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA 1991;265(10):1287‐9.

16. American Cancer Society. How is cancer of the esophagus diagnosed? Atlanta: American Cancer Society; 2006. Available: http://www.cancer.org/docroot/cri/content/cri_2_4_3x_how_is_esophagus_cancer_diagnosed_12.asp?si tearea=cri .

17. Scottish Intercollegiate Guidelines Network. Management of oesophageal and gastric cancer: a national clinical guideline. 87. Edinburgh: Scottish Intercollegiate Guidelines Network (SIGN); 2006. Available: http://www.sign.ac.uk/pdf/sign87.pdf .

18. Jacobson BC, Hirota W, Baron TH, Leighton JA, Faigel DO. The role of endoscopy in the assessment and treatment of esophageal cancer. Gastrointest Endosc 2003;57(7):817‐22.

19. McAllaster JD, Buckles D, Al‐Kasspooles M. Treatment of Barrett's esophagus with high‐grade dysplasia. Expert Rev Anticancer Ther 2009;9(3):303‐16.

20. Puli SR, Reddy JB, Bechtold ML, Antillon D, Ibdah JA, Antillon MR. Staging accuracy of esophageal cancer by endoscopic ultrasound: a meta‐analysis and systematic review. World J Gastroenterol 2008;14(10):1479‐90.

21. American Joint Committee on Cancer. AJCC cancer staging manual. 6th ed. New York: Springer; 2002.

22. National Cancer Institute. Esophageal cancer treatment. In. Bethesda (MD): US National Cancer Institute; 2009. Available: http://www.cancer.gov/cancertopics/types/esophageal/.

23. Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 2006;24(14):2137‐50.

24. Pohl H, Welch HG. The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence. J Natl Cancer Inst 2005;97(2):142‐6.

25. Cancer Care Ontario. Changing patterns of esophageal cancer: adenocarcinoma on the rise [Ontario Cancer Facts]. Toronto: Cancer Care Ontario; 2008. Available: http://www.cancercare.on.ca/documents/CF_July2008‐esophageal‐adenocaontherise.pdf.

26. Barritt AS, Shaheen NJ. Should patients with Barrett's oesophagus be kept under surveillance? The case against. Best Pract Res Clin Gastroenterol 2008;22(4):741‐50.

27. Canadian Cancer Society. Canadian Cancer Statistics 2009. Toronto: Canadian Cancer Society / National Cancer Institute of Canada; 2009. Available: http://www.cancer.ca/canada‐ wide/about%20cancer/cancer%20statistics/canadian%20cancer%20statistics.aspx?sc_lang=en.

28. Blazeby JM, Conroy T, Hammerlid E, Fayers P, Sezer O, Koller M, et al. Clinical and psychometric validation of an EORTC questionnaire module, the EORTC QLQ‐OES18, to assess quality of life in patients with oesophageal cancer. Eur J Cancer 2003;39(10):1384‐94.

29. Alberta Cancer Board. Alberta cancer registry: 2005 annual report of cancer statistics. Edmonton: Alberta Cancer Board / Alberta Health Services; 2008. Available: http://www.cancerboard.ab.ca/NR/rdonlyres/2BADD738‐9C4D‐487F‐B8C1‐ 68D5D962CD81/0/AlbertaCancerRegistry200531Oct08.pdf.

193

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta 30. Clifton JC, Finley RJ, Gelfand G, Graham AJ, Inculet R, Malthaner R, et al. Development and validation of a disease‐specific quality of life questionnaire (EQOL) for potentially curable patients with carcinoma of the esophagus. Dis Esophagus 2007;20(3):191‐201.

31. Cancer Care Ontario. The most fatal cancers in Ontario [Ontario Cancer Facts; November 2005]. Toronto: Cancer Care Ontario; 2005. Available: http://www.cancercare.on.ca/english/home/ocs/snapshot/ont‐ cancer‐facts/mostfatal/.

32. Potential years of life lost due to cancer, Canada 2003. In: Canadian Cancer Statistics 2007. Toronto: Canadian Cancer Society; 2007. p.59. Available: http://www.cancer.ca/canada‐ wide/about%20cancer/cancer%20statistics/canadian%20cancer%20statistics.aspx?sc_lang=en.

33. Drummond MF, Sculpher MJ, Torrance GW, O'Brien BJ, Stoddart GL. Methods for the economic evalution of health care programmes. 3rd. New York: Oxford University Press; 2005.

34. Statistics Canada. Income in Canada 2005. Ottawa: Statistics Canada; 2007. Available: http://dsp‐ psd.pwgsc.gc.ca/collection_2007/statcan/75‐202‐X/75‐202‐XIE2005000.pdf.

35. Conroy T, Marchal F, Blazeby JM. Quality of life in patients with oesophageal and gastric cancer: an overview. Oncology 2006;70(6):391‐402.

36. Gillham CM. Quality of Life and Survival in Patients Treated with Radical Chemoradiation Alone for Oesophageal Cancer. Clin Oncol 2008;20(3):227‐33.

37. Djarv T, Lagergren J, Blazeby JM, Lagergren P. Long‐term health‐related quality of life following surgery for oesophageal cancer. Br J Surg 2008;95(9):1121‐6.

38. Viklund P. Quality of life and persisting symptoms after oesophageal cancer surgery. Eur J Cancer 2006;42(10):1407‐14.

39. Lagergren P, Avery KN, Hughes R, Barham CP, Alderson D, Falk SJ, et al. Health‐related quality of life among patients cured by surgery for esophageal cancer. Cancer 2007;110(3):686‐93.

40. Wang KK. Endoscopic therapy of early cancer in Barretts esophagus [clinical trial protocol] [ClinicalTrials.gov]. Bethesda, MD: US National Institutes of Health, National Library of Medicine; 2009. Available: http://www.clinicaltrials.gov/ct2/show/NCT00217087?term=NCT00217087&rank=1.

41. Mortensen MB. Esophageal cancer: Biology, natural history, staging and therapeutic options. Minerva Medica 2007;98(4):299‐303.

42. Green SR, Tawil A, Barr H, Bennett C, Bhandari P, DeCaestecker J, et al. Surgery versus radical endotherapies for early cancer and high grade dysplasia in Barrett's oesophagus. Cochrane Database of Systematic Reviews: Protocols 2008;Issue 3. Available: http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD007334/frame.html.

43. Qureshi I, Nason KS, Luketich JD. Is minimally invasive esophagectomy indicated for cancer? Expert Rev Anticancer Ther 2008;8(9):1449‐60.

44. Maloney JD, Weigel TL. Minimally invasive esophagectomy for malignant and premalignant diseases of the esophagus. Surg Clin North Am 2008;88(5):979‐90.

45. Alberta Cancer Board. Guide to chemotherapy. Edmonton: Alberta Cancer Board; 2008. Available: http://www.cancerboard.ab.ca/treatment/treatmenttypes/chemotherapy.htm.

194

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta 46. Kantsevoy SV, Adler DG, Conway JD, Diehl DL, Farraye FA, Kwon R, et al. Endoscopic mucosal resection and endoscopic submucosal dissection. Gastrointest Endosc 2008;68(1):11‐8.

47. Petersen BT, Chuttani R, Croffie J, DiSario J, Liu J, Mishkin D, et al. Photodynamic therapy for gastrointestinal disease. Gastrointest Endosc 2006;63(7):927‐32.

48. Unger SA. Photodynamic therapy: a bench‐to‐bedside success story. Buffalo Physician 2004;Autumn:8‐18. Available: http://www.smbs.buffalo.edu/bp/2004_FALL/10978_08_19.pdf.

49. Erickson L. Assessment of photodynamic therapy using porfimer sodium for esophageal, bladder and lung cancers. 2004. Available: http://www.aetmis.gouv.qc.ca/fr/publications/scientifiques/cancer/2004_01_res_en.pdf.

50. Notice of compliance database. Ottawa: Health Canada. Drugs & Health Products; 2009. Available: http://www.hc‐sc.gc.ca/dhp‐mps/prodpharma/notices‐avis/noc‐acc/index‐eng.php.

51. Medical Devices Active Licence Listing. Ottawa: Health Canada. Drugs & Health Products; 2009. Available: http://www.hc‐sc.gc.ca/dhp‐mps/md‐im/licen/mdall_overview_apercu‐eng.php.

52. Systematic reviews in health care: meta‐analysis in context. Egger M, Smith GD, Altman DG, editors. Systematic reviews in health care: meta‐analysis in context. 2nd ed. London: BMJ; 2001.

53. Photodynamic therapy for cancer: summaries and evidence tables. Edmonton, AB: University of Alberta, School of Public Health, Health Technology and Policy Unit; 2008.

54. Cohen J. A coefficient of agreement for nomial scales. Educ Psychol Meas 1960;20(1):37‐46.

55. National Institute for Health and Clinical Excellence. Photodynamic therapy for early‐stage oesophageal cancer. London: National Institute for Health and Clinical Excellence (NICE); 2006. 200. Available: http://www.nice.org.uk/guidance/IPG200.

