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Home , Medullary carcinoma, Pseudomyxoma peritonei

PRINCESS MARGARET CENTRE CLINICAL PRACTICE GUIDELINES

GASTROINTESTINAL

COLON CANCER AND PERITONEAL SURFACE

GI Site Group – Colon Cancer and Peritoneal surface malignancy

Authors: Dr. Jennifer Knox, Dr. Mairead McNamara

1. INTRODUCTION 3

2. SCREENING AND EARLY DETECTION 3

3. DIAGNOSIS 3

4. PATHOLOGY 4

5. MANAGEMENT 4

5.1 SURGERY: COLON CANCER 4 5.2 5 5.3 RECURRENT OR METASTATIC DISEASE: SURGICAL, SYSTEMIC OPTIONS 6 5.4 NURSING PRACTICE 9

6. PERITONEAL SURFACE MALIGNANCY 9

7. SUPPORTIVE CARE 10

7.1 PATIENT EDUCATION 10 7.2 PSYCHOSOCIAL CARE 10 7.3 SYMPTOM MANAGEMENT 10 7.4 CLINICAL NUTRITION 10 7.5 PALLIATIVE CARE 10

8. FOLLOW-UP CARE 10

9. REFERENCES 12

These guidelines are evidence-based and thus subject to change. Some recommendations are currently funded in this jurisdiction, while others are in negotiation. 2 Last Revision Date – August 2015

1. Introduction

Cancers of the colon and are the third most common tumour type worldwide. About 70% of patients with colon cancer are >65 years of age and the disease is rare under the age of 45 (2 per 100,000/year). most commonly occurs sporadically and is inherited in 5-10% of cases. Diet is the most important exogenous factor identified up to now in the etiology of colorectal cancer. Recently, regular use of aspirin after diagnosis has been associated with longer survival among patients with mutated-phosphatidylinositol 3-kinase, catalytic subunit alpha polypeptide gene (PI3KCA) colorectal cancer and may serve as a predictive molecular biomarker for adjuvant aspirin therapy (Liao et al., 2012).

2. Screening and early detection

The polyposis and colorectal cancer syndromes include familial adenomatous polyposis (FAP), Turcot syndrome, Hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome), Peutz-Jeghers syndrome and all increase the risk of colorectal cancer.

Inflammatory bowel disease, particularly ulcerative colitis is associated with an increased risk for colon cancer, estimated to be 5% to 10% by 20 years after diagnosis and is also associated with a high incidence of synchronous affecting 10% to 20% of cases. Crohn’s disease may also have a role in increasing colorectal cancer risk, particularly in the ileocolic region.

The screening tests for colorectal cancer include digital rectal examination, fecal occult blood testing (FOBT), sigmoidoscopy, colonoscopy, barium enema and CT colonography. Standard of care in Ontario is currently FOBT, beginning at the age of 50, and colonoscopy at the age of 40 (or 10 years younger than the youngest case in the family) for those with a first degree relative with colorectal cancer.

Screening should be more regular for patients at high risk such as those with inherited syndromes, inflammatory bowel disease, and previous adenomatous polyps or colorectal cancer.

Individuals with Lynch Syndrome should be screened with complete colonoscopy every year beginning between ages 20 and 25 because of the lack of a visible premalignant lesion in this population, accelerated -to- sequence, and the higher risk for right-sided colon cancers. Individuals with FAP should start screening colonoscopies as early as age 10, after genetic counseling and genetic testing.

3. Diagnosis

Colon cancer may be diagnosed when a patient presents with symptoms or as the result of a screening program. A history and physical examination of the patient is necessary.

3 Last Revision Date – August 2015 Investigations should include complete blood count, electrolytes, function tests and carcinoembryonic antigen (CEA), full colonoscopy or proctosigmoidoscopy, CT chest and abdomen. A MRI might be useful for locally advanced cases, but its use is generally restricted to rectal cancer. Positron emission tomography may be useful to detect recurrent colorectal cancer.

A histopathological diagnosis is required. Surgical staging should include an assessment of liver metastases, nodal spread of disease and extension of tumour through the bowel wall and onto adjacent structures. At least 12-14 local nodes should be removed for staging.

4. Pathology

The vast majority of colorectal cancers are . The World Health Organization classification of of the colon and rectum include in situ/severe dysplasia, adenocarcinoma, mucinous (colloid) adenocarcinoma (>50% mucinous), carcinoma (>50% signet ring cell), squamous cell (epidermoid) carcinoma, adenosquamous carcinoma, small cell (oat cell) carcinoma, , undifferentiated carcinoma and others such as papillary carcinoma.

