Disclosure. Nothing to Disclose Will not be discussing off label use of any of the medications

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2 Disclosure Nothing to Disclose Will not be discussing off label use of any of the medications

3 Where s Cranbrook?

4 Follow Up of Colorectal Cancer Stage 0 (in-situ disease) and Stage I (T1-2 N0) Follow up completion colonoscopy within the first year of diagnosis Colonoscopy at the discretion of the endoscopist No routine imaging or CEA testing is indicated

5 Follow Up of Colorectal Cancer Stage II T3/T4, N0, M0 Stage III Any T, N1-2, M0 Stage IV Any T, Any N, M1 with no evidence of disease (NED)

6 Patient ED 65 y/o F 2012 Cecal cancer Open Right Hemicolectomy and primary ileocolic anastomosis pt3 pn2b (7/15) M0 with LVI and PNI Adjuvant CAPOX, switched to FOLFOX due to side effects Completed 6 months of therapy Completion CT scan negative CEA 1 What do we do next?

7 Intensive Surveillance of CRC Survivors Why? 80% recurrences occur within 3 years 95% recurrences occur within 5 years Who? Asymptomatic CRC patients treated with curative intent Good functional status Would tolerate further treatment

8 Stage II, III, and IV (NED) Clinical Review Hx and P/E q 3-6 months x 3 yrs, then q 6 months x 2 yrs Recurrences Liver, lung Less common to bone, brain, spleen, adrenals, peritoneum, retroperitoneal nodes Anastomotic site Metachronous cancer Symptomatic patients should be seen promptly

9 Stage II, III, and IV (NED) CEA At each visit for examination as above CEA < 15 mcg/l may be false positive Repeat within 28 days Positive CEA CT scan, Colonoscopy, consider PET/CT Investigations negative: Repeat CEA and imaging until disease is identified or CEA stabilizes or declines CEA may be normal in up to 40% of recurrences More sensitive in liver and peritoneal mets, less in lung and retroperitoneal

10 Stage II, III, and IV (NED) Imaging Stage II/III: CT chest/abdomen/pelvis annually for 5 years Stage IV with NED: CT chest/abdo/pelvis q 3-6 months for 2 years, then q 6-12 months for 3 years Colonoscopy Completion colonoscopy within the first year of diagnosis At the discretion of the endoscopist based on findings

11 Stage II, III, and IV (NED) Lifestyle modifications Eat more like grandma did Exercise: 150 minutes per week of moderate intensity, or 75 minutes per week of high aerobic intensity ASA? Still insufficient evidence to recommend ASA for CRC prevention Screening of other family members Transfer of Care Detailed, specific, and clear

12 Patient ED: pt3 pn2b (7/15) M0 with LVI and PNI Apr/13: Treatment completion CEA 1, CT negative Q 3/12: CEA 1 and exam normal Dec/13: Colonoscopy Anastomosis neg. Sessile polyp in sigmoid, tubular adenoma, no high grade dysplasia Repeat colonoscopy 2 years Jan/14: CEA 1 and exam normal Apr/14: CT negative, exam normal, CEA 1

13 Asymptomatic/stable for another year Apr/15: CEA 1 CT shows 2 enhancing lesions consistent with metastasis 3.3 cm and 2.1 cm in right hepatic lobe No other evidence of metastatic disease Biopsy proven. Contrast enhanced MRI confirms only 2 mets Can show more metastases, particularly in the presence of fatty liver. PET scan shows disease localized only to the liver

14 Liver Anatomy

15 Limited Hepatic Metastases Multidisciplinary Conference Resectability: Hepatic lesions that can be completely resected (<10 mm margin may be ok with ablation therapy as well) Adequate functional reserve (> 20%) No involvement of hepatic artery, bile ducts, main portal vein, para-aortic or celiac lymph nodes