56. Institute for Clinical Systems Improvement. Photodynamic therapy for head and neck, tracheobronchial, and esophageal cancer. Bloomington, MN: Institute for Clinical Systems Improvement (ICSI); 2002. Available: http://www.icsi.org/technology_assessment_reports_‐ _active/ta_photodynamic_therapy_for_head_and_neck__tracheobronchial__and_esophageal_cancer.ht ml.

57. Green S, Tawil A, Barr H, Bennett C, Bhandari P, DeCaestecker J, et al. Surgery versus radical endotherapies for early cancer and high grade dysplasia in Barrett's oesophagus. Cochrane Library 2009;(Issue 2).

58. UK Centre for Reviews and Dissemination. Photodynamic therapy (PDT) in the treatment of Barrett's oesophagus and cancers of the biliary tract, brain, head and neck, lung, oesophagus and skin [forthcoming review]. York: UK Centre for Reviews and Dissemination; 2009. Available: http://www.york.ac.uk/inst/crd/projects/photodynamic_therapy_2009.htm.

59. Wang KK, Sampliner RE. Updated guidelines 2008 for the diagnosis, surveillance and therapy of Barrett's esophagus. Am J Gastroenterol 2008;103(3):788‐97.

60. Ormsby AH, Petras RE, Henricks WH, Rice TW, Rybicki LA, Richter JE, et al. Observer variation in the diagnosis of superficial oesophageal adenocarcinoma. Gut 2002;51(5):671‐6.

195

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta 61. Provenzale D, Kemp JA, Arora S, Wong JB. A guide for surveillance of patients with Barrett's esophagus. Am J Gastroenterol 1994;89(5):670‐80.

62. Alikhan M, Rex D, Khan A, Rahmani E, Cummings O, Ulbright TM. Variable pathologic interpretation of columnar lined esophagus by general pathologists in community practice. Gastrointest Endosc 1999;50(1):23‐6.

63. Provenzale D, Schmitt C, Wong JB. Barrett's esophagus: a new look at surveillance based on emerging estimates of cancer risk. Am J Gastroenterol 1999;94(8):2043‐53.

64. Iannettoni MD, Vlessis AA, Whyte RI, Orringer MB. Functional outcome after surgical treatment of esophageal perforation. Ann Thorac Surg 1997;64(6):1606‐9.

65. Adamek HE, Jakobs R, Dorlars D, Martin WR, Kromer MU, Riemann JF. Management of esophageal perforations after therapeutic upper gastrointestinal endoscopy. Scand J Gastroenterol 1997;32(5):411‐4.

66. Ballesta‐Lopez C, Vallet‐Fernandez J, Catarci M, Bastida‐Vila X, Nieto‐Martinez B. Iatrogenic perforations of the esophagus. Int Surg 1993;78(1):28‐31.

67. Moghissi K, Pender D. Instrumental perforations of the oesophagus and their management. Thorax 1988;43(8):642‐6.

68. Dumot JA, Greenwald BD. Argon plasma coagulation, bipolar cautery, and cryotherapy: ABC's of ablative techniques. Endoscopy 2008;40(12):1026‐32.

69. Swisher SG, Wynn P, Putnam JB, Mosheim MB, Correa AM, Komaki RR, et al. Salvage esophagectomy for recurrent tumors after definitive chemotherapy and radiotherapy. J Thorac Cardiovasc Surg 2002;123(1):175‐83.

70. Darnton SJ, Archer VR, Stocken DD, Mulholland PJ, Casson AG, Ferry DR. Preoperative mitomycin, ifosfamide, and cisplatin followed by esophagectomy in squamous cell carcinoma of the esophagus: pathologic complete response induced by chemotherapy leads to long‐term survival. J Clin Oncol 2003;21(21):4009‐15.

71. Yamada K, Murakami M, Okamoto Y, Okuno Y, Nakajima T, Kusumi F, et al. Treatment results of chemoradiotherapy for clinical stage I (T1N0M0) esophageal carcinoma. Int J Radiat Oncol Biol Phys 2006;64(4):1106‐11.

72. van Meerten E, van der GA, Looman CW, Tilanus HW, Muller K, Essink‐Bot ML. Quality of life during neoadjuvant treatment and after surgery for resectable esophageal carcinoma. Int J Radiat Oncol Biol Phys 2008;71(1):160‐6.

73. Avery KN, Metcalfe C, Barham CP, Alderson D, Falk SJ, Blazeby JM. Quality of life during potentially curative treatment for locally advanced oesophageal cancer. Br J Surg 2007;94(11):1369‐76.

74. de Boer AG, Stalmeier PF, Sprangers MA, de Haes JC, van Sandick JW, Hulscher JB, et al. Transhiatal vs extended transthoracic resection in oesophageal carcinoma: patients' utilities and treatment preferences. Br J Cancer 2002;86(6):851‐7.

75. Hur C, Wittenberg E, Nishioka NS, Gazelle GS. Quality of life in patients with various Barrett's esophagus associated health states. Health Qual Life Outcomes 2006;4:45.

196

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta 76. Barbour AP, Lagergren P, Hughes R, Alderson D, Barham CP, Blazeby JM. Health‐related quality of life among patients with adenocarcinoma of the gastro‐oesophageal junction treated by gastrectomy or oesophagectomy. Br J Surg 2008;95(1):80‐4.

77. Mucosal ablation devices. Gastrointest Endosc 2008;68(6):1031‐42.

78. Alberta Health and Wellness. Health costing in Alberta: 2006 annual report. Edmonton: Alberta Health and Wellness, Health Authority Funding and Financial Accountability Branch, Health MIS and Costing Unit; 2006. Available: http://www.health.alberta.ca/documents/health‐costing‐report‐2006.pdf.

79. Comay D, Blackhouse G, Goeree R, Armstrong D, Marshall JK. Photodynamic therapy for Barrett's esophagus with high‐grade dysplasia: a cost‐effectiveness analysis. Can J Gastroenterol 2007;21(4):217‐ 22.

80. Briggs A, Claxton K, Sculpher M. Decision modelling for health economic evaluation [Handbooks in Health Economic Evaluation Series]. Oxford (UK): Oxford University Press; 2006.

81. Mauskopf JA, Sullivan SD, Annemans L, Caro J, Mullins CD, Nuijten M, et al. Principles of good practice for budget impact analysis: report of the ISPOR Task Force on good research practices‐‐budget impact analysis. Value Health 2007;10(5):336‐47.

82. Corti L, Skarlatos J, Boso C, Cardin F, Kosma L, Koukourakis MI, et al. Outcome of patients receiving photodynamic therapy for early esophageal cancer. Int J Radiat Oncol Biol Phys 2000;47(2):419‐24.

83. Craig C, Gray J, Macpherson M, Hodgson H, Zammit M, Fullarton G. Porfimer sodium photodynamic therapy in the treatment of early oesophageal carcinoma. Photodiagn Photodyn Ther 2007;4(4):244‐8.

84. Duvall GA, Scheider D, Cirocco M, Siemens M, Marcon N. Photodynamic therapy (PDT) for early esophageal cancer in high risk surgical patients and patients refusing esophagectomy [abstract]. Gastrointest Endosc 1996;43(4):334.

85. Etienne J, Dorme N, Bourg‐Heckly G, Raimbert P, Flejou JF. Photodynamic therapy with green light and m‐ tetrahydroxyphenyl chlorin for intramucosal adenocarcinoma and high‐grade dysplasia in Barrett's esophagus. Gastrointest Endosc 2004;59(7):880‐9.

86. Foroulis CN, Thorpe JA. Photodynamic therapy (PDT) in Barrett's esophagus with dysplasia or early cancer. Eur J Cardiothorac Surg 2006;29(1):30‐4.

87. Gossner L, May A, Pech O. Photodynamic therapy of Barrett's esophagus with dysplasia or early cancer [abstract]. Gastroenterology 1999;116(Suppl):G1811.

88. Gossner L, May A, Sroka R, Stolte M, Hahn EG, Ell C. Photodynamic destruction of high grade dysplasia and early carcinoma of the esophagus after the oral administration of 5‐aminolevulinic acid. Cancer 1999;86(10):1921‐8.

89. Jamieson NF, Mosse A, Bown SG, Lovat LB. Photodynamic therapy to eradicate dysplasia and early carcinoma in Barrett's oesophagus [abstract]. Gut 2002;50(Suppl 2):A6‐A7.

90. Keeley SB, Pennathur A, Gooding W, Landreneau RJ, Christie NA, Luketich J. Photodynamic therapy with curative intent for Barrett's esophagus with high grade dysplasia and superficial esophageal cancer. Ann Surg Oncol 2007;14(8):2406‐10.

197

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta 91. Lovat LB, Jamieson NF, Novelli MR, Mosse CA, Selvasekar C, Mackenzie GD, et al. Photodynamic therapy with m‐tetrahydroxyphenyl chlorin for high‐grade dysplasia and early cancer in Barrett's columnar lined esophagus. Gastrointest Endosc 2005;62(4):617‐23.

92. Maunoury V, Mordon S, Bulois P, Mirabel X, Hecquet B, Mariette C. Photodynamic therapy for early oesophageal cancer. Dig Liver Dis 2005;37(7):491‐5.