Cancer of the vermiform appendix is rare. Primary malignant tumours of the appendix are found in 0.1% of all appendectomy specimens, the majority of which are , but approximately one third are adenocarcinomas. Metachronous or synchronous primary , particularly involving the , are not uncommon in patients with appendiceal tumours. Appendiceal neoplasms commonly spread intraperitoneally and when they are secreting (e.g.mucinous ) and present with peritoneal dissemination, they produce the clinical picture of a . Details on treatment are included in section on peritoneal surface .

Other tumours involving the large bowel include Kaposi’s sarcoma and lymphomas whose treatment details are not discussed here and tumours (treatment is discussed in section on neuroendocrine tumours).

The American Joint Committee on Cancer (AJCC) and Union for International Cancer Control (UICC) TNM staging (colon cancer and appendiceal cancer) is available online at www.nccn.org.

5. Management

5.1 Surgery - Colon cancer

Surgical resection is the only curative modality for localized colon cancer. The goal of surgery is a wide resection of the involved segment of bowel including a segment of colon of at least 5cm on either side of the tumour with removal of its lymphatic drainage.

4 Last Revision Date – August 2015

A family history of colorectal cancer and other extracolonic cancers should be sought prior to surgery, as an inherited predisposition to colon cancer may alter the surgical approach, prompting consideration of subtotal or total colectomy in high-risk individuals.

5.2 Adjuvant therapy

Adjuvant treatment is recommended for stage III and high risk stage II colon cancer patients. Patients with stage II are at high risk if they present with at least one of the following characteristics:

Lymph node sampling <12 Poorly differentiated tumour Vascular or lymphatic or perineural invasion Tumour presentation with obstruction or perforation pT4 stage

The early initialization of adjuvant therapy is important. A meta-analysis of studies determined that optimal survival benefits were seen in patients starting adjuvant therapy within 4-6 weeks of their curative intent surgery (Biagi et al., 2005, Jonker et al., 2008).

High levels of DNA microsatellite instability (MSI-H) is associated with longer survival than either MSI-low or microsatellite stable tumours in both HNPCC and sporadic cases. Adjuvant 5-FU based is less beneficial for patients with MSI-positive tumours based on large retrospective data bases. However, this finding has not been validated in prospective studies. Therefore, microsatellite instability should not be routinely used to develop treatment recommendations in patients with resected colorectal cancer until prospective data becomes available. At this time for stage 2 patients we would check MSI status and not use 5-FU monotherapy as an adjuvant if MSI-high and also discuss no adjuvant chemotherapy at all with the patient.

Adjuvant chemotherapy is controversial in stage II and elderly patients >70 years. A recent posthoc analysis of the Multicenter International study of Oxaliplatin/Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) revealed that there was no statistically significant benefit (overall or disease free survival) for the addition of oxaliplatin to fluorouracil/leucovorin as adjuvant treatment for either stage II or elderly patients (Tournigand et al., 2012).

The addition of oxaliplatin to 5-FU/leucovorin (FOLFOX) for 6 months has been adopted worldwide as the standard of care for adjuvant treatment in stage III colon cancer based on results of the National Surgical Adjuvant and Bowel Project (NSABP) C-07 trial (Yothers et al., 2011) and the MOSAIC trial (André et al., 2009). Preliminary data on capecitabine in combination with oxaliplatin indicated a benefit in disease free survival in the adjuvant setting but has been presented in abstract form only.

5 Last Revision Date – August 2015 Neither bevacizumab nor cetuximab prolong disease free survival when added to adjuvant chemotherapy in resected stage III colon cancer and is not recommended in the adjuvant treatment of patients with curatively resected stage III colon cancer (de Gramont et al., 2012, Alberts et al., 2012).

The role of adjuvant treatment for adenocarcinoma of the appendix following a right colectomy is unknown. Adjuvant 5-FU based chemotherapy is recommended in patients with node positive intestinal type adenocarcinoma, extrapolating from data on adjuvant chemotherapy for node positive colon cancer.

5.3 Recurrent or metastatic disease

5.3.1 Surgical options

Patients with metastatic colon cancer should be assessed by a multidisciplinary team including surgical oncology, hepatobiliary surgery, thoracic surgery if indicated, medical oncology and radiation oncology. Surgical resection should be considered for metastases confined to the liver and/or . In patients with resectable liver metastases, perioperative chemotherapy with the FOLFOX regimen improves progression free survival by 7%-8% at 3 years (Nordlinger et al., 2008). Perioperative chemotherapy is given for 3 months before and 3 months after the surgical resection of the metastases. In some cases, chemotherapy post-liver resection for colorectal carcinoma (CRC) metastases (vs perioperative chemotherapy) may be preferred at the discretion of the hepatobiliary surgeon.

