Colon Cancer Stage I-III Palak Desai, MD

Trends in Cancer incidence rates among men 1975-2010

Trends in Cancer incidence rates among women 1975-2010

The risk of an American woman developing cancer over her lifetime is a little more than one in three.

Colon Cancer Etiology Sporadic (65%–85%) Familial (10%–30%) Rare CRC syndromes (<0.1%) Hereditary nonpolyposis colorectal cancer (HNPCC) (5%) Familial adenomatous polyposis (FAP) (1%) Adapted from Burt RW et al. Prevention and Early Detection of CRC, 1996

Risk Factors Physical Inactivity/obesity Smoking NSAIDS Adenomatous polyps Age >50 Inflammatory Bowel Disease History of Cancer Family History of Colorectal Cancer Physical Inactivity/obesity Smoking NSAIDS Diets/Supplements Race

Diet dietary fiber vegetables fruits antioxidant vitamins calcium folate (B Vitamin) decreased risk

Diet consumption of red meat animal and saturated fat refined carbohydrates alcohol increased risk

Familial Risk Approximate Familial setting Life time risk of Colon Ca Gen population risk in US 6% 1 first degree relative with colon ca Two-Three fold increase 2 first degree relatives with colon ca Three-Four fold increase 1st° relative Δ with colon ca ≤ 50 yrs Three-Four fold increase One 2nd or 3rd ° relative with colon ca 1.5 fold increase Two 2nd ° relatives with colon ca Two-Three fold increase One 1st ° relative with polyp Two fold increased

Adenoma- Cancer Sequence Loss of APC Activation of K-ras Deletion of 18q Loss of TP53 Other alterations Normal epithelium Hyper- proliferative epithelium Early adenoma Inter- mediate adenoma Late adenoma Carcinoma Metastasis Adapted from Fearon ER. Cell 61:759, 1990

Risk of Colorectal Cancer General population 5% Personal history of colorectal neoplasia 15%–20% Inflammatory bowel disease 15%–40% 70%–80% HNPCC mutation >95% FAP 20 40 60 80 100 Lifetime risk (%) 3

Clinical Presentation

Colorectal Cancer by Site

Stage at Diagnosis Adapted from NCI Cancer Facts and Figures 2010

Stages of Colon Cancer

Prognosis and 5 yr survival rates for Colon Cancer Stage I (T1-2N0) - 93% Stage IIA (T3N0) - 85% Stage IIB (T4N0) - 72% Stage IIIA (T1-2 N1) - 83% Stage IIIB (T3-4 N1) - 64% Stage IIIC (N2) - 44% Stage IV - 8%

Dukes Classification

Initial Treatment

Evidence Blocks

High Risk Features T4 tumors (stage IIB/IIC) poorly differentiated histology Lymphovascular invasion Perineural invasion Bowel obstruction Less than 12 lymph nodes sampled + margins

Adjuvant Therapy Consideration IMPACT Meta-analysis 1995 The three studies were pooled for combined analysis. Each trial was multicenter and used the same treatment regimen (fluorouracil 370-400 mg/m2 plus folinic acid 200 mg/m2 daily for 5 days, every 28 days for 6 cycles). 1526 patients with resected B (56%) and C (44%) carcinoma of the colon were enrolled 736 were assigned to the treatment group and 757 to the control group. Fluorouracil/folinic acid significantly reduced mortality by 22% (95% Cl 3- 38; p=0·029) and events by 35% (22-46; p<0·0001), increasing 3-year event-free survival from 62% to 71% and overall survival from 78% to 83%. Compliance with treatment was good; more than 80% of patients completed the planned treatment. Side-effects were clinically acceptable with only 1 treatment-related death. The commonest side-effects were gastrointestinal, but severe toxic effects (WHO grade 4) occurred in fewer than 3% of cases. Study showed that fluorouracil plus high-dose folinic acid is a well- tolerated and effective 6-month adjuvant regimen for colon cancer. IIa to IIIc IMPACT group, Lancet 1995

Adjuvant Therapy for Stage II Disease? Gill et al, Meta-analysis pooled data set of 3,302 patients with stage II and III colon cancer from seven randomized trials comparing FU + leucovorin or FU + levamisole to surgery alone Nodal status, T stage, and grade were the only prognostic factors independently significant for both disease-free survival and OS. Age was significant only for OS. Adjuvant therapy showed a beneficial treatment effect across all subsets. Treatment benefits were consistent across sex, location, age, T-stage, and grade. A significant stage by treatment interaction was present, with treatment benefiting stage III patients to a greater degree than stage II patients. Gill et al, JCO 2004

These results suggest that the benefit of adjuvant therapy is greater in patients at higher risk because of nodal status.