93. McCaughan JS, Jr., Ellison EC, Guy JT, Hicks WJ, Jones JJ, Laufman LR, et al. Photodynamic therapy for esophageal malignancy: a prospective twelve‐year study. Ann Thorac Surg 1996;62(4):1005‐9.

94. Messmann H, Szeimies RM, Baumler W, Knuchel R, Zirngibl H, Scholmerich J, et al. Enhanced effectiveness of photodynamic therapy with laser light fractionation in patients with esophageal cancer. Endoscopy 1997;29(4):275‐80.

95. Moghissi K, Dixon K. Photodynamic therapy (PDT) in esophageal cancer: a surgical view of its indications based on 14 years experience. Technol Cancer Res Treat 2003;2(4):319‐26.

96. Nakamura T, Fukui H, Shirakawa K, Fujii Y, Fujimori T, Terano A. Photodynamic therapy of superficial esophageal cancer with a transparent hood. Gastrointest Endosc 2004;60(1):120‐4.

97. Okunaka T, Kato H, Conaka C, Yamamoto H, Bonaminio A, Eckhauser ML. Photodynamic therapy of esophageal carcinoma. Surg Endosc 1990;4(3):150‐3.

98. Overholt BF, Panjehpour M. Photodynamic therapy in Barrett's esophagus: reduction of specialized mucosa, ablation of dysplasia, and treatment of superficial esophageal cancer. Semin Surg Oncol 1995;11(5):372‐6.

99. Overholt BF, Panjehpour M, Ayres M. Photodynamic therapy for Barrett's esophagus: cardiac effects. Lasers Surg Med 1997;21(4):317‐20.

100. Overholt BF, Panjehpour M, Halberg DL. Photodynamic therapy for Barrett's esophagus with dysplasia and/or early stage carcinoma: long‐term results. Gastrointest Endosc 2003;58(2):183‐8.

101. Savoy AD, Wolfsen HC, Raimondo M, Woodward TA, Noh K, Pungpapong S, et al. The role of surveillance endoscopy and endosonography after endoscopic ablation of high‐grade dysplasia and carcinoma of the esophagus. Dis Esophagus 2008;21(2):108‐13.

102. Shim CS, Cheon YK, Jung IS, Ko BM, Cho JY, Lee JS, et al. Photodynamic therapy for early esophageal cancer [abstract]. Gastrointest Endosc 2007;65(5 (Suppl)):AB149.

103. Tan WC, Fulljames C, Stone N, Dix AJ, Shepherd N, Roberts DJ, et al. Photodynamic therapy using 5‐ aminolaevulinic acid for oesophageal adenocarcinoma associated with Barrett's metaplasia. J Photochem Photobiol B 1999;53(1‐3):75‐80.

104. Yachimski P, Puricelli WP, Nishioka NS. Patient predictors of esophageal stricture development after photodynamic therapy. Clin Gastroenterol Hepatol 2008;6(3):302‐8. Available: PM:18255349.

105. Yano T, Muto M, Minashi K, Ohtsu A, Yoshida S. Salvage photodynamic therapy (PDT) for local failure after definitive chemoradiotherapy (CRT) for esophageal cancer (EC) [abstract]. 2006 Gastrointestinal Cancers Symposium 2006;Abstract #34. Available: http://www.asco.org.

106. Yoshida K, Suzuki S, Mimura S, Narahara H, Tanimura H, Nagai Y, et al. A Clinical Study of Photodynamic Therapy for Superficial Esophageal Carcinoma by YAG‐OPO Laser. Diagn Ther Endosc 1998;4(4):173‐6.

198

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta 107. Pacifico RJ, Wang KK, Wongkeesong LM, Buttar NS, Lutzke LS. Combined endoscopic mucosal resection and photodynamic therapy versus esophagectomy for management of early adenocarcinoma in Barrett's esophagus. Clin Gastroenterol Hepatol 2003;1(4):252‐7.

108. Nomura T. Argon plasma coagulation for the treatment of superficial esophageal carcinoma. J Nippon Med Sch 2007;74(2):163‐7.

109. Van Laethem JL, Jagodzinski R, Peny MO, Cremer M, Deviere J. Argon plasma coagulation in the treatment of Barrett's high‐grade dysplasia and in situ adenocarcinoma. Endoscopy 2001;33(3):257‐61.

110. Pouw RE, Gondrie JJ, Sondermeijer CM, Ten Kate FJ, van Gulik TM, Krishnadath KK, et al. Eradication of Barrett esophagus with early neoplasia by radiofrequency ablation, with or without endoscopic resection. J Gastrointest Surg 2008;12(10):1627‐36.

111. Conio M, Repici A, Cestari R, Blanchi S, Lapertosa G, Missale G, et al. Endoscopic mucosal resection for high‐grade dysplasia and intramucosal carcinoma in Barrett's esophagus: an Italian experience. World J Gastroenterol 2005;11(42):6650‐5.

112. Ell C, May A, Pech O, Gossner L, Guenter E, Behrens A, et al. Curative endoscopic resection of early esophageal adenocarcinomas (Barrett's cancer). Gastrointest Endosc 2007;65(1):3‐10.

113. Giovannini M, Bories E, Pesenti C, Moutardier V, Monges G, Danisi C, et al. Circumferential endoscopic mucosal resection in Barrett's esophagus with high‐grade intraepithelial neoplasia or mucosal cancer. Preliminary results in 21 patients. Endoscopy 2004;36(9):782‐7.

114. Katada C, Muto M, Momma K, Arima M, Tajiri H, Kanamaru C, et al. Clinical outcome after endoscopic mucosal resection for esophageal squamous cell carcinoma invading the muscularis mucosae‐‐a multicenter retrospective cohort study. Endoscopy 2007;39(9):779‐83.

115. Lopes CV, Hela M, Pesenti C, Bories E, Caillol F, Monges G, et al. Circumferential endoscopic resection of Barrett's esophagus with high‐grade dysplasia or early adenocarcinoma. Surg Endosc 2007;21(5):820‐4.

116. Manner H, May A, Pech O, Gossner L, Rabenstein T, Gunter E, et al. Early Barrett's Carcinoma With "Low‐ Risk" Submucosal Invasion: Long‐Term Results of Endoscopic Resection With a Curative Intent. Am J Gastroenterol 2008;103:2589‐97.

117. Pech O, May A, Gossner L, Rabenstein T, Manner H, Huijsmans J, et al. Curative endoscopic therapy in patients with early esophageal squamous‐cell carcinoma or high‐grade intraepithelial neoplasia. Endoscopy 2007;39(1):30‐5.

118. Seewald S, Akaraviputh T, Seitz U, Brand B, Groth S, Mendoza G, et al. Circumferential EMR and complete removal of Barrett's epithelium: a new approach to management of Barrett's esophagus containing high‐ grade intraepithelial neoplasia and intramucosal carcinoma. Gastrointest Endosc 2003;57(7):854‐9.

119. Shimizu Y. Histologic results of EMR for esophageal lesions diagnosed as high‐grade intraepithelial squamous neoplasia by endoscopic biopsy. Gastrointest Endosc 2006;63(1):16‐21.

120. Tanabe S, Koizumi W, Higuchi K, Sasaki T, Nakatani K, Hanaoka N, et al. Clinical outcomes of endoscopic oblique aspiration mucosectomy for superficial esophageal cancer. Gastrointest Endosc 2008;67(6):814‐ 20.

199

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta 121. Ishihara R, Iishi H, Takeuchi Y, Kato M, Yamamoto S, Yamamoto S, et al. Local recurrence of large squamous‐cell carcinoma of the esophagus after endoscopic resection. Gastrointest Endosc 2008;67(6):799‐804.

122. Tanabe S, Koizumi W, Mitomi H, Kitamura T, Tahara K, Ichikawa J, et al. Usefulness of EMR with an oblique aspiration mucosectomy device compared with strip biopsy in patients with superficial esophageal cancer. Gastrointest Endosc 2004;59(4):558‐63.

123. Heroor A. Adjuvant chemotherapy after radical resection of squamous cell carcinoma in the thoracic esophagus: Who benefits? A retrospective study. Dig Surg 2003;20(3):229‐35.

124. Malaisrie SC, Hofstetter WL, Correa AM, Ajani JA, Komaki RR, Rice DC, et al. The addition of induction chemotherapy to preoperative, concurrent chemoradiotherapy improves tumor response in patients with esophageal adenocarcinoma. Cancer 2006;107(5):967‐74.

125. Nemoto K. Results of radiation therapy for superficial esophageal cancer using the standard radiotherapy method recommended by the Japanese Society of Therapeutic Radiology and Oncology (JASTRO) Study Group. Anticancer Res 2006;26(2 B):1507‐12.

126. Kawashima M, Kagami Y, Toita T, Uno T, Sugiyama M, Tamura Y, et al. Prospective trial of radiotherapy for patients 80 years of age or older with squamous cell carcinoma of the thoracic esophagus. Int J Radiat Oncol Biol Phys 2006;64(4):1112‐21.

127. Kodaira T. Multivariate analysis of treatment outcome in patients with esophageal carcinoma treated with definitive radiotherapy. Am J Clin Oncol: Cancer Clinical Trials 2003;26(4):392‐7.

