Medical Management of Colorectal Cancer Dr. Patricia Tang MD FRPCP Southern Alberta GI Tumor Group Leader Medical Oncologist Tom Baker Cancer Centre

Faculty/Presenter Disclosure Dr. Patricia Tang Relationships with commercial interests: Speakers Bureau/Honoraria: Roche, Sanofi, Amgen, Celgene

Colorectal Cancer

Epidemiology 4th most commonly diagnosed cancer in Canadians (22,000 new cases per year) 2nd leading cause of cancer death after lung cancer lifetime risk of developing CRC is 1 in 18

What are risk factors for developing colorectal cancer?

Risk Factors for Colorectal Cancer (CRC) age (>50) lifestyle: diet (high calorie and fat, low fibre), smoking, alcohol, obesity genetics (family Hx of CRC, FAP, HNPCC, MUTYH associated polyposis) personal Hx of CRC or adenomas (esp. villous) ulcerative colitis, Crohn’s disease Prior abdominal or pelvic radiation

Patient Case 1

Presentation Next steps? 68 year old man presents to his family doctor with fatigue: hemoglobin 100 (Normal Range = 137-180) MCV 75 (Normal Range = 82-100) Past Medical History Diabetes Mellitus Type 2 on metformin Hypertension on ramipril Dyslipidemia on atorvastatin ASA 81 mg / day Next steps?

Diagnosis Physical examination is performed Digital rectal exam reveals a palpable mass in the rectum Copyright unknown

Work up Baseline laboratory work: CBC CR LYTES LFTS CEA, (INR if on warfarin) Refer for urgent endoscopy: in Calgary, page the gastroenterologist on call at the nearest hospital (ROCA)

Diagnosis A gastroenterologist performs an urgent colonoscopy a mass consistent with cancer that was near obstructing noted at 10 cm from anal verge http://www.cancercare.ns.ca/en/home/preventionscreening/coloncancerprevention/faq.aspx

Diagnosis: Rectal Cancer A biopsy of the mass was taken and sent to a pathologist who confirms moderately differentiated adenocarcinoma (up to 1 week) http://www.proteinatlas.org/dictionary/cancer/colorectal+cancer/detail+1

Staging Gastroenterologist receives the pathology report and orders a CT scan of the chest, abdomen and pelvis CT scan: Rectal mass, otherwise, completely normal http://www.radiologyinfo.org/en/photocat/gallery3.cfm?image=abdo-ct-ped.jpg&pg=abdominct

Which has the highest risk of local recurrence? Colon Cancer Rectal Cancer Copyright unknown

Staging If emergent surgery is not needed, the surgeon would order a MRI pelvis Copyright unknown

Preoperative “Neoadjuvant” Treatment Locally advanced rectal adenocarcinomas (T3/4 or node positive on MRI) would be referred to the cancer centre for neoadjuvant chemoradiation Goal: reduce local recurrence & shrink the tumor Then surgery to cut out the cancer Then further adjuvant chemotherapy Copyright unknown

Treatment: Chemoradiotherapy Referred to the cancer centre to see a radiation oncologist and medical oncologist Capecitabine (pills) given concurrently with radiation for 5 weeks The patient has mild diarrhea and hand-foot syndrome 6-8 week wait prior to OR Copyright unknown

Treatment: Surgery Surgery: low anterior resection with diverting loop ileostomy Loose ileostomy output: metamucil, imodium, codeine Ileostomy sometimes Copyright unknown

Lower tumors, Abdominoperineal resection: Permanent colostomy

An ostomy is life changing

Pathologic Staging Pathologist evaluates the specimen, the tumor is staged at T3N1 (3 out of 20 lymph nodes)M0 Stage III Referred back to the cancer centre for adjuvant chemotherapy and the patient receives 4 months of capecitabine Physical & CT scan Stage I-III Curative Intent

How you can help while the patient is on treatment Past Medical History Diabetes Mellitus Type 2 on metformin: if a patient receives IV chemo, we often worsen diabetic control Backup plan for hyperglycemia Chemo can cause nausea/vomiting: back up plan for poor oral intake Hypertension on ramipril Some patients lose weight, which treats their hypertension May need adjustments Dyslipidemia on atorvastatin: ongoing prescriptions for continuitiy ASA 81 mg / day: This is fine. However, A fib requiring anticoagulation often requires LMWH, Novel anticoagulants controversial

Surveillance: Family Medicine Loop ileostomy is reversed. Bowel function takes awhile to improve Surveillance: CEA (blood test) q 3 mo x 3 yrs then q6 months x 2 yrs physical exam q6 mo x 3 yrs then annually CT Chest abdomen pelvis annually x 3 years colonoscopy within 6-12 mos of surgery then q3-5 years What are common places of metastases? Ask Mr. Leaper what it was like How is the venous drainage of the rectum different from the colon?

