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Colorectal Adjuvant Chemotherapy: Timing Is Something
Abstract & Commentary
By William B. Ershler, MD
Synopsis: In a retrospective review, delay beyond 60 days in initiating adjuvant chemotherapy after surgery for colorectal cancer was associated with poorer overall survival. Although factors such as surgical complications or the existence of comorbidities may explain the delays for some of the cases, other "administrative" factors, such as delays resulting from insurance authorizations or referral setbacks, are to be avoided, if at all possible.
Source: Bayraktar UD, et al. Does delay of adjuvant chemotherapy impact survival in patients with resected stage II and III colon adenocarcinoma. Cancer2011;117:2364-2370.
It's a commonly held notion that prompt institution of adjuvant chemotherapy for patients with newly diagnosed colon cancer after surgical resection is optimal, although this primarily is based on hypothetical reasoning, perhaps accumulated experience but not on well-controlled clinical investigation. It has been held that during recovery from surgery there is enhanced angiogenesis and transient depression of immune function resulting in both a period of enhanced growth of microscopic residual disease and a window of opportunity to eradicate proliferating cells with effective cytotoxic chemotherapy.1-3 Accordingly, most clinical trials of adjuvant chemotherapy call for a minimal delay after surgery before the initiation of treatment and exclude enrollment if there has been a delay of 8 weeks or more. Yet, it remains unclear from the published literature to what extent the time to initiating chemotherapy influences the overall benefit.
Capitalizing on a rich database from Jackson Memorial Hospital and the Sylvester Comprehensive Cancer Center in Miami, Bayraktar and colleagues performed a retrospective analysis to address this question. Patients with stage II-III colon adenocarcinoma who received adjuvant chemotherapy at either of these two centers were identified through the institutional tumor registry. Time to adjuvant chemotherapy, overall survival (OS), and relapse-free survival (RFS) were calculated from the day of surgery. Patients with rectal cancer were not included, nor were patients who had adjuvant chemotherapy started beyond 120 days or patients who had less than 3 months of follow-up. Patients were dichotomized into early (time to adjuvant chemotherapy < 60 days) and late (time to adjuvant chemotherapy > 60 days) treatment groups. OS and RFS were compared using log-rank test and multivariate analysis by the Cox proportional hazards model.
Of 186 patients included in the study, 49 (26%) had received adjuvant chemotherapy > 60 days after surgical resection. Thirty percent of the delays were system-related (e.g., late referrals, insurance authorizations). Time to adjuvant chemotherapy > 60 days was associated with significantly worse OS by both univariate analysis and a Cox proportional hazards model (hazard ratio, 2.17; 95% confidence interval, 1.08-4.36). Although difference in RFS between the two groups favored time to adjuvant chemotherapy < 60 days, this did not reach statistical significance.
There are several reasons adjuvant chemotherapy might be delayed. Some are administrative, such as insurance authorization or delayed clinic appointments. However, others, such as delays that result from postoperative complications or the need to attend to comorbidities prior to the induction of chemotherapy, might, in themselves, predict a less favorable outcome based either upon the higher likelihood of greater residual microscopic disease (such as might be expected after surgery associated with perforation) or dose reductions/schedule delays that are more likely to exist among those with significant comorbidities. In the current report, there was a trend (although not statistically significant) that patients who were married were more likely to start adjuvant chemotherapy within 60 days, a finding consistent with other reports.4 However, there was no association between adjuvant chemotherapy delay and race/ethnicity or among those who had delays from diagnosis to surgery.
The current report provides an inkling that time itself is a relevant factor inasmuch as by multivariate analysis delays that resulted from surgical complications or administrative factors that were controlled (covariates in the multivariate analysis). It was apparent that overall survival was better for most subgroups, although with the relatively small sample size, statistical significance was reached for only a few. Unfortunately, the important issue of comorbidities could not be addressed adequately because of the small numbers and incomplete data, so it remains unclear to what extent delays in the initiation of adjuvant chemotherapy can explain decrements in survival for those with additional medical problems. But for the group as a whole, the analysis indicates that delays in starting adjuvant chemotherapy beyond 60 days is associated with less optimal overall survival.
The true impact of delayed adjuvant therapy only would be addressed adequately by a prospective, controlled clinical trial, and such is not likely to be undertaken for ethical reasons. Nonetheless, retrospective analyses such as this are useful in identifying factors that might be associated with delays, some of which may be correctable. Although supporting evidence is incomplete, it remains prudent to initiate adjuvant therapy within 2 months after surgery.
1. Baum M, et al. Does surgery unfavourably perturb the "natural history" of early breast cancer by accelerating the appearance of distant metastases? Eur J Cancer 2005;41:508-515.
2. Fisher B, et al. Presence of a growth-stimulating factor in serum following primary tumor removal in mice. Cancer Res 1989;49:1996-2001.
3. Hensler T, et al. Distinct mechanisms of immunosuppression as a consequence of major surgery. Infect Immun 1997;65:2283-2291.
4. Hershman D, et al. Timing of adjuvant chemotherapy initiation after surgery for stage III colon cancer. Cancer2006;107:2581-2588.