Colon Cancer Stages I-III Deepak Chander August 22nd, 2018

Epidemiology 140,250 new cases in 2017 Represent 8.1% of new cancer diagnoses. 4th most common Median age of diagnosis is 67 More common in African Americans SEER Cancer Stat Facts: Colon Cancer. National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/statfacts/html/colorect.html

Staging AJCC. Colon and Rectum Cancer Staging. 7th Edition. https://cancerstaging.org/references-tools/quickreferences/Documents/ColonLarge.pdf

Surgery Surgery is the mainstay of treatment of all local colon cancer Neoadjuvant chemotherapy can be considered for tumors invading local organs or tissue For inoperable patients single agent neoadjuvant chemotherapy can be considered NCCN Guidelines Colon Cancer Version 3.2018. COL- 2

Management by TNM Staging NCCN Guidelines Colon Cancer Version 3.2018. COL- 3

Stage I Recurrence rate of Stage I colon cancer is estimated to be 5-10% > 90% survival at 5 years T2 stage, lymphovascular invasion, low rectal lesions, poorly differentiated cancers and male sex associated with higher risk or recurrence To date no adjuvant chemotherapy has been shown to be beneficial in Stage I Colon Cancer To date no surveillance schedule has been shown to be beneficial in Stage I Colon Cancer J Korean Soc Coloproctol. 2012 Feb; 28(1): 49–55. N Engl J Med 1990; 322:352-358

Stage I Chan AT, Ogino S, Fuchs CS. Aspirin Use and Survival After Diagnosis of Colorectal Cancer. JAMA.2009;302(6):649–658. doi:10.1001/jama.2009.1112. Morales-Oyarvide V, Meyerhardt JA, Ng K. Vitamin D and Physical Activity in Patients with Colorectal Cancer: Epidemiological Evidence and Therapeutic Implications. Cancer journal (Sudbury, Mass). 2016;22(3):223-231. doi:10.1097/PPO.0000000000000197.

Stage II 5 year DFS in Stage II Colon Cancer is estimated to ~ 81% Features suggestive of high risk of recurrence are lymphovascular invasion, perineural invasion, obstruction, <12 lymph nodes examined, perforation, close, indeterminate or positive margins MSI-unstable (MMR preserved) is good prognostic marker and a marker of poor response to adjuvant flouropyrimidine Multi-gene assays (ColonPrint and Oncotype) do predict risk of recurrence, but do not predict benefit of adjuvant chemotherapy

Stage II 80% of recurrence occurs in the first 3 years and 95% occurs in the first 5 years The CEAWatch trial compared CEA monitoring to imaging and found an increased rate of detection of recurrences able to be treated with curative intent

Stage III 5 year DFS with surgery alone for Stage III Cancer ~60% 1st trial to show benefit of adjuvant chemotherapy was in the 1990’s 5-FU/levamasol superior to surgery alone 6 months of treatment was shown to be equivalent to 12 months Infusional 5-FU shown to be equivilant to weekly bolus 5-FU Capecitabine shown to be non-inferior (?slightly better) than 5-FU

Stage III MOSAIC and NSABP-C-07 trials compared 5-FU/LV to FOLFOX 3 DFS in FOLFOX was 78% versus 71% in 5-FU/LV Most, if not all, of the benefit was isolated to Stage III patients Subset analysis showed no benefit and trend to harm in patients > 70 yo with the addition of Oxaliplatin N Engl J Med 2004; 350:2343-2351

Stage III Capecitabine + Oxaliplatin was shown to have superior disease free survival (~70%) than 5-FU/Leucovorin alone (66%) No trial to date has compared CapeOx versus FOLFOX The dose of Oxaliplatin in CapeOx is higher than in FOLFOX J Clin Oncol. 2011 Apr 10;29(11):1465-71

Stage III Meta-analysis of previous trial data showed a decrease of 14% for every 4 week delay in start of adjuvant chemotherapy National Cancer Data Base analysis found that a delay of >8 weeks after surgery was found to be associated with worse survival Data is controversial because patient who were more likely to have delays were more likely to be older and have medical co-morbidities and more likely to have surgical complications No trial to date has shown benefit of Avastin (bevacizumab) or EGFR agents (Cetuximab, Panitumimab) in the Adjuvant setting.

Stage III IDEA Meta-analysis presented at ASCO 2017 looked at 3 versus 6 months of adjuvant treatment

Stage III In T1-3, N1 patients 3 months of FOLFOX was equivalent to 6 months of FOLFOX In T1-3, N1 patients 3 months of CapeOX was equivalent (trend to better) to 6 months of CapeOx In T4, N2 patients 3 months of FOLFOX was inferior to 6 months of FOLFOX In T4, N2 patients 3 months of CapeOX was equivalent to 6 months of CapeOx

Summary Stage I disease – no adjuvant chemo, no imaging surveillance Stage II, low risk and MSI Unstable (20%) – No adjuvant chemo, surveillance per NCCN Stage II, low risk and MSI Stable – Can consider single agent adjuvant chemo, surveillance per NCCN Stage II, high risk – Doublet Adjuvant chemotherapy Stage III disease – Doublet Adjuvant chemotherapy MSI-Unstable predicts harm to FU in low risk patients Multi-gene assays are not recommended to guide adjuvant chemotherapy Majority of benefit to adjuvant chemo is from 5-FU, majority of toxicity is from Oxaliplatin

Summary Addition of Oxaliplatin may be harmful in patients > 75 In patients with low risk (T1-3, N1) Stage III disease 3 months of doublet adjuvant chemotherapy is equivalent to 6 months In high risk (T4, N2) this is not the case Bevacizumab, Cetuximab and Panitumimab are not indicated in the adjuvant setting

The End