Surveillance: Family Medicine Intensive surveillance in colorectal cancer has been shown to improve survival since isolated liver and/or lung metastases can be resected and patients can still be cured 5 year Overall Survival 40%

Approach to a Rising CEA Repeat CEA, if still > 5, physical exam CT chest abdomen pelvis If resectable metastasis, send to appropriate surgeon (Thoracics or Hepatobiliary) If normal, colonoscopy Send back to medical oncology/Call the original medical oncologist fax 403-521-3245, May need a biopsy Thoracic Oncology Program for lung/mediastinal LN

Metastatic Colorectal Cancer Small pulmonary nodule seen in right lung on the CT scan suggestive of recurrent cancer (metastasis) Thoracic surgeon Resects the cancer Copyright unknown

Treatment of Resectable Metastatic CRC Pathology from the lung surgery revealed a 1 cm focus of metastatic rectal adenocarcinoma Started on “adjuvant” FOLFOX chemotherapy for 6 months At 5 years the CT scan was clear and the patient’s intensive surveillance was discontinued Ask Mr. Leaper what it was like

What are the current colorectal cancer screening guidelines?

Screening for CRC http://www.screeningforlife.ca/ beginning at age 50, all patients should have one of the following screening tests for CRC: FOBT q1year flexible sigmoidoscopy q5years double-contrast barium enema q5years colonoscopy q10years any positive or abnormal test should be followed up with colonoscopy http://www.topalbertadoctors.org/download/301/colorectal_summary.pdf?_20150805182214

Screening for CRC Lynch: Dr. W D Buie and Dr Bellutruti http://www.topalbertadoctors.org/download/301/colorectal_summary.pdf?_20150805182214

Clinical Presentation of CRC Copyright unknown

Clinical Presentation abdominal pain bowel change (diarrhea, constipation, pencil stools, tenesmus) hematochezia weight loss fatigue iron-deficiency anemia bowel obstruction elevated liver enzymes (liver mets)

Diagnostic Approach CBC, lytes, BUN, Cr, liver enzymes & LFTs, CEA CT chest/abdomen/pelvis colonoscopy (tissue diagnosis) liver lesions: may need extra imaging such as ultrasound and/or MRI rectal lesions: endoscopic ultrasound and/or MRI

TNM Staging

Colon Cancer Treatment Stage Treatment 5 year Overall Survival I: T1-2 N0 Surgery 93% II: T3 N0 T4 N0 Adjuvant chemotherapy for high risk 72% 85% IIIA: T1-2N0 IIIB: T3-4N1 IIIC: T1-4N2 64% 44% IV: Distant Metastases Chemotherapy if well enough Select patients may be eligible for Metastatectomy 10% 40%

Treatment after surgery for Stage II Colorectal Cancer surgical resection adjuvant chemotherapy can be considered for patients with tumours exhibiting high-risk features: T4 poorly differentiated histology lymphovascular or perineural invasion inadequately sampled lymph nodes (<13) clinical bowel perforation clinical bowel obstruction

Treatment of Stage II Colon Cancer adjuvant chemotherapy for resected stage II CRC is controversial since many studies have only shown trends towards a survival benefit if a survival benefit exists it is likely 2% to 3% at 5 years and 5Y-OS in stage II CRC with surgery alone is 75%

Treatment of Stage III Colon Cancer surgical resection adjuvant chemotherapy recommended for all patients 5-fluorouracil (5-FU) + folinic acid x 6 months has been shown in a number of phase III trials to increase 5Y-OS by 5% to 15% in stage III CRC (5Y-OS with surgery alone 30% to 80%)

