Colorectal Cancer in Older Patients Key Issues Etienne GC Brain, MD PhD Institut Curie Saint-Cloud, France www.siog.org etienne.brain@curie.fr

Epidemiology Screening > 75??? 23-45% digestive tumours are diagnosed > 75 yo (FRANCIM 2010) CRC (INCa 2012) 75-84 yo 14.7% of all cancers > 85 yo 18.7% of all cancers 1st cancer any sex in elderly 30% new cases 75-84 yo Median age at diagnosis 70 yo Screening > 75???

28 independent studies & 34 194 patients Older patients Increased frequency of comorbid conditions More later-stage disease More emergency surgery Less curative surgery More postoperative morbidity and mortality Worse OS but less striking for CRC-specific survival Lancet 2000

Undertreatment 110 cases > 75 yo (1995-2000) Treatment according guidelines = 48% pts Surgery 87% (R0 56%) Chemotherapy III 26% IV 17% XRT (rectum) Early stage 17% Palliative 21% Apparicio CROH 2009

Doat Eur J Cancer 2014

75+ vs < 75: median OS 8.4 months vs 22.3 months (17.1 months in 75+ w/ chemo) Doat Eur J Cancer 2014

Adjuvant Setting Sargent NEJM 2001

Benefits of oxaliplatin beyond fluoropyrimidine in pts > 70 years is uncertain Increased risk for AE’s with combination chemo (25% SAE w/ 15% neuropathy) Decision based on clinician’s clinical judgment Recurrence risk Fluoropyrimidine monotherapy is appropriate when oxaliplatin is felt to add excessive risk of toxicity for a patient

Questions Stratification on frailty/life expectancy for oxaliplatin vs none or chemo ves none (ADAGE/PRODIGE 34) Deficiency in mismatch repair & MSI (high frequency in older patients and improved prognosis)?

Metastatic Setting Most studies show similar benefit to systemic treatments as younger patients Few specific studies in older patients FOCUS 2, FFCD, AVEX Chemo Mono vs bi-therapy (oxaliplatin, irinotecan) ! Capecitabine > 70 Targeted treatments Anti-EGFR, anti-VEGF ! Bevacizumab with ATE history

A : LV5 FU2 q2w B : FOLFOX q2w Frail and elderly C : capecitabine q3w PS: FOCUS 1 (Fluorouracil, Oxaliplatin, CPT11 [irinotecan]: Use and Sequencing): median age 64 yo (vs 60% deaths > 75+) (Lancet 2007) > 6 w: 100% if good tolerance Initial: 80% Dose A : LV5 FU2 q2w R 1:1:1:1 B : FOLFOX q2w Frail and elderly C : capecitabine q3w D : XELOX q3w Stratification: centre, PS, surgery of primary, age Primary objective: Overall Treatment Utility = oxaliplatin and PFS (A vs B + C vs D), capecitabine and QoL (A vs C et B vs D) Secondary objectives: RR, toxicity, OS Statistics: 2x2, PFS 6 vs 9 mth, α 5% β 20%, QoL 40% vs 60% improvement at 12w, α 5% β 10%, 460 patients

Oxaliplatine 5 FU More AE grade ≥ 3 if Multivariate Median PFS 5.8 [3.3-7.5] vs 4.5 [2.8-6.4], HR 0.84 (0.69-1.01, p = 0.07) More RR 41-54% vs 35-37%) 5 FU QOL mprovement by 56% w/FU or capecitabine More AE grade ≥ 3 if Oxaliplatin 39% vs 32% p = 0.17 Cape 40% vs 30% p = 0.03 Multivariate Less symptoms Limited disease  Better OTU

FFCD 2001-02 123 patients with mCRC, first line of chemotherapy 5-FU-based chemo ± irinotecan Median age 80 yo (75-91) Charlson index≤ 1 75% MMSE ≤ 27/30 31% IADL impairment 34% Toxicity grade 3-4 toxicity 71 patients (58%): IRI, MMSE, IADL Dose-intensity reduction > 33% 41 patients (33%): IRI, Alk phosph ≥ 1 unexpected hospitalization (4 mth) 54 patients (44%): MMSE, GDS Cognitive function and autonomy impairment should be taken into account when choosing a regimen for chemotherapy Aparicio J Clin Oncol 2013

Cunningham Lancet Oncol 2013

AVEX PFS: 9.1 vs 5.1 mos (HR 0.53, p<0.001) OS: 20.7 vs 16.8 mos (HR 0.79, p=0.182) [AVF2107g results: IFL+/- BEV 20.3 mos vs 15.6 mos (HR 0.66, p<0.001)] RR: 19.3% vs 10% p=0.042 Grade 3+ AEs: 59% vs 44.1% Conclusions: Cape + BEV could be a standard for selected elderly patients Cunningham Lancet Oncol 2013

SEER database 3,039 patients ≥ 66, stage IV breast, lung, colon cancer, 2004-2007, bevacizumab Contra-indication defined as 2 claims for thrombosis, cardiac disease, stroke, hemorrhage, hemoptysis, or GI perforation Toxicity defined as 1st development of 1 condition > beva Beva use associated w/ white race, later year of diagnosis, tumor type, and decreased comorbid conditions 35.5% had contra-indication Black race, increased age, comorbidity, later year of diagnosis, lower socioeconomic status, lung and CRC If no contra-indication  30% complication (black race) Hershman J Clin Oncol 2013

Cetuximab Pooled analysis from KRAS wild-type pts CRYSTAL (FOLFIRI +/- cetuximab) OPUS (FOLFOX +/- cetuximab) OS, PFS and safety were all similar among older ( ≥ 70 years) and younger (<70 years) pts. Grade 3+ toxicity was increased in both treatment arms for elderly patients NO obvious interaction between age (< 70 vs ≥ 70 years) and the differences for treatment toxicity between the arms. Folprecht ESMO 2010

Treatment decisions should not be based on age alone Fit older patients can tolerate combination cytotoxic therapy as well and benefit as much as younger patients Same for biologics Consider less intense regimens for those who are not candidates for standard regimens Reduced dose FP + oxaliplatin Cape + BEV