In selected patients, initially unresectable liver metastases can become resectable after downsizing with chemotherapy and, if so, resection should be considered after multidisciplinary discussions.

Criteria for resectability of liver metastases include the ability to resect all known metastases while leaving a future remnant liver of 2 contiguous segments with adequate vascular supply, venous and biliary drainage and adequate liver volume. Multiple liver resections can also be performed. Patients with normal can tolerate resections of up to 80% of the liver volume, but this drops to about 60% to 70% in patients with steatosis, underlying liver disease or extensive previous chemotherapy.

For patients who have hepatic metastases at initial presentation of colorectal carcinoma, the optimal timing of primary and liver resection is uncertain. Multidisciplinary discussion is advised. The role of surgical resection for liver metastases and isolated (non-lung) extrahepatic metastases is controversial and should be considered within the context of careful multidisciplinary evaluation and/or clinical trials. There are also recent cancer care ontario guidelines on liver metastases in CRC

Following complete resection of liver metastases, the best postoperative strategy is uncertain. In the absence of published randomized trials to guide clinical practice

6 Last Revision Date – August 2015 following metastasectomy, completion of a 6 month course of systemic chemotherapy containing oxaliplatin is recommended.

Radiation therapy can play a role in the management of patients with oligometastatic disease and should be considered for patients who are not surgical candidates or refuse surgery. Long term disease control and cure has been reported with stereotactic body radiation therapy (SBRT) for oligometastatic disease, for disease sites such as liver metastases.

5.3.2 Systemic options

Active drugs in the treatment of metastatic colorectal carcinoma include the fluoropyrimidines, oxaliplatin, irinotecan, and the therapeutic monoclonal antibodies bevacizumab, cetuximab, and panitumumab, the recombinant fusion protein aflibercept and the tyrosine kinase inhibitor regorafenib.

The optimal way to combine and sequence these agents is debatable and in general, exposure to all active drugs is more important than the specific sequence of administration. The optimal duration of chemotherapy for metastatic colorectal carcinoma remains controversial with options being a fixed treatment period (3-6 months) or treatment until progression or toxicity. Patients who are given chemotherapy drug holidays should be followed for symptomatic and/or significant radiological progression and treatment re-instituted if warranted.

First line treatment

For patients who are able to tolerate it, a chemotherapy doublet such as FOLFOX, XELOX (combination of capecitabine and oxaliplatin) or FOLFIRI (combination of 5- fluorouracil/leucovorin with irinotecan) may be given in first line treatment of metastatic colorectal carcinoma (Goldberg et al., 2004, Tournigand et al., 2006, Cassidy et al., 2008). Choice may be determined by patient selection or expected toxicity profiles.

In patients, who receive oxaliplatin containing regimens in first line in the metastatic setting, oxaliplatin can be discontinued after three to four months in responding patients before the onset of severe neurotoxicity, while maintaining infusional 5-FU/leucovorin plus bevacizumab if given, with reintroduction at disease progression (Tournigand et al., 2006). However, this approach is currently not funded by Cancer Care Ontario but is under review in their Program in Evidence-based Care (PEBC) for 2013.

Regardless of whether an oxaliplatin-based or an irinotecan-based chemotherapy regimen is selected, it is recommended that it is administered in combination with bevacizumab. However, it must be balanced against the potential for serious treatment-related toxicity (Hurwitz et al., 2004, Saltz et al., 2008). In particular, the use of bevacizumab in elderly patients with a history of an arterial thromboembolic event within 6 to 12 months must be carefully considered. Because of the risk of impaired wound healing, bowel perforation,

7 Last Revision Date – August 2015 and fistula formation, at least 28 days should elapse between major surgery and administration of bevacizumab, except in emergency situations.

For selected patients, e.g. those with wild type K-ras tumours, and/or a contraindication to bevacizumab, adding cetuximab to a first-line irinotecan based therapy is a reasonable option if funding is available in this setting (Jonker et al., 2007). This approach is currently not funded by Cancer Care Ontario at PMCC. Patients receiving cetuximab or panitumumab should have monitoring of serum electrolytes, including magnesium, calcium, and potassium.

Second line treatment

In the absence of a clinical trial, for patients initially treated with FOLFOX or XELOX, a switch can be made to FOLFIRI or irinotecan alone at the time of disease progression. Cetuximab/panitumumab alone in K-ras wild-type patients may be considered for patients who are intolerant of irinotecan if funding approval can be obtained.