128. Sugahara S. T. Clinical results of proton beam therapy for cancer of the esophagus. Int J Radiat Oncol Biol Phys 2005;61(1):76‐84.

129. Zhao K‐L. Late‐course accelerated hyperfractionated radiotherapy for localized esophageal carcinoma. Int J Radiat Oncol Biol Phys 2004;60(1):123‐9.

130. Ishikawa H, Sakurai H, Tamaki Y, Nonaka T, Yamakawa M, Saito Y, et al. Radiation therapy alone for stage I (UICC T1N0M0) squamous cell carcinoma of the esophagus: indications for surgery or combined chemoradiotherapy. J Gastroenterol Hepatol 2006;21(8):1290‐6.

131. Sai H. Long‐term results of definitive radiotherapy for stage I esophageal cancer. Int J Radiat Oncol Biol Phys 2005;62(5):1339‐44.

132. Czito BG, Kelsey CR, Hurwitz HI, Willett CG, Morse MA, Blobe GC, et al. A Phase I study of capecitabine, carboplatin, and paclitaxel with external beam radiation therapy for esophageal carcinoma. Int J Radiat Oncol Biol Phys 2007;67(4):1002‐7.

133. Sato Y, Takayama T, Sagawa T, Okamoto T, Miyanishi K, Sato T, et al. A phase I/II study of nedaplatin and 5‐fluorouracil with concurrent radiotherapy in patients with esophageal cancer. Cancer Chemother Pharmacol 2006;58(5):570‐6.

134. Wang S, Liao Z, Chen Y, Chang JY, Jeter M, Guerrero T, et al. Esophageal cancer located at the neck and upper thorax treated with concurrent chemoradiation: A single‐institution experience. J Thorac Oncol 2006;1(3):252‐9.

200

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta 135. de Manzoni G., Pedrazzani C, Laterza E, Pasini F, Grandinetti A, Bernini M, et al. Induction chemoradiotherapy for squamous cell carcinoma of the thoracic esophagus: impact of increased dosage on long‐term results. Ann Thorac Surg 2005;80(4):1176‐83.

136. Hironaka S, Ohtsu A, Boku N, Muto M, Nagashima F, Saito H, et al. Nonrandomized comparison between definitive chemoradiotherapy and radical surgery in patients with T(2‐3)N(any) M(0) squamous cell carcinoma of the esophagus. Int J Radiat Oncol Biol Phys 2003;57(2):425‐33.

137. Donahue JM, Nichols FC, Li Z, Schomas DA, Allen MS, Cassivi SD, et al. Complete pathologic response after neoadjuvant chemoradiotherapy for esophageal cancer is associated with enhanced survival. Ann Thorac Surg 2009;87(2):392‐8.

138. Alexiou C, Khan OA, Black E, Field ML, Onyeaka P, Beggs L, et al. Survival after esophageal resection for carcinoma: the importance of the histologic cell type. Ann Thorac Surg 2006;82(3):1073‐7.

139. Egberts JH, Schniewind B, Bestmann B, Schafmayer C, Egberts F, Faendrich F, et al. Impact of the site of anastomosis after oncologic esophagectomy on quality of life‐‐a prospective, longitudinal outcome study. Ann Surg Oncol 2008;15(2):566‐75.

140. Mariette C, Piessen G, Balon JM, Van S, I, Triboulet JP. Surgery alone in the curative treatment of localised oesophageal carcinoma. Eur J Surg Oncol 2004;30(8):869‐76.

141. Moraca RJ. Outcomes and health‐related quality of life after esophagectomy for high‐grade dysplasia and intramucosal cancer. Arch Surg 2006;141(6):545‐9.

142. Nguyen NT, Roberts P, Follette DM, Rivers R, Wolfe BM. Thoracoscopic and laparoscopic esophagectomy for benign and malignant disease: lessons learned from 46 consecutive procedures. J Am Coll Surg 2003;197(6):902‐13.

143. Thomson BNJ, Cade RJ. Oesophagectomy for early adenocarcinoma and dysplasia arising in Barrett's oesophagus. ANZ J Surg 2003;73(3):121‐4.

144. Udagawa H. Surgical treatment of superficial esophageal cancer, its result and perspective. Esophagus 2007;4(4):155‐8.

145. Wang H‐W. Surgical results of upper thoracic esophageal carcinoma. J Chin Med Assoc 2004;67(9):447‐57.

146. Wang G‐Q. Long‐term results of operation for 420 patients with early squamous cell esophageal carcinoma discovered by screening. Ann Thorac Surg 2004;77(5):1740‐4.

147. Westerterp M, Koppert LB, Buskens CJ, Tilanus HW, ten Kate FJW, Bergman JJHG, et al. Outcome of surgical treatment for early adenocarcinoma of the esophagus or gastro‐esophageal junction. Virchows Archiv 2005;446(5):497‐504.

148. Wolfsen HC, Hemminger LL, DeVault KR. Recurrent Barrett's esophagus and adenocarcinoma after esophagectomy. BMC Gastroenterol 2004;4:18.

149. Yamamoto S. K. Minimally invasive esophagectomy for stage I and II esophageal cancer. Ann Thorac Surg 2005;80(6):2070‐5.

150. Benzoni E, Terrosu G, Bresadola V, Uzzau A, Intini S, Noce L, et al. A comparative study of the transhiatal laparoscopic approach versus laparoscopic gastric mobilisation and right open transthoracic esophagectomy for esophageal cancer management. J Gastrointestin Liver Dis 2007;16(4):395‐401.

201

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta 151. Braghetto I, Csendes A, Cardemil G, Burdiles P, Korn O, Valladares H. Open transthoracic or transhiatal esophagectomy versus minimally invasive esophagectomy in terms of morbidity, mortality and survival. Surg Endosc 2006;20(11):1681‐6.

152. Javle MM. Management of locoregional stage esophageal cancer: A single center experience. Dis Esophagus 2006;19(2):78‐83.

153. Peyre CG, DeMeester SR, Rizzetto C, Bansal N, Tang AL, Ayazi S, et al. Vagal‐sparing esophagectomy: the ideal operation for intramucosal adenocarcinoma and barrett with high‐grade dysplasia. Ann Surg 2007;246(4):665‐71.

154. Smithers BM, Gotley DC, Martin I, Thomas JM. Comparison of the outcomes between open and minimally invasive esophagectomy. Ann Surg 2007;245(2):232‐40.

155. Agranovich A, McGahan CE, Gurjal A. Long‐term survivorship of esophageal cancer patients treated with radical intent. Can J Gastroenterol 2008;22(4):393‐8.

156. Ajani JA. Phase II randomized trial of two nonoperative regimens of induction chemotherapy followed by chemoradiation in patients with localized carcinoma of the esophagus: RTOG 0113. J Clin Oncol 2008;26(28):4551‐6.

157. Homesh NA, Alsabahi AA, Al‐Agmar MH, Alwashaly AA, Valenzuela RE, Alhadid MA, et al. Transhiatal versus transthoracic resection for oesophageal carcinoma in Yemen. Singapore Med J 2006;47(1):54‐9.

158. Ancona E, Rampado S, Cassaro M, Battaglia G, Ruol A, Castoro C, et al. Prediction of lymph node status in superficial esophageal carcinoma. Ann Surg Oncol 2008;15(11):3278‐88.

159. Ando N, Iizuka T, Ide H, Ishida K, Shinoda M, Nishimaki T, et al. Surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma of the thoracic esophagus: a Japan Clinical Oncology Group Study‐‐JCOG9204. J Clin Oncol 2003;21(24):4592‐6.

160. Benzoni E, Bresadola V, Terrosu G, Uzzau A, Cedolini C, Intini S, et al. Minimally invasive esophagectomy: a comparative study of transhiatal laparoscopic approach versus laparoscopic right transthoracic esophagectomy. Surg Laparosc Endosc Percutan Tech 2008;18(2):178‐87.

161. Bergquist H. Functional and radiological evaluation of free jejunal transplant reconstructions after radical resection of hypopharyngeal or proximal esophageal cancer. World J Surg 2007;31(10):1988‐95.

162. Bernabe KQ, Bolton JS, Richardson WS. Laparoscopic hand‐assisted versus open transhiatal esophagectomy: a case‐control study. Surg Endosc 2005;19(3):334‐7.

163. Blackmon SH, Correa AM, Wynn B, Hofstetter WL, Martin LW, Mehran RJ, et al. Propensity‐matched analysis of three techniques for intrathoracic esophagogastric anastomosis. Ann Thorac Surg 2007;83(5):1805‐13.

164. Bresadola V, Terrosu G, Cojutti A, Benzoni E, Baracchini E, Bresadola F. Laparoscopic versus open gastroplasty in esophagectomy for esophageal cancer: a comparative study. Surg Laparosc Endosc Percutan Tech 2006;16(2):63‐7.