16 Conventional vs Aggressive < 4, unilobar Size < 5 cm Margin > 1 cm No extrahepatic mets Adequate liver remnant No mets at confluence of vena cava/hepatic vein No hepatic pedicle LN No limits. Chemo/staged No limits Cryo or RF ablation of margins Resectable Pulmonary mets Portal vein embolization Resection and reconstruction can be performed No celiac axis metastases Khatri et al, J Clinical Oncology 2005; 23:8490 Copyright 2005 ASCO

17 Hepatic Metastases Resection benefit five-year survival rates after resection range from 24 to 58 percent, averaging 40 percent surgical mortality rates are generally < 5 % five-year survival rates with the most active systemic chemotherapy regimens are only 10 to 11 %

18 Induction Chemotherapy for Surgery Patient ED did not require induction therapy If potentially resectable (larger size, number, location, no other mets except lung) Chemotherapy for 4-6 cycles Imaging 6-8 weeks prior to surgical date to assess response Pseudoadjuvant chemo after resection to complete 12 cycles?

19 Induction Chemotherapy FOLFOX Disease appeared after 12 months Oxaliplatin sinusoidal obstructive syndrome FOLFIRI Recent Oxaliplatin Irinotecan induced steatohepatitis +/- Bevacizumab Still considered investigational for benefit Needs to be stopped at least 4-6 weeks prior to surgery

20 Adjuvant therapy after metastasectomy Generally done EORTC 40983: RCT FOLFOX 6 cycles vs surgery alone Peri-op chemo Surgery alone p - value PFS 20.9 mos 12.5 mos p = 0.04 OS (all pts) 63.7 mos 55.0 mos p = 0.30 OS (resected) 77.5 mos 73.3 mos p = 0.35 Consider 5FU/capecitabine alone for older patients or residual neuropathy Nordlinger, Lancet Oncology 2013; Primrose, Lancet Onc 2014

21 Non-Surgical Options Ablative therapy Less than 3 cm and less than 3 tumours Radiofrequency or cryoablation Also used when margin is < 10 mm Stereotactic Body Radiotherapy SBRT Less than 6 cm and less than 3 tumours Child Pugh A or very early B Embolic therapy Radioembolization Y90 not funded Hepatic artery vs portal circulation Chemoembolization investigational

22 Patient ED Jun/15: Partial right hepatectomy Follow up: Stage IV NED Same as Stage II/III except CT chest/abdo/pelvis q 3-6 months for 2 years, then q 6-12 months for 3 years Follow up CEA 1-2 and CT s negative at 3 and 6 months

23 Patient ED Jan/16: CEA 1 and presented with abdominal cramps and change in bowel function, no blood in stool or wt loss CT shows pulmonary, hepatic, pelvic mets with RPLNs and thickening at anastomosis.

24 Patient ED Unresectable mcrc Colonoscopy: narrowing of lumen, high risk of obstruction Biopsy positive for mcrc GI conference No down staging with chemo, Proceed to surgery Laparotomy, excised anastomotic recurrence and biopsied pelvic mass, anastomosis ileum to transverse colon

25 Navigating the Terrain

26 Chemotherapy for mcrc 5FU, Capecitabine Oxaliplatin Panitumumab Raltitrexed Irinotecan Bevacizumab Regorafenib? Cetuximab Pembrolizumab?

27 Chemotherapy for mcrc Multiple combinations, important that a patient receive as many drugs as tolerated. Supportive Care Median Overall Survival of < 6 months Chemotherapy MOS months Some have prolonged response measured in years Choice based on disease related factors, patient factors and patient preferences

28 Does Side Matter? mcrc by left (distal/rectal) vs. right (proximal) colon site OS (months) Overall Cetuximab Bevacizumab Left Right p < p < p < Replicated by large SEER population based analysis Likely driven by different molecular profiles No difference with age, gender, race, synch/metachronous, MSI, BRAF, RAS, CMS Venoook, ASCO 2016 and 2017, Schrag ASCO 2017

29 Chemotherapy for mcrc Patient ED Didn t tolerate 5FU/oxliplatin very well as adjuvant, refused more oxaliplatin Mar/16: Started GIFFIRB KRAS testing requested CT at 3 and 6 months showed stability of disease by RECIST criteria CEA 1