If irinotecan-based therapy was utilized in first line, a switch to FOLFOX or XELOX is appropriate at the time of disease progression for suitable patients.

Another option which may be available in the near future, for patients treated initially with FOLFOX, is FOLFIRI alone or FOLFIRI plus intravenous aflibercept (Van Cutsem et al., 2012).

Research has revealed that maintenance of vascular endothelial growth factor inhibition with bevacizumab plus standard second line treatment beyond disease progression has clinical benefits in patients with metastatic colorectal cancer (Bennouna et al., 2012) but again, current funding mechanisms may not allow.

Third line Treatment:

Panitumumab alone or Cetuximab with irinotecan rechallenge in K-ras wild-type patients may be considered for patients suitable for further systemic therapy and is currently funded.

Beyond Third line treatment

For patients with metastatic colorectal carcinoma who have been previously treated with fluoropyrimidine, oxaliplatin and irinotecan based chemotherapy, an anti-vascular endothelial growth factor receptor agent, and if K-ras wild type, an anti-epidermal growth factor receptor therapy, and who require additional therapy, single agent regorafenib, if funding available could be considered (Grothey et al., 2012), or enrollment in a phase I or II trial testing novel agents/combinations.

8 Last Revision Date – August 2015 Reutilizing the regimen initially used in the treatment sequence (e.g. FOLFOX) is reasonable if there was initial response. During the often lengthy phase of sequential therapy, tumours may regain sensitivity to previously used drugs.

The benefit of systemic chemotherapy for advanced appendiceal adenocarcinoma is unknown.

5.4 Oncology Nursing

Refer to general oncology nursing practices

6. Peritoneal surface malignancy

Peritoneal surface malignancy can be defined as either primary peritoneal malignancy or secondary peritoneal malignancy having metastatically spread to the from a different primary site.

Peritoneal surface malignancies can be subdivided into three main categories based on site of origin; peritoneum, gastrointestinal tract (, appendix, colon, rectum, ) and .

The most common histology for peritoneum is mesothelioma. The most common histologies for the gastrointestinal tract are mucinous adenocarcinoma, intestinal/colonic type adenocarcinoma, signet ring cell adenocarcinoma, (adenocarcinoid) and carcinoid. The most common histology for ovary is epithelial carcinoma.

“Pseudomyxoma peritonei” is a clinical entity characterized by intraperitoneal mucinous dissemination from a variety of pathological sources, the most common of which is a low-grade mucinous of the appendix (sometimes termed ). However, mucinous adenocarcinomas of the appendix (sometimes termed ) or other organs can also produce the clinical picture of pseudomyxoma peritonei.

A diagnosis of primary peritoneal malignancy should be made based on findings of a number of investigations including history and physical examination, laboratory investigations including Ca125, mesothelin, Ca 19-9, CEA, CT abdomen/thorax/pelvis, colonoscopy if an appendix primary is suspected, diagnostic laparoscopy to evaluate the extent and resectability of the disease, histological diagnosis and discussion in a multidisciplinary setting.

Selected patients may be treated with aggressive surgical cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) which enhances drug penetration. This approach is best suited to patients with minimal residual disease (deposits smaller than 2 to 2.5mm) after surgical cytoreduction. The experience of the treating team is critical and should only be done in experienced centres.

9 Last Revision Date – August 2015 In Toronto, the agent utilized in HIPEC for mesothelioma is oxaliplatin but other options include mitomycin-C, doxorubicin or cisplatin. Mitomycin C is the agent used for appendix primaries and oxaliplatin (concurrently used with intravenous 5-FU/leucovorin) is the HIPEC agent utilized for peritoneal only colorectal carcinoma. Mitomycin C is another option and is used by many centres (Cukier et al., 2012).

The follow-up care advised for patients post-surgical cytoreduction and HIPEC is history and clinical examination, laboratory investigations as described previously if elevated pre-operatively, CT abdomen/thorax/pelvis every 3-4 months for 2 years and then every 6 months.

There is very little data on how to treat patients with recurrence of peritoneal surface malignancy and in selected patients with a good performance status and a low peritoneal cancer index (Esquivel & Sugarbaker, 1999), repeat cytoreductive surgery and HIPEC could possibly be performed.