165. Chang AC. Outcomes After Transhiatal and Transthoracic Esophagectomy for Cancer. Ann Thorac Surg 2008;85(2):424‐9.

202

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta 166. Chiu PW, Chan AC, Leung SF, Leong HT, Kwong KH, Li MK, et al. Multicenter prospective randomized trial comparing standard esophagectomy with chemoradiotherapy for treatment of squamous esophageal cancer: early results from the Chinese University Research Group for Esophageal Cancer (CURE). J Gastrointest Surg 2005;9(6):794‐802.

167. Chou SH, Kao EL, Chuang HY, Wang WM, Wu DC, Huang MF. Transthoracic or transhiatal resection for middle‐ and lower‐third esophageal carcinoma? Kaohsiung J Med Sci 2005;21(1):9‐14.

168. Ciocirlan M, Chemali M, Lapalus MG, Lefort C, Souquet JC, Napoleon B, et al. Esophageal varices and early esophageal cancer: can we perform endoscopic mucosal resection (EMR)? Endoscopy 2008;40 Suppl 2:E91.

169. Dabrowski A, Skoczylas T, Ciechanski A, Wallner G, Zinkiewicz K, Cwik G, et al. Dukes' classification as a prognostic factor in patients with squamous cell carcinoma of the thoracic esophagus undergoing combined‐modality treatment. Med Sci Monit 2006;12(10):CR409‐CR415.

170. Dan H‐L. A new three‐layer‐funnel‐shaped esophagogastric anastomosis for surgical treatment of esophageal carcinoma. W J Gastroenterol 2003;9(1):22‐5.

171. Dapri G, Himpens J, Cadiere GB. Minimally invasive esophagectomy for cancer: laparoscopic transhiatal procedure or thoracoscopy in prone position followed by laparoscopy? Surg Endosc 2008;22(4):1060‐9.

172. Darnton SJ, Archer VR, Stocken DD, Mulholland PJ, Casson AG, Ferry DR. Preoperative mitomycin, ifosfamide, and cisplatin followed by esophagectomy in squamous cell carcinoma of the esophagus: pathologic complete response induced by chemotherapy leads to long‐term survival. J Clin Oncol 2003;21(21):4009‐15.

173. Das A, Singh V, Fleischer DE, Sharma VK. A comparison of endoscopic treatment and surgery in early esophageal cancer: an analysis of surveillance epidemiology and end results data. Am J Gastroenterol 2008;103(6):1340‐5.

174. de Boer AG, van Lanschot JJ, van Sandick JW, Hulscher JB, Stalmeier PF, de Haes JC, et al. Quality of life after transhiatal compared with extended transthoracic resection for adenocarcinoma of the esophagus. J Clin Oncol 2004;22(20):4202‐8.

175. Di Fiore F., Lecleire S, Galais MP, Rigal O, Vie B, David I, et al. Impact of radiation schedule and chemotherapy duration in definitive chemoradiotherapy regimen for esophageal cancer. Gastroenterol Clin Biol 2006;30(6‐7):845‐51.

176. Di Franco F. Iatrogenic perforation of localized oesophageal cancer. Br J Surg 2008;95(7):837‐9.

177. Doki Y, Okada K, Miyata H, Yamasaki M, Fujiwara Y, Takiguchi S, et al. Long‐term and short‐term evaluation of esophageal reconstruction using the colon or the jejunum in esophageal cancer patients after gastrectomy. Dis Esophagus 2008;21(2):132‐8.

178. Donington JS. Tumor response to induction chemoradiation: Influence on survival after esophagectomy. Eur J Cardio‐Thorac Surg 2003;24(4):631‐7.

179. Dunkin BJ, Martinez J, Bejarano PA, Smith CD, Chang K, Livingstone AS, et al. Thin‐layer ablation of human esophageal epithelium using a bipolar radiofrequency balloon device. Surg Endosc 2006;20(1):125‐30.

180. Ell C, May A, Gossner L, Pech O, Gunter E, Mayer G, et al. Endoscopic mucosal resection of early cancer and high‐grade dysplasia in Barrett's esophagus. Gastroenterology 2000;118(4):670‐7.

203

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta 181. El‐Rayes BF, Shields A, Zalupski M, Heilbrun LK, Jain V, Terry D, et al. A phase II study of carboplatin and paclitaxel in esophageal cancer. Ann Oncol 2004;15(6):960‐5.

182. Ertan A, Zimmerman M, Younes M. Esophageal Adenocarcinoma Associated with Barretts‐Esophagus ‐ Long‐Term Management with Laser‐Ablation. Am J Gastroenterol 1995;90(12):2201‐3.

183. Farran L, Llop J, Sans M, Kreisler E, Miro M, Galan M, et al. Efficacy of enteral decontamination in the prevention of anastomotic dehiscence and pulmonary infection in esophagogastric surgery. Dis Esophagus 2008;21(2):159‐64.

184. Ferahkose Z, Bedirli A, Kerem M, Azili C, Sozuer EM, Akin M. Comparison of free jejunal graft with gastric pull‐up reconstruction after resection of hypopharyngeal and cervical esophageal carcinoma. Dis Esophagus 2008;21(4):340‐5.

185. Frechette E. B. Esophageal cancer: Outcomes of surgery, neoadjuvant chemotherapy, and three‐ dimension conformal radiotherapy. J Surg Oncol 2004;87(2):68‐74.

186. Go JT,, Dumot JA Lopez R, Vargo J, Zuccaro G, Falk G, et al. Photodynamic therapy in Barrett's esophagus with high grade dysplasia and intra‐mucosal carcinoma [abstract]. Am J Gastroenterol 2006;101(9 (Suppl)):S64.

187. Gockel I, Sultanov FS, Domeyer M, Goenner U, Junginger T. Developments in esophageal surgery for adenocarcinoma: a comparison of two decades. BMC Cancer 2007;7:114. Available: http://www.biomedcentral.com/1471‐2407/7/114 .

188. Goldberg M, Farma J, Lampert C, Colarusso P, Coia L, Frucht H, et al. Survival following intensive preoperative combined modality therapy with paclitaxel, cisplatin, 5‐fluorouracil, and radiation in resectable esophageal carcinoma: a phase I report. J Thorac Cardiovasc Surg 2003;126(4):1168‐73.

189. Gossner L, May A, Sroka R, Rabenstein T, Schneider TH, Hahn EG, et al. Photodynamic therapy of Barrett's esophagus with high‐grade dysplasia and early cancer [abstract]. Gastroenterology 1998;114(Suppl 1):A137.

190. Gossner L, Stolte M, Sroka R, Rick K, May A, Hahn EG, et al. Photodynamic ablation of high‐grade dysplasia and early cancer in Barrett's esophagus by means of 5‐aminolevulinic acid. Gastroenterology 1998;114(3):448‐55.

191. Govindan R, McLeod H, Mantravadi P, Fineberg N, Helft P, Kesler K, et al. Cisplatin, fluorouracil, celecoxib, and RT in resectable esophageal cancer: preliminary results. Oncology (Williston Park) 2004;18(14 Suppl 14):18‐21.

192. Gradauskas P, Rubikas R, Saferis V. Changes in quality of life after esophageal resections for carcinoma. Medicina (Kaunas ) 2006;42(3):187‐94. Available: http://medicina.kmu.lt.login.ezproxy.library.ualberta.ca/0603/0603‐02e.pdf.

193. Greenwald BD, Horwhat JD, Abrams JA, Lightdale CJ, Dumot JA. Endoscopic cryotherapy ablation is safe and well‐tolerated in Barrett's esophagus, esophageal dysplasia, and esophageal cancer [abstract]. Digestive Disease Week 2008, May 17‐22, 2008, San Diego, CA. In. Bethesda, MD: Digestive Disease Week; 2008. p. 235. Available: http://www.ddw.org.

194. Aust S, Obrist P, Jaeger W, Klimpfinger M, Tucek G, Wrba F, et al. Subcellular localization of the ABCG2 transporter in normal and malignant human gallbladder epithelium. Lab Invest 2004;84(8):1024‐36.

204

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta 195. Radu A, Grosjean P, Fontolliet C, Wagnieres G, Woodtli A, Bergh HV, et al. Photodynamic therapy for 101 early cancers of the upper aerodigestive tract, the esophagus, and the bronchi: a single‐institution experience. Diagn Ther Endosc 1999;5(3):145‐54.

196. Hainsworth JD. Concurrent chemoradiation followed by esophageal resection vs chemoradiation alone for localized esophageal cancer. Community Oncol 2007;4(7):431‐9. Available: http://www.communityoncology.net/journal/articles/0407431.pdf.

197. Halliday BP, Skipworth RJ, Wall L, Phillips HA, Couper GW, de Beaux AC, et al. Neoadjuvant chemotherapy for carcinoma of the oesophagus and oesophago‐gastric junction: a six‐year experience. Int Semin Surg Oncol 2007;4:24.

198. Heath EI, Burtness BA, Kleinberg L, Salem RR, Yang SC, Heitmiller RF, et al. Phase II, parallel‐design study of preoperative combined modality therapy and the matrix metalloprotease (mmp) inhibitor prinomastat in patients with esophageal adenocarcinoma. Invest New Drugs 2006;24(2):135‐40.

199. Herman LL, Gerdes H, Mendis R, Likier H, Lightdale CJ. Photodynamic therapy for completely obstructing esophageal cancer [abstract]. Gastrointest Endosc 1993;39(2):278.