30 Bevacizumab Anti VEGF monoclonal antibody Benefit if added to FOLFOX or FOLFIRI for first line in mcrc Some centers will continue it as 2 nd line increased risk of post-operative bleeding and wound healing,osteonecrosis of the jaw has been reported, uncontrolled HTN, VTE, arterial thromboembolic events, serious hypersensitivity reactions Caution with age > 65 years, congenital bleeding diatheses, acquired coagulopathy, full dose anticoagulants

31 KRAS and Oncopanel RAS mutations predict for lack of benefit from anti-egfr therapy (cetuximab and panitumumab) 7-10 days, less tissue Wild type 45% 15-17% wild type for KRAS on exon 2 are found to have a different RAS mutation Oncopanel days, more tissue KRAS, NRAS, BRAF and a host of other genetic markers of varying significance Rapid gene sequencing technology designed to be expandable Obtain consent for Predictive Genetic Panel Unexpected answers to questions you weren t asking

32 Hot Off the Press UGIFFOXPAN 1 st line therapy if not suitable for bevacizumab Patient becomes ineligible for 2 nd line bevacizumab Includes those with resection of mets and were not considered suitble for 1 st line bev Also ineligible for 3 rd line panitumumab Optimal timing of Oncopanel or KRAS testing? Anytime for fit patient with mcrc

33 Anti EGFR Therapy Patient ED: Clinical and CT progression after 28 cycles GIFFIRB KRAS negative for the mutation When EGF binds to EGFR WT this signals cell proliferation Mutated KRAS is continuously active. Proliferation occurs regardless of EGF-EGFR binding Panitumumab Human MAb Cetuximab Mouse/human chimeric MAb Median Overall Survival Benefit 10 mos.

34 What about the responders? Maintenance/de-escalation OPTIMOX: RCT to de-escalating to 5FU vs. continuous FOLFOX PFS, OS similar Less toxicity Other studies similar with FFOXB Treatment holiday OPTIMOX2: RCT chemo free interval vs. 5FU maintenance Disease control and PFS worse on holiday

35 Back to our patient Apr/17: Started Panitumumab Had not tolerated Irinotecan well after dose reductions Rash Moisturizers/sunscreen Clindamycin2%/Hydrocortisone1% Minocyline 100 mg bid Hypomagnesemia IV supplementation when oral failed Much improved quality of life Unfortunately, CT Sept/17 showed definite progression. CEA 1

36 Is it all downhill from here?

37 Other Options? Best supportive care But ECOG 1, age 65, and not ready to quit Regorafenib (Stivarga ) Oral multi-kinase inhibitor, 160 mg full dose CORRECT: RCT 2:1 to regorafenib vs placebo 53% grade 3/4 toxicity HFS, fatigue, rash, GI, HTN, RPLS OS: 6.4 vs 5.0 mos p = PFS: 1.9 vs 1.7 mos p < Patient support program available

38 And because every cancer talk now includes Immunotherapy

39 Anti PD1 therapy in MSI high KEYNOTE trials of pembrolizumab in mcrc and other cancers Response: MSI high (dmmr) much greater than MSI low (pmmr) Somatic MSI > germline (Lynch) 5-10% mcrc somatic MSI (sporadic) Objective Response Rate 36% The median duration of response was not yet reached (range, 1.6+ months to months) Among patients who responded to pembrolizumab, 78% had responses that lasted for at least 6 months

40 Immune therapy in MSI high Pembrolizumab FDA approved May/17 Nivolumab FDA approved Aug/17 Should every mcrc be tested for MSI/dMMR? Histology comments on MSI in path report Tailoring to Biomarkers Something to watch for in the future BRAF, HER2, ERCCI, CIMP, NTRK, ALK Stemness High-Cancer cell Inhibitor

41 Advance Care Planning Have the Discussion

42 Thank-you and Questions