A SPECIAL ARTICLE

Photodynamic Therapy: An Emerging Treatment for GI Neoplasia

by S. Patel, B. Katanyutanon and J. Levey

Photodynamic therapy (PDT) is an emerging endoscopic technique used to treat a vari- ety of gastrointestinal . PDT is a safe and effective way to ablate neoplastic tissue within the and elsewhere in the body using a photosensitiz- ing agent and exposure to light. The following is a review of PDT including basic concepts, its use in Barrett’s , esophageal , and .

INTRODUCTION BASICS hotodynamic therapy (PDT) is an emerging ther- PDT utilizes a two-step process to achieve localized apy for the localized treatment of . Its tissue destruction. The essential components of PDT Ppotential use was first suspected nearly 100 years include a tumor-localizing photosensitizing agent, ago when visible light was noted to have a lethal effect laser light activation, and the presence of oxygen gas. on paramecia treated with acridine dye (1). More recently, PDT’s use has been extended to the treatment of cancers of the esophagus, , colon, bronchus, Photosensitizer bladder, brain, and biliary tree (2–8). Experience and The first step in PDT is the administration of a photo- expertise with PDT is rapidly growing. Currently, it is sensitizing agent. The photosensitizer is inert in its native FDA approved for the treatment of Barrett’s esophagus state and can be administered orally, intravenously, or with high-grade and superficial cancer as topically. Although taken up by all tissues in the body, well as for the palliation of in patients with most available photosensitizers have a 2–4 fold higher advanced esophageal cancer. The place of PDT within affinity for tumor cells than normal cells and therefore the therapeutic armamentarium is rapidly evolving. It achieve higher tissue concentrations within neoplastic is clear that PDT affords an alternative treatment tissue. This selectivity is thought to be due to multiple option for patients with various cancers who are not factors including variations in cellular uptake and metab- suitable candidates for other therapies. This article will olism between neoplastic and normal cells, differences in review the current knowledge of PDT as a treatment proliferation rates, and a more permeable vasculature modality. within neoplastic tissues. This selective uptake is subse- quently exploited in the activation step of PDT. S. Patel, B. Katanyutanon and J. Levey, Division At present, the majority of photosensitizers avail- of , University of Massachusetts/ able for use in clinical practice are derivatives of por- Memorial Medical Center, University of Massachu- phyrin compounds. The two most frequently used pho- setts Medical School, Worcester, MA. (continued on page 51)