Adjuvant Therapy for Stage II Disease? Quasar Trial After apparently curative resections of colon or rectal cancer, 3239 patients were randomly assigned to receive chemotherapy with fluorouracil and folinic acid (n=1622) or to observation (with chemotherapy considered on recurrence; n=1617). Chemotherapy was delivered as six 5-day courses every 4 weeks or as 30 once-weekly courses of intravenous fluorouracil (370 mg/m2) with high-dose (175 mg) L-folinic acid or low-dose (25 mg) L-folinic acid. Quasar Collaborative Group, Lancet 2007

Quasar Trial There were 293 recurrences in the chemotherapy group and 359 in the observation group; the relative risk of recurrence with chemotherapy versus observation alone was 0.78 (0.67-0.91; p=0.001). Treatment efficacy did not differ significantly by tumor site, stage, sex, age, or chemotherapy schedule. Authors proposed that Chemotherapy with fluorouracil and folinic acid could improve survival of patients with stage II colorectal cancer, although the absolute improvements are small: assuming 5-year mortality without chemotherapy is 20%, the relative risk of death translated into an absolute improvement in survival of 3.6% (95% CI 1.0-6.0). However, 64% of patients had less than 12 LNs sampled, therefore those patients may actually have been patients with higher risk disease who were more likely to benefit from adjuvant therapy

Adjuvant Therapy for Stage II Disease Wu et al, 2012 Meta-analysis of 12 randomized controlled trials from 1988 to 2010 in which surgery alone was the control arm, found a significant benefit to adjuvant therapy in patients with stage II colon cancer 5 year OS HR was 0.81 5 year DFS HR was 0.86. The trials used various chemotherapy regimens. Wu et al, J Gastrointest Surg, 2012

Adjuvant Therapy for Stage II Disease O’Connor et al, 2011 Analysis of 24,847 patients with stage II colon cancer from the SEER database Of the patients with stage II cancer, 75% had one or more poor prognostic features. Adjuvant chemotherapy was received by 20% of patients with stage II disease and 57% of patients with stage III disease. O’Connor et al, JCO 2011

After adjustment, 5-year survival benefit from chemotherapy was observed only for patients with stage III disease (hazard ratio[HR], 0.64; 95% CI, 0.60 to 0.67). No survival benefit was observed for patients with stage II cancer with no poor prognostic features (HR, 1.02; 95% CI, 0.84 to 1.25) or stage II cancer with any poor prognostic features (HR, 1.03; 95% CI, 0.94 to 1.13).

Addition of Oxaliplatin? MOSAIC Trial (more later) Post-hoc exploratory analysis of the MOSAIC trial did not show a significant DFS benefit of FOLFOX over 5-FU/LV for patients with stage II disease at a follow up of 10 years (HR= 0.64, P= 0.258). After a longer follow up, no difference in 10 year OS was observed in the stage II subpopulation (79.5% vs 78.4%, HR= 1.00, P= 0.98) In addition, patients with high risk disease receiving FOLFOX did not have improved DFS compared with those receiving infusional 5-FU/LV (HR = 0.72 ,P = 0.063). No OS benefit was seen in the stage II population overall or in the stage II population with high-risk features. André et al, JCO 2015

Microsatellite Instability MSI is an important piece of information to consider when deciding whether to use adjuvant chemotherapy in patients with stage II disease Evidence shows that MSI is a marker of a more favorable outcome and a predictor of decreased benefit from adjuvant therapy with a fluoropyrimidine alone in patients with stage II disease. Date from PETACC-3 trial showed that tumor specimens characterized by MSI-H are more common in stage II than in stage III disease (22% vs 12%, P<0.0001) Another study showed that only 3.5% of stage IV tumor were characterized as MSI-H, suggesting that these tumors have a decreased likelihood to metastasize. Because patients with stage II msi h tumors may have a good prognosis and do not benefit from 5-FU adjuvant therapy, the panel recommends that MMR or MSI testing be performed for al patinets with stage II disease and adjuvant therapy should not be given to patients with low risk stage II msi H tumors. Roth et al, JCO 2010, Koopman et al, Br J Cancer 2009

