Chemotherapy options in elderly and frail patients with metastatic colorectal cancer (MRC FOCUS2): an open-label, randomised factorial trial

Abstract

SummaryBackgroundElderly and frail patients with cancer, although often treated with chemotherapy, are under-represented in clinical trials. We designed FOCUS2 to investigate reduced-dose chemotherapy options and to seek objective predictors of outcome in frail patients with advanced colorectal cancer.MethodsWe undertook an open, 2 × 2 factorial trial in 61 UK centres for patients with previously untreated advanced colorectal cancer who were considered unfit for full-dose chemotherapy. After comprehensive health assessment (CHA), patients were randomly assigned by minimisation to: 48-h intravenous fluorouracil with levofolinate (group A); oxaliplatin and fluorouracil (group B); capecitabine (group C); or oxaliplatin and capecitabine (group D). Treatment allocation was not masked. Starting doses were 80% of standard doses, with discretionary escalation to full dose after 6 weeks. The two primary outcome measures were: addition of oxaliplatin ([A vs B] + [C vs D]), assessed with progression-free survival (PFS); and substitution of fluorouracil with capecitabine ([A vs C] + [B vs D]), assessed by change from baseline to 12 weeks in global quality of life (QoL). Analysis was by intention to treat. Baseline clinical and CHA data were modelled against outcomes with a novel composite measure, overall treatment utility (OTU). This study is registered, number ISRCTN21221452.Findings459 patients were randomly assigned (115 to each of groups A–C, 114 to group D). Factorial comparison of addition of oxaliplatin versus no addition suggested some improvement in PFS, but the finding was not significant (median 5·8 months [IQR 3·3–7·5] vs 4·5 months [2·8–6·4]; hazard ratio 0·84, 95% CI 0·69–1·01, p=0·07). Replacement of fluorouracil with capecitabine did not improve global QoL: 69 of 124 (56%) patients receiving fluorouracil reported improvement in global QoL compared with 69 of 123 (56%) receiving capecitabine. The risk of having any grade 3 or worse toxic effect was not significantly increased with oxaliplatin (83/219 [38%] vs 70/221 [32%]; p=0·17), but was higher with capecitabine than with fluorouracil (88/222 [40%] vs 65/218 [30%]; p=0·03). In multivariable analysis, fewer baseline symptoms (odds ratio 1·32, 95% CI 1·14–1·52), less widespread disease (1·51, 1·05–2·19), and use of oxaliplatin (0·57, 0·39–0·82) were predictive of better OTU.InterpretationFOCUS2 shows that with an appropriate design, including reduced starting doses of chemotherapy, frail and elderly patients can participate in a randomised controlled trial. On balance, a combination including oxaliplatin was preferable to single-agent fluoropyrimidines, although the primary endpoint of PFS was not met. Capecitabine did not improve QoL compared with fluorouracil. Comprehensive baseline assessment holds promise as an objective predictor of treatment benefit.FundingCancer Research UK and the Medical Research Council.

Experience with S-1 in older Caucasian patients with metastatic colorectal cancer (mCRC): Findings from an observational chart review

“…In the first-line setting with SOx we observed a response rate of 41%, DCR of 86%, median PFS of 8.5 months and median OS of 18.5 months, data which are in line with what would be expected in older mCRC patients treated with chemotherapy [18,19]. Our findings indicate that the SOx regimen is well tolerated even in older patients with a low rate of clinical adverse events similar to what would be expected with other fluoropyrimidine-oxaliplatin-based combinations, albeit with a much lower rate of HFS [20].…”

First-Line Mono-Chemotherapy in Frail Elderly Patients with Metastatic Colorectal Cancer

“…In this study, patients were randomized into four groups: infusional 5-FU with calcium folinate; oxaliplatin and 5-FU; capecitabine; or oxaliplatin and capecitabine. Comparison of addition of oxaliplatin versus no addition did not reveal a significant improvement in PFS (median 5.8 months vs 4.5 months p:0·07) (Seymour et al, 2011). There was also no significant difference between capecitabine and 5-FU in terms of survival.…”

“…There was also no significant difference between capecitabine and 5-FU in terms of survival. The risk of having any high grade toxicity was not significantly increased with oxaliplatin but was slightly higher with capecitabine than with fluorouracil (Seymour et al, 2011). In another remarkable study, Feliu et al analyzed mCRC patients >70 age or older who were considered ineligible for combination chemotherapy and treated them with capecitabine 1250 mg/m 2 twice daily for 14 of every 21 days.…”

Clinico-Pathological Caracteristics, Therapeutic Features and Post-operative Course of Colorectal Cancer in Elderly Patients

“…However, there currently exists no evidence-based method to combine the many data items generated by the CGA into one decision about whether to offer chemotherapy or which regimen to use [20]. As shown in previous reports [5], our patients were undertreated: there were significant differences between patients below 75 years and patients above 75 years concerning radio or radiochemotherapy for rectal cancer and chemotherapy for colic cancer.…”