Discussion
Dukes’ B2 disease, cancer, treatment-related adverse, Dukes’ B3 and C disease, C colon cancer, deaths
RECURRENCE, DUKES, CANCER, RECURRENT DISEASE, COLON CANCER, STRICTURES
The concept of perioperative chemotherapy is driven by the hypothesis that the timing of the start of systemic treatment for cancer after surgery is an important determinant of the therapeutic outcome.There is evidence that wound healing parallels the ability of cancer cells to metastasize. It has been shown that tumor-derived growth factors orchestrate the development of “premetastatic niches,” which are similar to the matrix of wound healing.This open-label randomized phase III study aimed to investigate the use of perioperative chemotherapy started within 24 h of the completion of surgery for patients with resected Dukes’ B2, B3, and C colon cancer. The study terminated early because of slow accrual and instead of the expected 2000 patients, only 859 enrolled. This study required a coordinated, multidisciplinary team approach so that patients could be consented prior to surgery and perioperative therapy could start within 24 h of resection. Most institutions did not have such a mechanism in place, and many surgeons were not in environments in which this effort could be accommodated; with the passage of time additional regulatory strictures became limiting. Furthermore, there were at least two competing multi-institutional adjuvant trials that opened during the course of this trial which were investigating postoperative adjuvant therapy, and were easier to enroll to because they required less cooperation between treatment modalities.This trial had limited power to answer the question of the usefulness of perioperative 5-FU. In total, 314 patients with Dukes’ B3 and C disease were enrolled, and this sample size could detect a hazard ratio of 0.625 with adequate power assuming exponential distribution of OS. The trial was revised to have adequate power to detect a 60% improvement in median OS, so it only could detect a big treatment effect. The results did not show significant improvement in OS or DFS in patients receiving perioperative 5-FU therapy compared with patients without such chemotherapy and, thus, the primary endpoint was not met. The study did not report on the location of recurrent disease, nor what was the treatment of the recurrence. In patients with Dukes’ B2 disease, perioperative 5-FU was not associated with statistically significant improvement in either OS or DFS. Yet the overall survival results in the perioperative arms were consistently better for all stages over the 15-year follow-up period.The study did establish that infusional 5-FU chemotherapy does not impair wound healing in the immediate postoperative period and is generally tolerable. Eighteen percent of patients developed grade 3 or higher treatment-related adverse events, although there were three deaths described as 5-FU treatment related.Clinically significant results of studies incorporating oxaliplatin established FOLFOX as the current adjuvant chemotherapy standard of care for high-risk colon cancer.Similarly, the NSABP study that changed practice from adjuvant therapy with 5-FU and levamisole to 5-FU and leucovorin showed a survival difference of 4% in favor of 5-FU/leucovorin (74% versus 70%).No other prospective randomized trial has tested perioperative chemotherapy for colon cancer, yet it remains a highly relevant question today given our advanced understanding of the metastatic process and availability of better systemic therapies, including immune modulators. The conduct of adequately powered, prospective randomized trials is the only way to determine the optimal timing and effects on survival of a perioperative approach to adjuvant therapy.