MOSAIC Trial Compared the efficacy of FOLFOX and 5-FU/LV in the adjuvant setting in 2246 patients with completely resected stage II and III colon cancer. Updated 10 year data was published last year in JCO André et al, JCO 2015

MOSAIC Trial After a median follow-up of 9.5 years, 10-year OS rates in the bolus/infusional fluorouracil plus leucovorin (LV5FU2) and LV5FU2 plus oxaliplatin (FOLFOX) arms were 67.1% versus 71.7% (hazard ratio [HR], 0.85; P = .043) in the whole population 79.5% versus 78.4% for stage II (HR, 1.00; P = .980), and 59.0% versus 67.1% for stage III (HR, 0.80; P = .016) disease. Ninety-five patients (9.4%) had MMR-deficient (dMMR) tumors, and 94 (10.4%) had BRAF mutation. BRAF mutation was not prognostic for OS (P = .965), but dMMR was an independent prognostic factor (HR, 2.02; 95% CI, 1.15 to 3.55; P = .014). HRs for DFS and OS benefit in the FOLFOX4 arm were: 0.48 (95% CI, 0.20 to 1.12) and 0.41 (95% CI, 0.16 to 1.07), respectively, in patients with stage II to III dMMR 0.50 (95% CI, 0.25 to 1.00) and 0.66 (95% CI, 0.31 to 1.42), respectively, in those with BRAF mutation.

Patients below age of 75 A low stage 2, b high stage 2, 3 n1 stage 3, 4 n2 stage 3

FOLFOX For Stage III Disease Sanoff et al Analysis of 5 observational data sources, including the SEER-medicare and NCCN Outcomes Databases Showed that the addition of oxaliplatin to 5-FU/LV gave a survival advantage to the general stage III colon cancer population treated in the community. The survival advantage associated with the addition of oxaliplatin to adjuvant 5-FU was evident across diverse practice settings (3-year OS: RCTs, 86% [n = 1273]; SEER-Medicare, 80% [n = 1152]; CanCORS, 88% [n = 129]; NYSCR-Medicaid, 82% [n = 54]; NYSCR-Medicare, 79% [n = 180]; and NCCN, 86% [n = 438]). A statistically significant improvement in 3-year overall survival was seen in the largest cohort, SEER-Medicare, and in the NYSCR-Medicare cohort (non-oxaliplatin-containing vs oxaliplatin-containing adjuvant therapy, adjusted HR of death: pooled RCTs: HR = 0.80, 95% CI = 0.70 to 0.92, P = .002; SEER-Medicare: HR = 0.70, 95% CI = 0.60 to 0.82, P < .001; NYSCR-Medicare patients aged ≥65 years: HR = 0.58, 95% CI = 0.38 to 0.90, P = .02). The association between oxaliplatin treatment and better survival was maintained in older and minority group patients, as well as those with higher comorbidity. Sanoff et al, J Natl Cancer Inst, 2012

Solid line = oxaliplatin; Dotted line = non-oxaliplatin Solid line = oxaliplatin; Dotted line = non-oxaliplatin. ACCENT shown in black; SEER–Medicare, green; CanCORS, red; NYSCR– Medicare, yellow; NYSCR–Medicaid, purple; NCCN, blue. B) ACCENT. C) SEER–Medicare (HR of death = 0.74, 95% CI = 0.63 to 0.86, P < .001). D) CanCORS (HR of death = 0.68, 95% CI = 0.44 to 1.04, P = .07). E) NYSCR–Medicaid (HR of death = 0.76, 95% CI = 0.34 to 1.72, P = .51). F) NYSCR–Medicare

FLOX NSABP- C 07 Randomized, phase III trial comparing the efficacy of FLOX vs Bolus 5FU/LV in patients with stage II or III colon cancer 2407 Patients who had undergone a potentially curative resection were randomly assigned to either: FU 500 mg/m2 intravenous (IV) bolus weekly for 6 weeks plus leucovorin 500 mg/m2 IV weekly for 6 weeks during each 8- week cycle for three cycles (FULV), or the same FULV regimen with oxaliplatin 85 mg/m2 IV administered on weeks 1, 3, and 5 of each 8-week cycle for three cycles (FLOX). Kuebler et al, JCO 2007

NSABP C-07 Rates of 4 year DFS were 73.2% for FLOX and 67% for FULV with a HR of 0.81 (P=0.005) Recent update on this study showed benefit of FLOX in DFS was maintained at 7 year median follow up.