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(continued from page 46) tosensitizers are sodium porfimer and 5-aminolevulinic oxygen-derived free radicals (9–11). The process begins acid (5-ALA). Although these compounds disperse to with the absorption of light energy by the photosensi- all tissues of the body upon administration, it has been tizer followed by the transference of this energy to mol- shown that normal tissues tend to retain the porphyrin ecular oxygen. The latter step results in the production compounds for only several hours. On the other hand, of the high-energy oxygen species that can interact with neoplastic tissues maintain measurable drug concentra- the tissue to induce necrosis. Damage to the tissues is tions for up to several days after administration. thought to result from direct singlet oxygen-induced Sodium porfimer (Photofrin®) is the most com- injury to the cellular machinery such as mitochondria, monly used photosensitizer in the U.S. and the only mitochondrial enzymes, lysosomes, and cell membrane one approved by the FDA. It is administered as an as well as to the surrounding vasculature (9,12,13). Ulti- intravenous infusion over 3–5 minutes approximately mately, this injury leads to cellular apoptosis and vascu- 48 hours prior to laser application. Sodium porfimer lar ischemia (14–17) . Because of the integral role that tends to accumulate in the submucosal layers of vari- oxygen and its derivatives play in PDT, tissues with ous tissues, including the skin where it can remain for higher blood flow are considered better targets for treat- up to thirty days and lead to photosensitivity reactions. ment and the desired tissue destruction. On the other hand, 5-ALA is a prodrug that must first be converted via the heme synthetic pathway to proto- porphyrin IX which then serves as the active photo- TREATMENT sensitizer. 5-ALA is administered orally or topically Although use of PDT in the local treatment of several 4–6 hours before laser activation and accumulates pre- cancers has been investigated, it has been most exten- dominantly in the mucosa. It tends to have a signifi- sively studied in the setting of esophageal dysplasia cantly shorter period of potential photosensitivity (1–2 and cancer. days). Because sodium porfimer accumulates to a Newer data has also shown that PDT can be benefi- greater degree in the deeper layers of the neoplastic tis- cial in patients with non-resectable cholangiocarcinoma. sue as compared to 5-ALA, the subsequent depth of Lastly, PDT has received attention for its potential appli- treatment is correspondingly greater with its use. This cations in the treatment of non-small cell cancer. finding has clinical implications that will be discussed. Barrett’s and Laser Light Activation Barrett’s esophagus (BE) is a condition in which the Approximately 48 hours (4–6 hours with 5-ALA) after normal, stratified squamous of the distal photosensitizer administration, laser light is applied lead- esophagus is replaced by abnormal, intestinal-type ing to a photochemical reaction. Both sodium porfimer epithelium called specialized . and protoporphyrin IX (derived from 5-ALA) can be acti- This condition develops in the setting of chronic gas- vated with visible red light at 630–635 nm. An optical troesophageal reflux disease and is considered an fiber is passed through the accessory channel of a video important premalignant precursor to esophageal adeno- endoscope to deliver the activating light. Upon laser . In fact, the relative risk of developing application, the initially non-toxic photosensitizer is acti- esophageal in patients with BE vated to become cytotoxic which then leads to subsequent appears to be 30–125 times that of the general popula- local tissue destruction. With the ability to target light tion. Over the past three decades, there has been a dra- delivery to certain areas and therefore confine activation, matic 5%–10% rise in the incidence of adenocarcinoma a second level of selectivity in treatment is possible. of the distal esophagus with the majority of cases aris- ing from BE (18). It is postulated that the development Oxygen Free Radicals of cancer progresses through a series of molecular The mechanism of cytotoxicity (or phototoxicity) is pri- events in the unstable metaplastic epithelium leading to marily mediated by the generation of singlet oxygen and progressive dysplasia and ultimately carcinoma.

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Table 1 PDT and esophageal dysplasia/cancer series

Pts w/ residual Pts w/ residual dysplasia and/or Author Patients (n) Photosensitizer Barrett’s (%) CA (%) Complications (%) Barr (25) 5 (HGD) 5-ALA 40 0 None Gossner (28) 32 (10 HGD, 22 CA) 5-ALA NR 0 HGD -47 23 CA Mild ALT/AST elevation-65 Overholt 100 (14 LGD, Porfimer 50 LGD, 57 HGD, 7 LGD, 21 HGD, Chest pain-NR (26) 73 HGD, 13 CA) 70 CA 31 CA Strictures-34 Atrial fibrillation-3 Pleural effusions-NR Phototoxicity-4 Ackroyd (30) 18 (LGD) 5-ALA 100 0 Chest pain-100 Phototoxicity-6 Wolfsen (31) 48 (34 HGD, 14 CA) Porfimer 44* 0 HGD, 7 CA Stricture-23 Phototoxicity-15 Atrial fibrillation-2 Congestive heart failure-2 Esophageal perforation-2 Overholt (27) 103 (14 LGD, Porfimer 29 LGD, 46 HGD, 7 LGD, 23 HGD, Strictures-30 80 HGD, 9 CA) 66 CA 46 CA Overholt (29) 138 (HGD) Porfimer NR 33 Strictures-37

LGD, low grade dysplasia; HGD, high-grade dysplasia; CA, cancer; NR, not reported; *not further specified.

