Timing of adjuvant chemotherapy initiation and mortality among colon cancer patients at a safety-net health system

Adjuvant chemotherapy following surgical resection of colon cancer is intended to eliminate micrometastatic disease and increase overall and disease-free survival [1]. Evidence from randomized controlled trials (RCTs) established that adjuvant chemotherapy increased survival among stage III colon cancer patients, [2‐4] and thus adjuvant chemotherapy for stage III colon cancer is standard of care. In addition, evidence suggests that early initiation of adjuvant chemotherapy may improve survival among colon cancer patients, [5‐8] and timing of adjuvant chemotherapy initiation is included in quality of care guidelines [9, 10]. Nevertheless, the evidence for timing of adjuvant chemotherapy was derived from observational studies, which may be sensitive to time-related biases [11, 12].

In contrast to RCTs, where the design ensures alignment of key elements such as treatment allocation, eligibility, and follow-up at a common starting point (i.e., time zero) to minimize time-related biases, this alignment requires additional methodologic considerations in observational studies [11, 12]. For example, prior studies [5‐8] included comparisons of survival between patients who initiated adjuvant chemotherapy ≤8 weeks and patients who initiated adjuvant chemotherapy > 8 weeks following surgical resection. Such comparisons are problematic because patients must survive a specified duration before initiating treatment, and analyses that do not properly account for this duration will incur immortal time bias [11, 13‐17]. Several studies have illustrated severe overestimation of treatment effects on survival in observational studies of cancer patients, which was attributable to immortal time bias [18‐20]. Immortal time bias has not been addressed in the context of timing of adjuvant chemotherapy initiation for colon cancer survival and could have implications for current quality of care guidelines. Therefore, we aimed to estimate the effect of initiating adjuvant chemotherapy for stage III colon cancer within an interval of interest (8 or 12 weeks) following surgical resection on survival using a study design that helps align time zero and reduce immortal time bias.

Our analyses were based on 222 evaluable observations after pooling 3 sequential trials for evaluating initiation ≤8 weeks and 310 evaluable observations after pooling 5 sequential trials for evaluating initiation ≤12 weeks of surgical resection. Table 1 summarizes the distribution of the baseline characteristics of these observations. The median age of the study population was 56 years (interquartile range [IQR]: 50–61), and the majority were female (56–57%), racial/ethnic minorities (64–65%), or uninsured with or without enrollment in our hospital-based medical assistance program (68–71%). Median time from diagnosis to surgical resection was 4 days (IQR: 1–28). Median time from surgical resection to adjuvant chemotherapy was 56 days (IQR: 46–78) for observations that initiated adjuvant chemotherapy in the 8-week analysis and 69 days (IQR: 51–86) for observations that initiated adjuvant chemotherapy in the 12-week analysis. For the 8-week analysis, 28% did not initiate adjuvant chemotherapy at any time, and for the 12-week analysis 34% did not initiate adjuvant chemotherapy at any time. The most common reason for not initiating adjuvant chemotherapy was patient refusal (71%). FOLFOX (including modified FOLFOX) was the most common adjuvant chemotherapy regimen (71–73%).

We observed 62 deaths and 57 recurrences within 5 years of surgical resection among observations in the 8-week analysis, and 84 deaths and 79 recurrences among observations in the 12-week analysis. Figures 1 and 2 illustrate the marginal overall and disease-free survival curves for initiators and non-initiators of adjuvant chemotherapy ≤8 or ≤ 12 weeks of surgical resection. The crude risk of all-cause mortality was 17% lower (RR = 0.83; 95% CL: 0.46, 1.51) and the crude risk of recurrence or mortality was 7% lower at 5 years (RR = 0.93; 95% CL: 0.55, 1.57) for patients who initiated adjuvant chemotherapy ≤8 weeks compared with patients who did not initiate adjuvant chemotherapy ≤8 weeks of surgical resection. The crude risk of all-cause mortality was 14% higher (RR = 1.14; 95% CL: 0.77, 1.68) and the crude risk of recurrence or mortality was 22% higher at 5 years (RR = 1.22; 95% CL: 0.85, 1.76) for patients who initiated adjuvant chemotherapy ≤12 weeks compared with patients who did not initiate adjuvant chemotherapy ≤12 weeks of surgical resection.

The adjusted risk (i.e., after weighting) of 5-year all-cause mortality was 4% higher for patients who initiated adjuvant chemotherapy ≤8 weeks compared with patients who did not initiate adjuvant chemotherapy ≤8 weeks of surgical resection, but our data were compatible with 43% lower risk or 92% higher risk of mortality (RR = 1.04, 95% CL: 0.57, 1.92). The adjusted risk of recurrence or mortality at 5 years was 7% higher for patients who initiated adjuvant chemotherapy ≤8 weeks compared with patients who did not initiate adjuvant chemotherapy ≤8 weeks of surgical resection, but our data were compatible with 39% lower risk or 88% higher risk of recurrence or mortality (RR = 1.07, 95% CL: 0.61, 1.88). The results were similar for initiation of adjuvant chemotherapy ≤12 weeks of surgical resection (Table 2).