200. Higuchi A. Evaluation of the quality of life after surgical treatment for thoracic esophageal cancer. Esophagus 2006;3(2):53‐9.

201. Higuchi K, Tanabe S, Koizumi W, Sasaki T, Nakatani K, Saigenji K, et al. Expansion of the indications for endoscopic mucosal resection in patients with superficial esophageal carcinoma. Endoscopy 2007;39(1):36‐40.

202. Imdahl A. Impact of neoadjuvant therapy of perioperative morbidity in patients with esophageal cancer. Am J Surg 2004;187(1):64‐8.

203. Ishikawa H. Clinical outcomes and prognostic factors for patients with early esophageal squamous cell carcinoma treated with definitive radiation therapy alone. J Clin Gastroenterol 2005;39(6):495‐500.

204. Jamieson NF, Thorpe S, Mosse A, Bown SG, Lovat LB. Photodynamic therapy using MTHPC for early Barrett's‐associated oesophageal cancers [abstract]. Gut 2003;52(Suppl 1):A46‐A47.

205. Jamieson N, Thorpe S, Mosse A, Novelli M, Lovat L, Bown S. Photodynamic therapy using mTHPC for early Barretts‐associated esophageal cancer [abstract]. Gastroenterology 2003;124(4 (Suppl)):A298.

206. Jin J, Liao Z, Zhang Z, Ajani J, Swisher S, Chang JY, et al. Induction chemotherapy improved outcomes of patients with resectable esophageal cancer who received chemoradiotherapy followed by surgery. Int J Radiat Oncol Biol Phys 2004;60:427‐36.

207. Jo WM, Shin JS, Lee IS. Mid‐term outcomes of side‐to‐side stapled anastomosis in cervical esophagogastrostomy. J Korean Med Sci 2006;21(6):1033‐6.

208. Junginger T, Gockel I, Heckhoff S. A comparison of transhiatal and transthoracic resections on the prognosis in patients with squamous cell carcinoma of the esophagus. Eur J Surg Oncol 2006;32(7):749‐55.

209. Kashtan H, Konikoff F, Haddad R, Skornick Y. Photodynamic therapy of cancer of the esophagus using systemic aminolevulinic acid and a non laser light source: a phase I/II study. Gastrointest Endosc 1999;49(6):760‐4.

205

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta 210. Kashtan H, Umansky M, Birkenfeld S, Scherubl H, Haddad R, Greenberg R, et al. Photodynamic therapy of Barrett's esophagus with dysplasia using systemic aminolevulinic acid and a non‐laser light source. A phase I/II study. Gastrointestinal Oncology 2002;4(2‐3):153‐7.

211. Katada C, Muto M, Manabe T, Boku N, Ohtsu A, Yoshida S. Esophageal stenosis after endoscopic mucosal resection of superficial esophageal lesions. Gastrointest Endosc 2003;57(2):165‐9.

212. Kelsen DP, Winter KA, Gunderson LL, Mortimer J, Estes NC, Haller DG, et al. Long‐term results of RTOG trial 8911 (USA Intergroup 113): a random assignment trial comparison of chemotherapy followed by surgery compared with surgery alone for esophageal cancer. J Clin Oncol 2007;25(24):3719‐25.

213. Kelsey CR, Chino JP, Willett CG, Clough RW, Hurwitz HI, Morse MA, et al. Paclitaxel‐based chemoradiotherapy in the treatment of patients with operable esophageal cancer. Int J Radiat Oncol Biol Phys 2007;69(3):770‐6.

214. Keresztes RS, Port JL, Pasmantier MW, Korst RJ, Altorki NK. Preoperative chemotherapy for esophageal cancer with paclitaxel and carboplatin: results of a phase II trial. J Thorac Cardiovasc Surg 2003;126(5):1603‐8.

215. Kim J‐H. Treatment outcomes of 70 cases of early esophageal carcinoma: 12 years of experience. Dis Esophagus 2007;20(4):297‐300.

216. Kleinberg L, Knisely JP, Heitmiller R, Zahurak M, Salem R, Burtness B, et al. Mature survival results with preoperative cisplatin, protracted infusion 5‐fluorouracil, and 44‐Gy radiotherapy for esophageal cancer. Int J Radiat Oncol Biol Phys 2003;56(2):328‐34.

217. Kodaira T, Fuwa N, Kamata M, Furutani K, Tachibana H, Yamazaki T. Single‐institute phase I/II trial of alternating chemoradiotherapy with 5‐FU and nedaplatin for esophageal carcinoma. Anticancer Res 2006;26(1B):471‐8.

218. Kunisaki C, Makino H, Otsuka Y, Kojima Y, Takagawa R, Kosaka T, et al. Appropriate routes of reconstruction following transthoracic esophagectomy. Hepatogastroenterology 2007;54(79):1997‐2002.

219. Lee JL, Park SI, Kim SB, Jung HY, Lee GH, Kim JH, et al. A single institutional phase III trial of preoperative chemotherapy with hyperfractionation radiotherapy plus surgery versus surgery alone for resectable esophageal squamous cell carcinoma. Ann Oncol 2004;15(6):947‐54.

220. Lew RJ, Scotiniotis IA, Kochman ML, Sanfilipo NJ, Hahn SM, Rosato EF, et al. Long‐term outcomes of esophagectomy, endoscopic mucosal resection, or photodynamic therapy for superficial esophageal cancer [abstract]. Gastrointest Endosc 2002;55(5 (Suppl)):AB219.

221. Li JH, Guo ZH, Jin ML, Zhao FY, Cai WM, Gao ML, et al. Photodynamic therapy in the treatment of malignant tumours: an analysis of 540 cases. J Photochem Photobiol B 1990;6(1‐2):149‐55.

222. Lovat LB, Thorpe SM, Francis H, Buonoacorssi G, Moss S, Bown SG. Photodynamic therapy using 5 amino laevulinic acid for high grade dysplasia in Barrett's oesophagus [abstract]. Gut 2000;46(Suppl 2):A93.

223. Kelty CJ, Ackroyd R, Brown NJ, Brown SB, Stephenson TJ, Reed MWR. Photodynamic therapy (PDT) for Barrett's oesophagus: Establishing the optimum dose of 5‐aminolaevulinic acid (ALA) [abstract]. Gut 2002;50(Suppl 2):A123.

206

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta 224. Luechakiettisak P, Kasetsunthorn S. Comparison of hand‐sewn and stapled in esophagogastric anastomosis after esophageal cancer resection: a prospective randomized study. J Med Assoc Thai 2008;91(5):681‐5.

225. Luu TD, Gaur P, Force SD, Staley CA, Mansour KA, Miller JI, Jr., et al. Neoadjuvant chemoradiation versus chemotherapy for patients undergoing esophagectomy for esophageal cancer. Ann Thorac Surg 2008;85(4):1217‐23.

226. Ma JY, Wu Z, Wang Y, Zhao YF, Liu LX, Kou YL, et al. Clinicopathologic characteristics of esophagectomy for esophageal carcinoma in elderly patients. World J Gastroenterol 2006;12(8):1296‐9.

227. Maish MS, DeMeester SR. Endoscopic mucosal resection as a staging technique to determine the depth of invasion of esophageal adenocarcinoma. Ann Thorac Surg 2004;78(5):1777‐82.

228. Malhi‐Chowla N, Wolfsen HC, DeVault KR. Esophageal dysmotility in patients undergoing photodynamic therapy. Mayo Clin Proc 2001;76(10):987‐9.

229. May A, Gossner L, Behrens A, Kohnen R, Vieth M, Stolte M, et al. A prospective randomized trial of two different endoscopic resection techniques for early stage cancer of the esophagus. Gastrointest Endosc 2003;58(2):167‐75.

230. Pech O. Endoscopic resection of superficial esophageal squamous‐cell carcinomas: Western experience. Am J Gastroenterol 2004;99(7):1226‐32.

231. van Meerten E, Muller K, Tilanus HW, Siersema PD, Eijkenboom WM, van DH, et al. Neoadjuvant concurrent chemoradiation with weekly paclitaxel and carboplatin for patients with oesophageal cancer: a phase II study. Br J Cancer 2006;94(10):1389‐94.

232. Michel P, Adenis A, Di FF, Boucher E, Galais MP, Dahan L, et al. Induction cisplatin‐irinotecan followed by concurrent cisplatin‐irinotecan and radiotherapy without surgery in oesophageal cancer: multicenter phase II FFCD trial. Br J Cancer 2006;95(6):705‐9.

233. Miyashita M. Response to preoperative chemotherapy affects prognosis in esophageal cancer. Dis Esophagus 2003;16(2):99‐101.

234. Monnier P, Savary M, Fontolliet C, Wagnieres Chatelain GA, Cornaz P, Depeursinge C, et al. Photodetection and photodynamic therapy of 'early' squamous cell carcinomas of the pharynx, oesophagus and tracheo‐bronchial tree. Lasers Med Sci 1990;5(2):149‐68.

235. Monnier P, Fontolliet C, Ollyo JB. Endoscopic findings of 100 early‐stage esophageal cancers. Diagn Ther Endosc 1994;1(2):83‐92.