The understanding of the malignant potential asso- even at experienced centers (18). A further complicat- ciated with BE has led to periodic endoscopic surveil- ing matter is that many patients are unsuitable surgical lance with random for dysplasia. In theory, candidates based on significant comorbidities. this approach allows gastroenterologists the opportu- Clearly, there is a need for the development of nity to detect dysplastic changes prior to the develop- minimally invasive treatment modalities for HGD or ment of advanced . Once high-grade dys- superficial cancer within BE. In the past several years, plasia (HGD) is found, the current recommendation is several endoscopic ablative modalities have been that patients should undergo an . Pro- explored including thermal, mechanical, and photody- ponents of this strategy argue that such patients with namic (20–24). PDT has shown particular promise in HGD have a 30% likelihood of having concurrent, this area (Table 1). Multiple case series evaluating undiagnosed invasive carcinoma that may have been PDT use have shown significant regression in the missed due to sampling error (19). Unfortu- length of BE including complete BE eradication in nately, esophagectomy is associated with significant select patients (25–31). In addition, these studies have morbidity (20%–47%) and mortality (average 4%) (continued on page 54)

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(continued from page 52) shed light on PDT’s ability to eliminate dysplasia and in 37.1% of patients following PDT with the vast superficial cancer (25–31). Numerous studies have majority (98%) resolving after dilation procedures. also confirmed that the use of PDT in conjunction with Lightdale, et al evaluated PDT with porfimer acid suppressive therapy can result in the regrowth of sodium versus Nd:YAG thermal ablation for the pallia- squamous epithelium in the esophagus (25–28,30). tion of dysphagia in advanced esophageal cancer using Overholt, et al followed 103 patients [77.7% with a prospective, multicenter, randomized study design HGD, 13.6% with low-grade dysplasia (LGD), and (32). Thermal tumor ablation with high-power 8.7% with early stage carcinoma] for a mean follow- Nd:YAG laser was considered the most efficacious up period of 50.7 months after PDT with porfimer endoscopically guided palliation technique available at sodium (27). This intention-to-treat analysis showed that time for patients with malignant dysphagia. A total complete eradication of BE in 54% of patients and a of 236 patients with either squamous cell or adenocar- mean reduction in length of BE of 6.92 cm. Success in cinoma were randomized either to treatment with PDT elimination of LGD, HGD, and cancer was 92.9%, or Nd:YAG laser therapy, and efficacy determinations 77.5%, and 44.4% respectively. Esophageal strictures were based on symptom palliation and objective tumor were seen in 30% of patients overall. Of concern, response. PDT showed comparable efficacy to Nd: metaplastic glands were found beneath the regenerated YAG therapy with nearly 50% in both groups reporting squamous mucosal in 4 patients and subsquamous can- an improvement in swallowing at 1 week post-treat- cer developed in 3 patients with initial HGD. ment, however PDT was also noted to have a statisti- In attempt to reduce the risk of post-PDT stricture cally significant effect on objective tumor response formation, Gossner, et al evaluated PDT using 5-ALA in (32% vs. 20%—p <0.05). PDT was found to be techni- 32 patients (10 with HGD and 22 with early adenocarci- cally easier to perform, better tolerated by patients, and noma) (28). HGD and cancer were eliminated in 10 of 10 required fewer treatment sessions to achieve a similar patients and 17 of 22 patients respectively. Notably, PDT effect. PDT was also more efficacious for treatment of had particular difficulty in treating cancerous lesions that longer tumors (>10 cm), tumors located in the upper were thicker that 2 mm which likely reflects the predilec- and lower third of the esophagus, and for patients who tion for superficial obliteration with this photosensitizer. had undergone previous cancer treatment or experi- Complete BE eradication was not seen in any patients, enced tumor recurrence. Photosensitivity was the most however, partial squamous reepithelialization was seen common adverse event (19%) seen in the PDT group. in 68% of patients. Once again, residual BE was Based on this data, PDT use in malignant esophageal observed beneath the newly formed squamous epithe- dysphagia received FDA approval. lium. No esophageal strictures were seen. FDA approval for the use of PDT in the treatment of HGD within BE was granted based on a follow-up Cholangiocarcinoma study presented in abstract-form by Overholt, et al Cholangiocarcinoma, or cancer of the bile ducts, is a (29). They evaluated the efficacy of PDT using por- rare tumor with a generally dismal prognosis. It fimer sodium plus omeprazole (PO) versus omepra- accounts for approximately 3 percent of all gastroin- zole (O) alone in a multicenter, partially blinded, ran- testinal and has been recognized to have domized study that included 208 patients with HGD in a rising incidence on three separate continents (33). BE. Patients were randomized in 2:1 ratio to the PO Early, presymptomatic detection and the potential for and O groups respectively. All patients received curative surgical resection are exceedingly uncom- omeprazole 20 mg po BID and were followed for a mon. Most patients are diagnosed after they manifest minimum of 24 months. The results impressively symptoms reflective of biliary obstruction, most showed statistically significant differences in favor of prominently . As obstruction of the bile ducts the PO group with regards to complete ablation of all is a consequence of advanced disease, curative surgi- areas of HGD (76.8% vs. 38.6%) and disease progres- cal resection is generally no longer a viable option in sion to cancer (13.0% vs. 28.0%). Strictures were seen (continued on page 56)