Our analysis aimed to align time zero and reduce immortal time bias, which were sources of error in prior studies about timing of adjuvant chemotherapy initiation for stage III colon cancer patients < 80 years. Our results suggest that the overall and disease-free survival benefits of initiating adjuvant chemotherapy ≤8 or ≤ 12 weeks of surgical resection may be overestimated in prior studies. Nevertheless, our data were compatible with either meaningful benefit or harm of initiation within specified intervals. Imprecision and potential sources of error require further consideration when interpreting our results.

Imprecision in survival analysis is a function of number of events (i.e., death or recurrence in our analysis) and person-time. A larger sample size or longer follow-up (assuming more events) could provide more precise estimates, but our sample size was limited to available data. Precision is certainly important but only addresses random error. Quantification of effects with reduced systematic error (i.e., mitigated biases) is also critical. Our analysis prioritized mitigating key biases in prior studies that could mislead interpretation. Consequently, our estimates may be useful despite imprecision, [41, 42] particularly if estimates from multiple studies with similar approaches are summarized in a meta-analysis to improve precision [41].

As with any observational study, our estimates may be sensitive to violations of exchangeability [43, 44] (i.e., unmeasured confounding or selection bias). For example, data were unavailable to allow adjustment for frailty at diagnosis. Nevertheless, unmeasured confounding by frailty would create bias away from the null because we would expect an inverse relation between frailty and initiation of adjuvant chemotherapy ≤8 or ≤ 12 weeks of surgical resection (i.e., initiation may require additional time for frail patients) and frailty would increase mortality risk. Adjustment would thus move the estimate further toward the null [45]. In addition, the crude and adjusted 95% confidence limits for risk ratios were largely overlapping despite adjustment for multiple covariates, particularly for the more stable 12-week estimates. The lack of notable differences in crude and adjusted estimates suggests that confounding may not be as prominent of a concern once time zero is aligned, which is a phenomenon observed in prior studies that explored the effects of misaligned time zero [23, 46]. Lastly, survival could be affected by adherence to adjuvant chemotherapy [47, 48], but addressing adherence would change the question of interest and require a different study design [49]. Our study was designed to address the effect of initiating adjuvant chemotherapy, which is the question of interest relevant to quality of care guidelines and the basis of prior studies.

Our findings differ from prior studies [50‐53], in which point estimates suggested 25–55% lower mortality hazards for initiation of adjuvant chemotherapy ≤8 weeks after surgical resection compared with later initiation or no initiation among colon cancer patients. Time-related biases [11, 12, 14, 15, 54] from misaligned start of eligibility, time of treatment assignment, and start of follow-up are a key consideration for effect heterogeneity between our study and prior studies. For example, immortal time bias is a concern in prior studies [50‐53, 55] because follow-up time was measured from surgical resection, but adjuvant chemotherapy was initiated after follow-up time began. The consequence is misclassified person-time, where the time between start of follow-up and treatment initiation is considered “immortal.” Several studies have reported substantial bias away from the null because of immortal time, [19, 20, 25, 56] and this bias can be more severe than unmeasured confounding [23, 46]. We used analytic methods to mitigate immortal time bias, [11, 57] which may partly explain why our point estimates are closer to the null than prior studies. In addition, prior studies [50‐52] excluded patients who were eligible for but did not initiate adjuvant chemotherapy, which incurs selection bias [58]. Lastly, effect heterogeneity across studies may be related to clinical setting and population characteristics. For example, our study was conducted in a cancer center that provides care for socioeconomically marginalized populations. Our estimates may be closer to the null if adverse effects of social determinants of health override benefits of earlier treatment initiation [59, 60]. Consequently, our results may generalize to other safety-net settings but not necessarily academic cancer centers.

In summary, assuming no substantial effect of biases, our results suggest that initiating adjuvant chemotherapy ≤8 or ≤ 12 weeks of surgical resection for stage III colon cancer patients < 80 years may not be as beneficial as reported in prior studies. Nevertheless, our results were imprecise and require confirmation. Future studies that also address time-related biases and have larger samples or longer follow-up may provide greater precision. Alternatively, estimates from multiple similar studies may be combined in a meta-analysis to improve precision. Such evidence could be valuable considering that cancer care delivery organizations dedicate considerable resources to meet guidelines for timely care, but some guidelines may not be optimized for meaningful outcomes or for certain settings.