236. Moorjani N, Junemann‐Ramirez M, Judd O, Fox B, Rahamim JS. Endoscopic ultrasound in esophageal carcinoma: comparison with multislice computed tomography and importance in the clinical decision making process. Minerva Chir 2007;62(4):217‐23.

237. Morgan MA, Lewis WG, Hopper AN, Escofet X, Havard TJ, Brewster AE, et al. Prospective comparison of transthoracic versus transhiatal esophagectomy following neoadjuvant therapy for esophageal cancer. Dis Esophagus 2007;20(3):225‐31.

238. Morita M, Egashira A, Yoshida R, Ikeda K, Ohgaki K, Shibahara K, et al. Esophagectomy in patients 80 years of age and older with carcinoma of the thoracic esophagus. J Gastroenterol 2008;43(5):345‐51.

207

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta 239. Murakami Y. Results of the 1999‐2001 Japanese patterns of care study for patients receiving definitive radiation therapy without surgery for esophageal cancer. Jpn J Clin Oncol 2007;37(7):493‐500.

240. Natsugoe S, Okumura H, Matsumoto M, Uchikado Y, Setoyama T, Yokomakura N, et al. Randomized controlled study on preoperative chemoradiotherapy followed by surgery versus surgery alone for esophageal squamous cell cancer in a single institution. Dis Esophagus 2006;19(6):468‐72.

241. Nemoto K, Takai K, Ogawa Y, Sakayauchi T, Sugawara T, Jingu K, et al. Salvage radiation therapy for residual superficial esophageal cancer after endoscopic mucosal resection. Int J Radiat Oncol Biol Phys 2005;63(5):1290‐4.

242. Oh DS, Hagen JA, Chandrasoma T, Dunst CM, DeMeester SR, Alavi M, et al. Clinical biology and surgical therapy of intramucosal adenocarcinoma of the esophagus. J Am Coll Surg 2006;203(2):152‐61.

243. Ohana M, Mino‐Kenudson M, Ban S, Puricelli W, Nishioka N. Frequent persistence of dysplasia by systematic pathological evaluation after photodynamic therapy for Barrett's esophagus with high‐grade dysplasia or early adenocarcinoma [abstract]. Gastroenterology 2005;129(3):1109.

244. Ohana M, Mino‐Kenudson M, Ban S, Puricelli W, Nishoka N. Frequent persistence of dysplasia by systematic pathological evaluation after photodynamic therapy for Barrett's Esophagus with high‐grade dysplasia or early adenocarcinoma [abstract]. Gastrointest Endosc 2005;61(5):AB94.

245. Ohana M, Mino‐Kenudson M, Ban SC, Puricelli W, Nishioka N, Lauwers G. Frequent persistence of dysplasia by systematic pathological evaluation after photodynamic therapy for Barrett's Esophagus with high‐grade dysplasia or early adenocarcinoma [abstract]. Gastroenterology 2005;128(4 (Suppl 2)):A72.

246. Okuyama M, Motoyama S, Suzuki H, Saito R, Maruyama K, Ogawa J. Hand‐sewn cervical anastomosis versus stapled intrathoracic anastomosis after esophagectomy for middle or lower thoracic esophageal cancer: a prospective randomized controlled study. Surg Today 2007;37(11):947‐52.

247. Omloo JM, Lagarde SM, Hulscher JB, Reitsma JB, Fockens P, van DH, et al. Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the mid/distal esophagus: five‐year survival of a randomized clinical trial. Ann Surg 2007;246(6):992‐1000.

248. Overholt B, Panjehpour M, Tefftellar E, Rose M. Photodynamic therapy for treatment of early adenocarcinoma in Barrett's esophagus. Gastrointest Endosc 1993;39(1):73‐6.

249. Overholt BF, Panjehpour M. Photodynamic therapy for Barrett's esophagus: Cardiac and pulmonary effects [abstract]. Gastroenterology 1996;110(4 (Suppl)):A220.

250. Oyama T, Tomori A, Hotta K, Morita S, Kominato K, Tanaka M, et al. Endoscopic submucosal dissection of early esophageal cancer. Clin Gastroenterol Hepatol 2005;3(7 Suppl 1):S67‐S70.

251. Patrice T, Foultier MT, Yactayo S, Douet MC, Maloisel F, Le BL. Endoscopic photodynamic therapy with haematoporphyrin derivative in gastroenterology. J Photochem Photobiol B 1990;6(1‐2):157‐65.

252. Peters F, Kara M, Rosmolen W, Ten Kate F, Bultje B, Krishnadath S, et al. Endoscopic resection combined with photodynamic therapy for high grade dysplasia and early cancer in Barrett's esophagus [abstract]. Gastrointest Endosc 2004;59(5 (Suppl)):AB251.

253. Peters FR, Kara MA, Rosmolen WD, Aalders MCG, ten Kate FJW, Bultje BC, et al. Endoscopic treatment of high‐grade dysplasia and early stage cancer in Barrett's esophagus. Gastrointest Endosc 2005;61(4):506‐ 14.

208

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta 254. Peters FP, Kara MA, Rosmolen WD, ten Kate FJW, Bultje AC, Krishnadath KK, et al. Endoscopic resection combined with photodynamic therapy for high grade dysplasia and early cancer in Barrett's esophagus [abstract]. Eur J Gastroenterol Hepatol 2005;17(1):A29‐A30.

255. Polee MB, Tilanus HW, Eskens FA, Hoekstra R, van der, Bur g ME Siersema PD, et al. Phase II study of neo‐ adjuvant chemotherapy with paclitaxel and cisplatin given every 2 weeks for patients with a resectable squamous cell carcinoma of the esophagus. Ann Oncol 2003;14(8):1253‐7.

256. Portale G, Peters JH, Hsieh CC, Hagen JA, DeMeester SR, DeMeester TR. Can clinical and endoscopic findings accurately predict early‐stage adenocarcinoma? Surg Endosc 2006;20(2):294‐7.

257. Pouw RE, Gondrie JJ, Curvers WL, Sondermeijer CM, Ten Kate FJ, Bergman JJ. Successful balloon‐based radiofrequency ablation of a widespread early squamous cell carcinoma and high‐grade dysplasia of the esophagus: a case report. Gastrointest Endosc 2008;68(3):537‐41.

258. Pouw RE, Gondrie JJ, Van Vilsteren FG, Sondermeijer C, Rosmolen W, Curvers WL, et al. A promising new combined treatment modality for Barrett's esophagus containing early neoplasia: endoscopic resection followed by step‐wise circumferential and focal radiofrequency energy ablation [abstract]. Digestive Disease Week 2008, May 17‐22, 2008, San Diego, CA. In. Bethesda, MD: Digestive Disease Week; 2008. p. M1323. Available: http://www.ddw.org.

259. Pouw RE, Gondrie JJ, Van Vilsteren FG, Sondermeijer C, Rosmolen W, Curvers WL, et al. Complications following circumferential radiofrequency energy ablation of Barrett's esophagus containing early neoplasia [abstract]. Digestive Disease Week 2008, May 17‐22, 2008, San Diego, CA. In. Bethesda, MD: Digestive Disease Week; 2008. p. S1475. Available: http://www.ddw.org.

260. Pouw RE, Gondrie JJ, Van Vilsteren FG, Sondermeijer C, Rosmolen W, Curvers WL, et al. Stepwise circumferential and focal radiofrequency ablation of Barrett's esophagus with high‐grade dysplasia or intramucosal cancer [abstract]. Digestive Disease Week 2008, May 17‐22, 2008, San Diego, CA. In. Bethesda, MD: Digestive Disease Week; 2008. p. 215. Available: http://www.ddw.org.

261. Pouw RE, Sondermeijer C, Ten Kate FJ, Fockens P, Eisendrath P, Deviere JM, et al. Stepwise circumferential and focal radiofrequency energy ablation of Barrett's esophagus with earlly ablation of Barrett's esophagus with early neoplasia: first European multi‐centre trial [abstract]. Digestive Disease Week 2008, May 17‐22, 2008, San Diego, CA. In. Bethesda, MD: Digestive Disease Week; 2008. p. S1441. Available: http://www.ddw.org.

262. Rahmani EY, Turpin C, Arney K. Photodynamic therapy for dysplastic Barrett's esophagus and early esophageal adenocarcinoma should be first line therapy! [abstract]. Gastrointest Endosc 2004;59(5 (Suppl)):AB250.

263. Rentz J, Bull D, Harpole D, Bailey S, Neumayer L, Pappas T, et al. Transthoracic versus transhiatal esophagectomy: a prospective study of 945 patients. J Thorac Cardiovasc Surg 2003;125(5):1114‐20.

264. Reynolds JV. Neoadjuvant chemoradiation may increase the risk of respiratory complications and sepsis after transthoracic esophagectomy. J Thorac Cardiovasc Surg 2006;132(3):549‐55.

265. Rizzetto C, DeMeester SR, Hagen JA, Peyre CG, Lipham JC, DeMeester TR. En bloc esophagectomy reduces local recurrence and improves survival compared with transhiatal resection after neoadjuvant therapy for esophageal adenocarcinoma. J Thorac Cardiovasc Surg 2008;135(6):1228‐36.