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Table 2 PDT and non-resectable cholangiocarcinoma series

Pts w/ Improvement Median reduction of in QOL survival Author Patients (n) Photosensitizer cholestasis (%) indices (mo.)* Complications (%) Ortner (6) 9 Porfimer 100 Yes 14.4 Skin hyperpigmentation-100 Fever-11 Berr (7) 23 Porfimer 100 Yes 11.0 Epigastric distress-NR Mild rise in ALT-NR Hemobilia-4 Cholangitis-35 Phototoxicity-17 Ortner (8) 54 Porfimer 73.8 Yes 14.4 Photosensitivity-10 Fibrotic stricture-4 Cholangitis-4 -2

NR, not reported; *as compared to median survival between 1.5–4.2 months in matched historical controls. these patients. Unfortunately, the role of received 7 sessions of PDT over a 4-year period (38). and has yet to be defined with the lit- This was followed by two studies by Ortner, et al. The erature containing disappointing and conflicting data first was an uncontrolled pilot study of PDT in nine (34–37). For these patients with inoperable tumors, patients with advanced non-resectable cholangiocarci- palliation is the primary focus of medical management noma (6). The authors demonstrated that PDT induced including consideration of biliary drainage options. a rapid decline in serum bilirubin levels and improved At present, two approaches are routinely utilized quality of life indices. In addition, its use was associ- to enhance biliary drainage: endoscopic retrograde ated with significantly longer median survival times as cholangiography (ERC) and percutaneous transhepatic compared to historical controls (439 days versus 70 cholangiography (PTC). Both approaches allow for the days). As a follow-up to this study, Ortner, et al per- subsequent placement of plastic or expandable metal formed the first randomized, prospective, controlled into the large intrahepatic ducts and common trial of PDT use in thirty-nine patients with non- to facilitate flow of biliary contents into the resectable cholangiocarcinoma (8). Patients were ran- duodenum. Unfortunately, both types of stents are domized to either PDT plus stenting (group A) versus prone to occlusion secondary to tumor infiltration and stenting alone (group B). They were once again able to biofilm formation. Despite our best attempts to ensure show that PDT significantly prolongs median survival adequate biliary drainage, patients remain at risk for time (493 days in group A vs. 98 days in group B) as infectious complications and hospital admissions due well as improves biliary drainage and quality of life. In to recurrent biliary obstruction. fact, the survival benefit was so impressive that the Several recent reports have shown the potential investigators terminated the study early as they usefulness of PDT with sodium porfimer in the pallia- deemed continued patient randomization to stenting tion of non-resectable cholangiocarcinoma (6–8,38) alone to be unethical. Photosensitivity was noted in (Table 2). The initial was a case report by McCaughan, 10% of patients treated with PDT and post-PDT biliary et al, which showed the potential benefit of this modal- strictures were seen in 2 patients. ity in a single patient with cholangiocarcinoma who (continued on page 58)