NSABP C-07 -- Safety Cross study comparisons between FLOX and FOLFOX showed that grade 3/4 diarrhea seemed to be considerably higher with FLOX than FOLFOX. Rates of grade 3/4 diarrhea were 6.6% and 10.8% for patients receiving FOLFOX and infusional 5-FU/LV, respectively in the MOSAIC trial. Whereas 38% (FLOX) and 32% (bolus 5-FU/LV) reported grade 3/4 diarrhea in the NSABP C-07 trial

Capecitabine Single-agent oral capecitabine as adjuvant therapy for patients with stage III colon cancer was shown to be at least equivalent to bolus 5-FU/LV with respect to DFS and OS

X-ACT Trial Multicenter randomized, open-label, trial compared oral capecitabine with bolus i.v. 5-fluorouracil (5-FU)/folinic acid (FA) as adjuvant therapy for stage III colon cancer. Patients were assigned to 24 weeks of capecitabine 1250 mg/m(2) twice daily on days 1-14 every 3 weeks or 5- FU/FA. The primary end point was disease-free survival (DFS). A total of 1987 patients were randomized to capecitabine (n = 1004) or 5-FU/FA (n = 983) between November 1998 and November 2001 Twelves et al, Annals of Oncology 2011

With a median follow-up of 6 With a median follow-up of 6.9 years, capecitabine was at least equivalent to 5-FU/FA in terms of DFS [hazard ratio (HR) = 0.88; 95% confidence interval (CI) 0.77-1.01] P<0.0001 overall survival (OS) (HR = 0.86; 95% CI 0.74-1.01). P<0.001 This pattern was maintained in all subgroups, including patients aged ≥ 70 years.

XELOX NO16968 trial After curative resection, patients were randomly assigned to receive XELOX, as oxaliplatin 130 mg/m(2) on day 1 + capecitabine 1,000 mg/m(2) twice daily on days 1 to 14 every 3 weeks bolus FU/FA, for 6 months. The primary end point was disease-free survival (DFS). Secondary end points included overall survival (OS). 1,886 patients (XELOX, n = 944; FU/FA, n = 942).

XELOX- NO16968 Seven-year DFS rates were Seven-year OS rates were 63% in XELOX group 56% in FU/FA group HR=0.80; 95% CI, 0.69 to 0.93; P = .004. Seven-year OS rates were 73% in XELOX group 67% FU/FA in group HR, 0.83; 95% CI, 0.70 to 0.99; P = .04. A total of 68% and 77% of patients who experienced relapse or a new colorectal cancer in the XELOX and FU/FA groups, respectively, received drug treatment for metastatic disease. XELOX improved OS compared with bolus FU/FA in patients with resected stage III colon cancer after a median follow-up of almost 7 years. Schmoll et al, JCO, 2015

XELOX vs. FOLFOX Patients with resected stage III colon cancer from four randomized controlled trials (NSABP C-08, XELOXA, X- ACT, and AVANT; 8734 patients in total) were pooled and analyzed. The treatment regimens included in the analyses were: XELOX leucovorin and fluorouracil capecitabine FOLFOX-4 (leucovorin, fluorouracil, and oxaliplatin) modified FOLFOX-6 (mFOLFOX-6).  Schmoll et al, Lancet Oncol 2014

3, 4, and 5 year DFS, RFS, and OS by Treatment Group

Post-Relapse Survival

Safety

Adjuvant XELOX and FOLFOX Schmoll and colleagues showed that combination therapy with oxaliplatin for stage III colon cancer provides consistently improved outcomes, irrespective of the fluoropyrimidine backbone (capecitabine or leucovorin and fluorouracil), and that the benefit of combining oxaliplatin with a fluoropyrimidine is not compromised by decreased survival following relapse. Based on these data XELOX and FOLFOX are listed in the NCCN guidelines as a category 1 designation as preferred adjuvant therapy for patients with stage III colon cancer