7. Supportive Care

7.1 Patient Education

Refer to general patient education practices

7.2 Psychosocial Care

Refer to general psychosocial oncology care guidelines

7.3 Symptom Management

Refer to general symptom management care guidelines

7.4 Clinical Nutrition

Refer to general clinical nutrition care guidelines

7.5 Palliative Care

Refer to general oncology palliative care guidelines

8. Follow-up care – Colon cancer

Following adjuvant treatment, in Princess Margaret Cancer Centre, a history and physical exam and CEA are recommended every 3 months for the first 2 years, every 4 months for year 3, every 6 months for year 4 and 5 and yearly from Year 6 to 10 (which can be done by primary physician or at a cancer survivorship clinic). CT abdomen/thorax and pelvis

10 Last Revision Date – August 2015 are recommended every 6 months for year 1 and 2, and yearly in years 3, 4 and 5. A colonoscopy is recommended in year 3 and 8 and every 5 years thereafter.

For patients who are receiving palliative chemotherapy in the metastatic setting, it is recommended that the patient be re-evaluated with CEA and a CT scan of the involved regions every 2-3 months. This should also apply during chemotherapy drug holiday periods. History, physical examination and evaluation of patient’s general condition including side effects of chemotherapy need to be elucidated during systemic treatment as per physician choice (usually every 2-4 weeks depending on regimen being administered).

11 Last Revision Date – August 2015 9. References

Alberts SR, Sargent DJ, Nair S et al. Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer : a randomized trial. JAMA 307: 1383-1393, 2012.

André T, Boni C, Navarro M et al. Improved overall survival with oxaliplatin, fluorouracil and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 27: 3109-3116, 2009.

Bennouna J, Sastre J, Arnold D et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML 18147): a randomised phase 3 trial. Lancet Oncol 14: 29-37, 2013.

Biagi JJ, Raphael, MJ, Mackillop, et al . Association between time to initiation of adjuvant chemotherapy and survival in colorectal cancer. JAMA 305 (22): 2335-2342, 2005.

Cassidy J, Clarke S, Diaz-Rubio E et al. Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol 26: 2006-2012, 2008.

Cukier M, Gillis A, Escallon J et al. (eds) Peritoneal surface malignancies. Surgical Oncology Manual, University of Toronto, 1st edition. Type & Graphics Inc. Toronto. p. 201-212, 2012. de Gramont A, Van Cutsem E, Schmoll HJ et al. Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol 13: 1225-1233, 2012.

Esquivel J, Sugarbaker PH. Elective surgery in recurrent colon cancer with peritoneal seeding: when to and when not to proceed. G Chir 20: 81-86, 1999.

Goldberg RM, Sargent DJ, Morton RF et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22: 23-30, 2004.

Grothey A, Van Cutsem EV, Sobrero A et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381: 303-312, 2013.

Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350: 2335- 2342, 2004.

12 Last Revision Date – August 2015 Jonker DJ, O’Callaghan CJ, Karapetis CS et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med 357: 2040-2048, 2007.

Jonker DJ, Spithoff K, MarounJ. Adjuvant systemic chemotherapy for stage II and III colon cancer following complete resection. Program in Evidence-based Care (PEBC), Cancer Care Ontario (CCO) conducted April 17, 2008. Series 2-29.

Levin B, Lieberman DA, McFarland B et al. Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. CA Cancer J Clin 58: 130-160, 2008.

Liao X, Lochhead P, Nishihara R et al. Aspirin use, tumour PIK3CA mutation, and colorectal-cancer survival. N Engl J Med 367: 1596-1606, 2012.

Nordlinger B, Sorbye H, Glimelius B et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomized controlled trial. Lancet 371: 1007-1016, 2008.

Saltz LB, Clarke S, Diaz-Rubio E et al. Bevacizumab in combination with oxaliplatin- based chemotherpay as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26: 2013-2019, 2008.

Tournigand C, André T, Achille E et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer : a randomized GERCOR study. J Clin Oncol 22: 229-237, 2004.

Tournigand C, Cervantes A, Figer A et al. OPTIMOX1 : a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-Go fashion in advanced colorectal cancer-a GERCOR study. J Clin Oncol 24: 394-400, 2006.

Tournigand C, Andre T, Bonnetain et al. Adjuvant therapy with fluorouracil and oxaliplatin in stage II and elderly patients (between 70 and 75 years) with colon cancer : subgroup analyses of the multicenter international study of oxaliplatin, fluorouracil, and leucovorin in the adjuvant treatment of colon cancer trial. J Clin Oncol 30: 3353-3327, 2012.

Van Cutsem E, Tabernero J, Lakomy R et al. Addition of Aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin based regimen. J Clin Oncol 30: 3499-3506, 2012.

Yothers G, O’Connell MJ, Allegra CJ et al. Oxaliplatin as adjuvant therapy for colon cancer: updated results of NSABP C-07 trial, including survival and subset analyses. J Clin Oncol 29: 3768-3774, 2011.

13 Last Revision Date – August 2015