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

Abstract

Background: 6 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.

Methods: The 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.

Findings: 6088 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).

Interpretation: In 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 might represent a new standard of care.

Funding: Medical Research Council, Swedish Cancer Society, NETSCC, and Cancer Research UK.

Figure 1

Trial profile ITT=intention to treat. CTCAE=Common Terminology Criteria for Adverse Events. *Based on retrospective review. †Patients could have more than one reason.

Figure 2

Disease-free survival (A) and overall survival (B) by study group HR=hazard ratio.

Figure 3

Disease-free survival and heterogeneity in subgroups by minimisation variables Categories are listed as recorded at randomisation; ten patients in the 3 month group and 15 patients in the 6 month group could not be allocated to high risk stage II or stage III based on T/N data recorded at randomisation. *These estimates differ slightly because the underlying multivariable Cox model on which they are based includes parameters for other minimisation variables, as well as those factors relating to stage; the increased flexibility in the expanded stage model allows the influence of these parameters on the high risk stage II estimates to modify.

Figure 4

Disease-free survival by study group and selected adjuvant regimen HR=hazard ratio.

Figure 5

Treatment delivery by selected adjuvant regimen Box and whisker plots indicate median and IQR (boxes) and range (whiskers). Dots represent outliers.

Figure 6

Disease-free survival by study group and stage III risk group HR=hazard ratio.

Figure 7

Peripheral neuropathy by study group Patients reported peripheral neuropathy with the GOG Ntx4 questionnaire. Although results were available beyond year 6, they have been omitted because of small numbers and resultant wide confidence intervals. Error bars show 95% CIs. *The low completion rates at these timepoints reflect the fact that, initially, neurotoxicity data were only collected up to 12 months and there was a delay before an amendment extended the collection to the whole study period. †Low return rate because patients were assessed at the start of last cycle rather than 6 months (which corresponds to end of cycle).