Other Adjuvant Regimens Other adjuvant regimens studied for the treatment of early- stage colon cancer include 5-FU based therapies incorporating Irinotecan CALGB 89803 1,264 patients were randomly assigned to receive either standard weekly bolus FU plus LV regimen or weekly bolus Irinotecan plus FU plus LV. The primary end points of the study were overall survival (OS) and disease-free survival (DFS). The addition of Irinotecan to weekly bolus FU plus LV did not result in improvement in DFS or OS in stage III disease, but did increase both lethal and nonlethal toxicity (neutropenia, neutropenic fever, and death) This trial demonstrates that advances in the treatment of metastatic disease do not necessarily translate into advances in adjuvant treatment Similar resutls were observed in a trial looking at IFL vs bolus 5 fu in stage II/III patients. Folfiri has not been shown to be superior to 5-fu/lv in the adjuvant setting. Saltz et al, JCO 2007

Adding Bevacizumab? NSABP C-08 2,673 patients Patients received; modified FOLFOX6 once every 2 weeks for a 6-month period (control group) modified FOLFOX6 for 6 months plus bevacizumab (5 mg/kg) once every 2 weeks for a 12-month period (experimental group). The primary end point of the study was disease-free survival (DFS) and overall survival (OS) was a secondary end point. Allegra et al, JCO 2013

Adding Bevacizumab?- NSABP C-08 With a median follow-up of 5 years, the addition of bevacizumab to mFOLFOX6 did not result in an overall significant increase in DFS (hazard ratio [HR], 0.93; 95% CI, 0.81 to 1.08; P = .35). The secondary end point of OS was no different between the two study arms for all patients (HR, 0.95; 95% CI, 0.79 to 1.13; P = .56) and for those with stage 3 disease (HR, 1.0; 95% CI, 0.83 to 1.21; P = .99).

Adding Bevacizumab?- NSABP C-08 Cancer recurred in 286 and 283 patients in the control and bevacizumab- containing arms, respectively. Of these patients, 191 and 190 died in each arm, respectively. Although not statistically significant (P = .10), patients in the bevacizumab arm appeared to have a more rapid rate of death relative to those whose disease recurred in the control arm (HR, 1.15; 95% CI, 0.94 to 1.41).

Cetuximab? NCCTG Intergroup, N0147 Trial PETACC-8 Trial Assessed the addition of Cetuximab to FOLFOX in adjuvant treatment of stage III colon cancer In patients with wild-type or mutant KRAS, cetuximab provided no added benefit and was associated with increases in grade 3/4 adverse events PETACC-8 Trial Open-label randomized, phase III trial Compared FOLFOX with or without Cetuximab as adjuvant therapy in stage III colon cancer patients Analysis of the wild-type KRAS exon 2 subset found that DFS was similar in both arms (HR= 0.99) Adverse events (rash, diarrhea, mucositis, infusion-related reactions) were more common in the cetuximab group. Cetuximab has no role in the adjuvant treatment of colon cancer Alberts et al, JAMA 2012, Taeib et al, Lancet Oncology 2014

Treatment Summary Patients with stage I disease and patients with MSI-High, low risk stage II disease do not require adjuvant therapy Patients with low risk stage II disease can be enrolled in a clinical trial, observed without adjuvant therapy, or considered for capecitabine or 5-FU/LV. Based on the results of the MOSAIC trial, and possible long term sequelae of oxaliplatin based chemo, the NCCN does not consider FOLFOX to be an appropriate adjuvant therapy option for patients with stage II disease without high risk features

Treatment Summary Patients are deemed high-risk stage II disease, if they have any of these poor prognostic features: T4 tumors (stage IIB/IIC) poorly differentiated histology Lymphovascular invasion Perineural invasion Bowel obstruction + margins These patients can be considered for adjuvant chemotherapy with 5-FU/LV, capecitabine, FOLFOX, XELOX, or FLOX Observation without chemo is also an option for this population

Treatment Summary For patients with stage III disease, the NCCN recommends 6 months of adjuvant chemotherapy after primary surgical treatment. Treatment options include FOLFOX, XELOX, FLOX, single agent capecitabine, or 5-FU/LV in patients whom oxaliplatin therapy is believed to be inappropriate.

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