A post hoc analysis of the international SCOT randomized clinical trial, published in JAMA Surgery on June 12, 2024, has found that starting adjuvant chemotherapy more than 6 weeks after surgery for colorectal cancer was associated with worse disease-free survival. This large-scale study provides important insights into the optimal timing of adjuvant chemotherapy for patients with high-risk stage II or stage III colorectal cancer.
The SCOT trial was a phase 3 randomized clinical trial conducted at 244 centers across 6 countries, investigating the non-inferiority of 3 versus 6 months of adjuvant chemotherapy for colorectal cancer. This post hoc analysis included 5,719 patients from the original trial, with a median follow-up of 72.0 months. The study was funded by various national cancer research organizations and pharmaceutical companies.
The primary purpose of this analysis was to examine the association between the timing of adjuvant chemotherapy after colorectal cancer surgery and disease-free survival. Patients were grouped according to whether they started adjuvant chemotherapy less than or equal to 6 weeks after surgery (early-start group, n=914) or more than 6 weeks after surgery (late-start group, n=4,805).
Inclusion criteria for the original SCOT trial were patients aged 18 years or older with high-risk stage II or stage III colorectal adenocarcinoma who had undergone curative resection. High-risk criteria included T4 disease, preoperative tumor obstruction, fewer than 10 harvested lymph nodes, poorly differentiated histology, perineural invasion, or extramural vascular invasion. Patients were enrolled within 11 weeks of surgery and had to have a World Health Organization performance status of 0 or 1.
The study population had a mean age of 63.4 years, with 39.4% being female. The majority of patients had colon cancer (81.4-85.4%), while the remainder had rectal cancer. Most patients had T3 or T4 disease and N1 or N2 nodal status.
The primary outcome measure was disease-free survival. Secondary outcomes included adverse events during the total treatment period or the first cycle of adjuvant chemotherapy. The results showed that 5-year disease-free survival was 78.0% in the early-start group compared to 73.2% in the late-start group. After adjusting for various factors, starting adjuvant chemotherapy more than 6 weeks after surgery was associated with worse disease-free survival (hazard ratio 1.24, 95% CI 1.06-1.46, p=0.01).
Importantly, there was no significant association between early start of adjuvant chemotherapy and increased adverse events, either in the total treatment period or the first cycle. This suggests that starting chemotherapy earlier does not pose additional risks to patients.
Subgroup analyses revealed that the association between delayed chemotherapy start and worse disease-free survival was particularly strong in patients with stage III disease, those randomized to 6 months of treatment, those treated with capecitabine and oxaliplatin (CAPOX), patients with rectal cancer, patients aged 70 years or younger, and those with a WHO performance status of 0.
The authors concluded that starting adjuvant chemotherapy more than 6 weeks after surgery for colorectal cancer was associated with worse disease-free survival, without an increase in adverse events. They suggest that efforts should be made to facilitate circumstances allowing patients to recover quickly from surgery so that adjuvant treatment can be initiated promptly.
However, the study has several limitations. Although the SCOT trial was randomized, patients were not randomized according to adjuvant chemotherapy start time. The analysis lacked information on surgical treatment details, including the surgical approach, use of enhanced recovery after surgery (ERAS) protocols, and postoperative complications. Additionally, the mean age of the cohort was younger than the general population of colorectal cancer patients, potentially limiting generalizability.
The potential clinical impact of this study is significant. It underscores the importance of timely initiation of adjuvant chemotherapy following colorectal cancer surgery. Clinicians may need to prioritize early referral to medical oncology and address factors that could delay the start of chemotherapy. Hospital systems may need to optimize pathways to ensure prompt initiation of adjuvant treatment.
Future research could focus on identifying and addressing barriers to early initiation of adjuvant chemotherapy. Additionally, prospective studies randomizing patients to different chemotherapy start times could provide stronger evidence for optimal timing. The interplay between neoadjuvant therapy, surgery, and adjuvant therapy timing in rectal cancer patients also warrants further investigation.
In conclusion, this large international study provides compelling evidence that starting adjuvant chemotherapy within 6 weeks of surgery for high-risk stage II or stage III colorectal cancer may improve long-term oncological outcomes without increasing treatment-related adverse events. These findings may inform clinical practice guidelines and help optimize the care of colorectal cancer patients.
References
Gögenur M, Rosen AW, Iveson T, et al. Time From Colorectal Cancer Surgery to Adjuvant Chemotherapy: Post Hoc Analysis of the SCOT Randomized Clinical Trial. JAMA Surg. 2024;159(8):865-871. doi:10.1001/jamasurg.2024.1555
