3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised, phase 3, non-inferiority trial

Abstract

SummaryBackground6 months of oxaliplatin-containing chemotherapy is usually given as adjuvant treatment for stage 3 colorectal cancer. We investigated whether 3 months of oxaliplatin-containing chemotherapy would be non-inferior to the usual 6 months of treatment.MethodsThe SCOT study was an international, randomised, phase 3, non-inferiority trial done at 244 centres. Patients aged 18 years or older with high-risk stage II and stage III colorectal cancer underwent central randomisation with minimisation for centre, choice of regimen, sex, disease site, N stage, T stage, and the starting dose of capecitabine. Patients were assigned (1:1) to receive 3 months or 6 months of adjuvant oxaliplatin-containing chemotherapy. The chemotherapy regimens could consist of CAPOX (capecitabine and oxaliplatin) or FOLFOX (bolus and infused fluorouracil with oxaliplatin). The regimen was selected before randomisation in accordance with choices of the patient and treating physician. The primary study endpoint was disease-free survival and the non-inferiority margin was a hazard ratio of 1·13. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who started study treatment. This trial is registered with ISRCTN, number ISRCTN59757862, and follow-up is continuing.Findings6088 patients underwent randomisation between March 27, 2008, and Nov 29, 2013. The intended treatment was FOLFOX in 1981 patients and CAPOX in 4107 patients. 3044 patients were assigned to 3 month group and 3044 were assigned to 6 month group. Nine patients in the 3 month group and 14 patients in the 6 month group did not consent for their data to be used, leaving 3035 patients in the 3 month group and 3030 patients in the 6 month group for the intention-to-treat analyses. At the cutoff date for analysis, there had been 1482 disease-free survival events, with 740 in the 3 month group and 742 in the 6 month group. 3 year disease-free survival was 76·7% (95% CI 75·1–78·2) for the 3 month group and 77·1% (75·6–78·6) for the 6 month group, giving a hazard ratio of 1·006 (0·909–1·114, test for non-inferiority p=0·012), significantly below the non-inferiority margin. Peripheral neuropathy of grade 2 or worse was more common in the 6 month group (237 [58%] of 409 patients for the subset with safety data) than in the 3 month group (103 [25%] of 420) and was long-lasting and associated with worse quality of life. 1098 serious adverse events were reported (492 reports in the 3 month group and 606 reports in the 6 month group) and 32 treatment-related deaths occurred (16 in each group).InterpretationIn the whole study population, 3 months of oxaliplatin-containing adjuvant chemotherapy was non-inferior to 6 months of the same therapy for patients with high-risk stage II and stage III colorectal cancer and was associated with reduced toxicity and improved quality of life. Despite the fact the study was underpowered, these data suggest that a shorter duration leads to similar survival outcomes with better quality of life and thus...

Long-term neuropathy and quality of life in colorectal cancer patients treated with oxaliplatin containing adjuvant chemotherapy

“…The risk of long-term neuropathy has been associated with cumulative dose of oxaliplatin in some studies [13,26,27], but not in all [12,28]. In the three registration studies, less neuropathy was noted in the study with 25% lower cumulative dose [4,6].…”

Impact of relative dose intensity of FOLFOX adjuvant chemotherapy on risk of death among stage III colon cancer patients

“…Our ndings from population-based cancer registry data con rmed that higher chemotherapy RDI was needed in high-risk stage III colon cancers, compared with low-risk cancers, and are consistent with the conclusions from six randomized, phase 3 clinical trials conducted by the International Duration Evaluation of Adjuvant Therapy (IDEA) collaboration, which found that 6 months of FOLFOX particularly bene ted high-risk stage III colon cancers. These clinical trials evaluated whether 3 months of FOLFOX or CAPOX is non-inferior to 6 months of therapy in the rate of disease-free survival at 3 years [4,9,32,33]. Results from a pooled analysis of six trials showed that in stage III colon cancer patients treated with FOLFOX, 6-month therapy had a higher rate of disease-free survival than 3-month therapy, particularly in the high-risk group [9].…”

Lessons learned from the maturation of a cancer drug: oxaliplatin in colorectal cancer

“…In one of the trials comparing 3 vs 6 months of adjuvant FOLFOX or CAPOX, the SCOT trial [11], another patientreported outcome measure than CIPN20, used by Soveri et al [9], the FACT/GOG NTx-4 scale was used. The scores in the 6-month arm (approximately 60% of patients actually received 6 months oxaliplatin) were about twice as high as in the 3-month arm (approximately 85% received 3 months), showing that longer treatment gives more acute and late neurotoxicity.…”

“…In the adjuvant setting, two aspects will decrease the use of oxaliplatin. One, and the reason most clinicians likely first think of, is, as described above, the recently reported trials revealing that 3 months of oxaliplatin-containing chemotherapy is for many patients not inferior to 6 months of therapy and that the shorter treatment results in less OIPN [10,11,14]. Since the release of trial data in the spring 2018 and the full publications later in 2018, the duration of adjuvant oxaliplatin-containing treatment has likely been shortened worldwide for many, if not all patients.…”

“…Controversies still exist about whether the two schedules, CAPOX or FOLFOX should be handled differently and for what subgroups, if any, the reference treatment still is 6 months. According to a substudy of the SCOT trial [11], the largest of the 5 trials in the IDEA consortium [10], 6 months of therapy is never costeffective [15]. It is beyond the purpose of this editorial to discuss pros and cons of 3 or 6 months of adjuvant therapy, but the clinical problem of long-lasting OIPN will diminish as a result of the practice changing 3 vs 6 months adjuvant trials.…”