209

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta 266. Rohatgi PR, Swisher SG, Correa AM, Wu TT, Liao Z, Komaki R, et al. Failure patterns correlate with the proportion of residual carcinoma after preoperative chemoradiotherapy for carcinoma of the esophagus. Cancer 2005;104(7):1349‐55.

267. Rutegard M, Lagergren P. No influence of surgical volume on patients' health‐related quality of life after esophageal cancer resection. Ann Surg Oncol 2008;15(9):2380‐7.

268. Sanfilippo NJ, Hsi A, DeNittis AS, Ginsberg GG, Kochman ML, Friedberg JS, et al. Toxicity of photodynamic therapy after combined external beam radiotherapy and intraluminal brachytherapy for carcinoma of the upper aerodigestive tract. Lasers Surg Med 2001;28(3):278‐81.

269. Schaffer M, Corti L, Hollenhorst H, Boso C, Schaffer PM, Busch M, et al. Combined treatment modality of esophageal cancer: Radiation therapy (RT) with photodynamic therapy (PDT) [abstract]. Eur J Cancer 1997;33(Suppl 5):S29.

270. Schembre DB, Huang JL, Lin OS, Cantone N, Low DE. Treatment of Barrett's esophagus with early neoplasia: a comparison of endoscopic therapy and esophagectomy. Gastrointest Endosc 2008;67(4):595‐ 601.

271. Seruga B. Preoperative concomitant chemoradiotherapy in esophageal cancer. Radiol Oncol 2006;40(4):231‐7.

272. Seung SK, Smith JW, Molendyk J, Bader SB, Phillips M, Regan J, et al. Selective dose escalation of chemoradiotherapy for esophageal cancer: role of treatment intensification. Semin Oncol 2004;31(6 Suppl 18):13‐9.

273. Shimoyama S. I. The useful combination of a higher frequency miniprobe and endoscopic submucosal dissection for the treatment of T1 esophageal cancer. Surg Endosc 2006;20(3):434‐8.

274. Smith BR, Hinojosa MW, Reavis KM, Nguyen NT. Outcomes of esophagectomy according to surgeon's training: general vs. thoracic. J Gastrointest Surg 2008;12(11):1907‐11.

275. Sonnenberg A, Fennerty MB. Medical decision analysis of chemoprevention against esophageal adenocarcinoma. Gastroenterology 2003;124(7):1758‐66.

276. Stahl M, Oliveira J. Esophageal cancer: ESMO clinical recommendations for diagnosis, treatment and follow‐up. Ann Oncol 2008;19 Suppl 2:ii21‐ii22.

277. Stein HJ, Feith M, Bruecher BL, Naehrig J, Sarbia M, Siewert JR. Early esophageal cancer: pattern of lymphatic spread and prognostic factors for long‐term survival after surgical resection. Ann Surg 2005;242(4):566‐73.

278. Sun SP, Liu YZ, Ye T, Zhang W, Shen WB, Shi JL, et al. Randomized clinical trial on seven‐day‐per‐week continuous accelerated irradiation for patients with esophageal carcinoma: preliminary report on tumor response and acute toxicity. World J Gastroenterol 2006;12(43):7047‐50.

279. Tachibana M, Yoshimura H, Kinugasa S, Shibakita M, Dhar DK, Ueda S, et al. Postoperative chemotherapy vs chemoradiotherapy for thoracic esophageal cancer: a prospective randomized clinical trial. Eur J Surg Oncol 2003;29(7):580‐7.

280. Tachibana M. Clinicopathologic features of superficial esophageal cancer: Results of consecutive 100 patients. Ann Surg Oncol 2008;15(1):104‐16.

210

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta 281. Tajiri H, Daikuzono N, Joffe SN, Oguro Y. Photoradiation therapy in early gastrointestinal cancer. Gastrointest Endosc 1987;33(2):88‐90.

282. Terrosu G, Cedolini C, Bresadola V, Baccarani U, Uzzau A, Signor M, et al. Preoperative chemoradiotherapy in cancer of the thoracic esophagus. Dis Esophagus 2003;16(1):9‐16.

283. Tetzlaff ED. Significance of thromboembolic phenomena occurring before and during chemoradiotherapy for localized carcinoma of the esophagus and gastroesophageal junction. Dis Esophagus 2008;21(7):575‐ 81.

284. Urba SG, Orringer MB, Ianettonni M, Hayman JA, Satoru H. Concurrent cisplatin, paclitaxel, and radiotherapy as preoperative treatment for patients with locoregional esophageal carcinoma. Cancer 2003;98(10):2177‐83.

285. van Heijl M, Omloo JM, van Berge Henegouwen MI, Busch OR, Tilanus HW, Bossuyt PM, et al. NEOadjuvant therapy monitoring with PET and CT in Esophageal Cancer (NEOPEC‐trial). BMC Med Phys 2008;8:3.

286. Vuong T. The safety and usefulness of high‐dose‐rate endoluminal brachytherapy as a boost in the treatment of patients with esophageal cancer with external beam radiation with or without chemotherapy. Int J Radiat Oncol Biol Phys 2005;63(3):758‐64.

287. Walther B, Johansson J, Johnsson F, Von Holstein CS, Zilling T. Cervical or thoracic anastomosis after esophageal resection and gastric tube reconstruction: a prospective randomized trial comparing sutured neck anastomosis with stapled intrathoracic anastomosis. Ann Surg 2003;238(6):803‐12.

288. Wang KK. Multimodality therapy for gastroesophageal cancers. Journal of Gastrointestinal Surgery 2002;6(4):527‐31.

289. Wang H, Ryu J, Gandara D, Bold RJ, Urayama S, Tanaka M, et al. A phase II study of paclitaxel, carboplatin, and radiation with or without surgery for esophageal cancer. J Thorac Oncol 2007;2(2):153‐7.

290. Wang S, Liao Z, Wei X, Liu HH, Tucker SL, Hu C, et al. Association between systemic chemotherapy before chemoradiation and increased risk of treatment‐related pneumonitis in esophageal cancer patients treated with definitive chemoradiotherapy. J Thorac Oncol 2008;3(3):277‐82.

291. Wang SJ, Wu ML, Zhang LW, Guo XQ, Xu ZB, Er LM, et al. [The value of endoscopic mucosal resection for dysplasia and early‐stage cancer of the esophagus and gastric cardia.]. Zhonghua Zhong Liu Za Zhi 2008;30(11):853‐7.

292. Wolfsen HC, Woodward TA. Photodynamic therapy for dysplastic Barrett's esophagus and mucosal, esophageal adenocarcinoma: The value of endoscopic ultrasound and results using the bare fiber technique [abstract]. Gastrointest Endosc 2000;51 (Part 2)(4):AB116.

293. Wolfsen HC, Woodward TA, Raimondo M. Photodynamic therapy for dysplastic Barrett esophagus and early esophageal adenocarcinoma. Mayo Clin Proc 2002;77(11):1176‐81.

294. Wolfsen HC, Hemminger LL, Wallace MB, DeVault KR. Clinical experience of patients undergoing photodynamic therapy for Barrett's dysplasia or cancer. Aliment Pharmacol Ther 2004;20(10):1125‐31.

295. Wolfsen HC, Hemminger LL, Raimondo M, Woodward TA. Photodynamic therapy and endoscopic mucosal resection for Barrett's dysplasia and early esophageal adenocarcinoma. South Med J 2004;97(9):827‐30.

211

Photodynamic Therapy for the Treatment of Early Esophageal Cancer: A Systematic Review and Economic Evaluation © 2009, University of Alberta 296. Wolfsen HC, Hemminger LL. Salvage photodynamic therapy for persistent esophageal cancer after chemoradiation therapy. Photodiagn Photodyn Ther 2006;3(1):11‐4.

297. Wood D, Block K. Photodynamic therapy (PDT) may not reliably ablate T‐2 esophageal cancer (ACA) but does not complicate subsequent esophago‐gastrectomy [abstract]. Gastrointest Endosc 1999;49(4 (Part 2)):AB107.

298. Yano T, Muto M, Minashi K, Ohtsu A, Yoshida S. Photodynamic therapy as salvage treatment for local failures after definitive chemoradiotherapy for esophageal cancer. Gastrointest Endosc 2005;62(1):31‐6.

299. Yoshinaga S, Gotoda T, Kusano C, Oda I, Nakamura K, Takayanagi R. Clinical impact of endoscopic submucosal dissection for superficial adenocarcinoma located at the esophagogastric junction. Gastrointest Endosc 2008;67(2):202‐9.

300. Zingg U. High dose N‐acetylcysteine to prevent pulmonary complications in partial or total transthoracic esophagectomy: Results of a prospective observational study. Dis Esophagus 2007;20(5):399‐405.

301. Selvasekar CR, Mackenzie GD, Clark BR, Novelli MR, Thorpe SM, Mosse CA, et al. Randomised controlled trial of photodynamic therapy using low dose 5 aminolevulinic acid activated by red or green light for high grade dysplasia in Barrett's oesophagus. Gut 2005;54(Suppl 2):A54‐A55.

212