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Non-small Cell Lung Cancer operating room lamps, unshaded light bulbs at close Lung cancer is currently the leading cause of cancer- proximity, etc.) during this time. The photosensitivity is related mortality in both men and women in developed a result of uptake of this drug by all parts of the skin and countries. Surgical resection is considered the treatment activation by visible light. The vast majority of these of choice for patients with early stage lung malignan- reactions can be prevented with the proper use of protec- cies. However, a significant number of these patients are tive gear including clothing, sunglasses, and hats. Ultra- not favorable operative candidates in light of cardiopul- violet sunscreens are of no value in protecting against monary comorbidities and the high risk of operative photosensitivity reactions because photoactivation mortality as well as post-operative reduction in func- occurs via exposure to visible light. tional lung capacity. In this setting, PDT has shown As described above, forma- promise as an alternative treatment option. Remission tion is commonly seen after PDT treatment of rates have ranged from 70%–81% in various reports esophageal disease, especially with the use of sodium evaluating PDT’s efficacy in the treatment of early stage porfimer as the photosensitizer. In greater than 90 % of non-small cell lung cancers, with better outcomes seen cases, such strictures were successfully treated with with smaller, more superficial lesions (39–42). Five- esophageal dilation and patients experienced improve- year survival rates for patients with early stage non- ment in dysphagia (27–29). The most frequently small cell lung cancers treated with PDT have varied observed, gastrointestinal symptoms with PDT include widely ranging from 43%–93% (39,43). In patients with abdominal pain, nausea, constipation, and diarrhea. more advanced, obstructing, endobronchial lesions, These complaints tend to be self-limited and can be PDT has been shown to safely improve airway patency generally controlled with over-the-counter and/or pre- in 74%–90% of treated patients (44,45). Based on this scription medications. body of literature, PDT has been approved by the FDA for the treatment of microinvasive, endobronchial non- THE FUTURE small cell lung cancers in patients who are not candi- Clearly, PDT has been shown to be an attractive, local dates for other therapies as well as for the palliation of cancer treatment option that has many advantages over obstructing, endobronchial non-small cell lung masses. other conventional therapies. As many cancer patients are debilitated from their underlying malignancy as well ADVERSE EVENTS as comorbidities, treatment options may be limited. The To date, the literature regarding PDT has shown that it is growing experience with this novel therapy has con- a generally safe and well-tolerated treatment modality. firmed PDT’s vast potential as a safe and effective ther- The most commonly seen adverse events include cuta- apeutic modality for various cancers. Future areas of neous and ocular photosensitivity (20%–68%) (46), investigation include developing newer photosensitizers esophageal stricture formation (0%–37.1%) (26–29,31), to optimize therapy for a given cancer, determining as well as non-specific gastrointestinal symptoms other cancers that are amenable to treatment, and defin- (5%–30%) (46). Photosensitivity reactions are predomi- ing the role of combination therapy with other modali- nantly mild and include skin erythema, edema, and blis- ties. Undoubtedly, PDT’s ease of application, favorable tering as well as ocular discomfort, erythema, and pho- safety profile, and promising results merit consideration tophobia. All patients who receive sodium porfimer may for use in select patients. Indeed, the future of PDT, just like the laser light that is essential to the phototoxic be photosensitive for up to thirty days post-infusion. A ■ significantly shorter photosensitivity period (24–48 process, is considerably bright. hours) is seen with the use of 5-ALA as the photosensi- References tizer. With the risk of photosensitivity reactions, all 1. Wang KK. Current status of photodynamic therapy of Barrett’s patients must strictly observe precautions to avoid expo- esophagus. Gastroint Endosc, 1999; 49: S20-S23. 2. Sibilie A, Lambert R, Souquet JC, et al. Long-term survival after sure of their eyes and skin to direct sunlight and bright photodynamic therapy for esophageal cancer. Gastroenterology, indoor light (from examination lamps, dental lamps, 1995; 108: 337-344.

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