Treatment after surgery for Stage III Colorectal Cancer FOLFOX is the standard of care for adjuvant treatment of stage III CRC and improves 5 year survival by 10% to 20% compared to no further chemotherapy Can cause chronic peripheral neuropathy Painful neuropathy can be helped with Duloxetine capecitabine has been shown to be equivalent to 5-FU/LV and is routinely used for patients who cannot tolerate oxaliplatin (FOLFOX) or those who prefer oral chemotherapy

Patient Case 2 55 year old post-menopausal woman presents with fatigue, 20 lb un-intentional weight loss, and progressively narrow stool caliber

Approach History Physical Exam Labwork

Results Hb 75, MCV 72 ALT is 1.5 x upper limit of normal (it was normal last year)

Results U/S Abdomen shows innumerable liver metastases Next step

Patient Case CT chest abd pelvis: innumerable liver and lung metastases Refer to GI for urgent scope Non-obstructing mass in the sigmoid colon Pathology: adenocarcinoma GP refers to cancer centre for further management

Stage IV CRC cancer has spread outside of colon or rectum to other areas of body stage IV cancer is usually treated with chemotherapy alone surgery to remove the primary tumor may be done additional surgery to remove metastases may also be done in carefully selected patients ASCO Colorectal Slide Deck 2008

Treatment of Metastatic CRC Median Survival (Months) Best Supportive Care 6 5-fluorouracil (60’s) + leucovorin (80’s) 8 - 12 IFL (irinotecan/5-FU/LV) (2000) 15 FOLFIRI (irinotecan/5-FU/LV) (2000) 17 FOLFOX (oxaliplatin/5-FU/LV) (2000) 20 FOLFIRI  FOLFOX (2004) 21 IFL + bevacizumab (2007) 20 FOLFIRI + cetuximab (2009) 24 FOLFIRI or FOLFOX + bevacizumab 29 or cetuximab (2014)

Chemotherapy: 5-fluorouracil Benefits: can shrink the cancer, delay time to progression and improve survival time Potential Toxicities: myelosuppression  febrile neutropenia rash, photosensitivity diarrhea fatigue coronary vasospasm/chest pain (rare) * low rates of nausea and vomiting * rare hair loss

Chemotherapy: Oxaliplatin Benefits: can shrink the cancer, delay time to progression and improve survival time Potential Toxicities: Myelosuppression  febrile neutropenia cold-induced dysesthesia peripheral neuropathy infusion reaction * moderate rates of nausea and vomiting * can have hair thinning

Metastatic CRC May Be Curable selected patients with oligometastatic disease isolated to liver and/or lung refer to hepatobiliary surgeon or thoracic surgeon for opinion regarding metastectomy refer to medical oncologist for perioperative chemotherapy in case series where patients had liver metastasis resection: 5Y-OS = 40%, 10Y-OS = 20%

Scenario 1 You are a family doctor You order a FIT test on your 51 year old female patient as part of routine screening It comes back POSITIVE Next step: Refer to the cancer centre Refer to surgeon Refer for colonoscopy

Scenario 2 You are an Emergency Room doctor A patient presents with a bowel obstruction, CT shows a mass suggestive of cancer in the colon that is obstructing, one mass in the liver suggestive of a metastasis Next step: Refer to the cancer centre because the CT is suggestive of cancer Refer to surgery because the patient is obstructed

Proposed Rectal Cancer Pathway Rectal Cancer Clinical Pathway – Standards of Care Proposed Rectal Cancer Pathway No neoadjuvant therapy for colon

In Summary colorectal cancer (CRC) is a common disease screen for CRC in general population age ≥50 surgical resection for cure in stage I-III CRC adjuvant chemotherapy (5-FU, capecitabine, FOLFOX) increases overall survival in stage III CRC and possibly in high-risk stage II

In Summary oligometastatic CRC isolated to the liver and/or lungs can be resected for chance at cure in selected patients modern chemotherapy and biologic therapy are effective and generally well-tolerated palliative treatments for metastatic CRC median survival for patients with metastatic CRC with treatment is now >2 years

Questions??? http://whatnow.atlargecommunications.com/ Above website will be eventually migrated to Cancerwhatnow.com http://www.colorectal-cancer.ca/en/ostomy/ patricia.tang@albertahealthservices.ca http://www.albertahealthservices.ca/info/cancerguidelines.aspx http://www.bccancer.bc.ca/health-professionals/professional-resources/cancer-management-guidelines