Impact of timing of adjuvant chemotherapy on survival in stage III colon cancer: a population-based study

Colon cancer is an important cause of cancer-related incidence and mortality and remains a major public health problem worldwide [1]. The current clinical practice guidelines from the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO) recommend adjuvant chemotherapy following surgical resection as a standard treatment for patients with stage III colon cancer because of the benefit of chemotherapy in reducing the risk of recurrence and death by eradicating micrometastases [2].

Several studies have reported that the surgical resection of a primary tumor might induce angiogenesis and proliferation of dormant micrometastases by releasing growth-stimulating factors and triggering immunosuppression that leads to tumor growth [3‐7]. Moreover, Harless et al. reported that the effectiveness of adjuvant chemotherapy was inversely proportional to the time from adjuvant chemotherapy initiation to surgical resection [8]. Therefore, it is a reasonable hypothesis that there may be a time-dependent cut-off point after surgery after which the benefit of adjuvant chemotherapy is not significant because of the failure to eradicate micrometastases. However, the NCCN and ESMO guidelines do not specify an optimal time to initiate adjuvant chemotherapy after surgical resection. Most clinical trials of adjuvant chemotherapy in colon cancer require adjuvant chemotherapy initiation within 6 to 8 weeks after surgical resection [9‐12]. Routine preclinical and clinical data suggest that adjuvant chemotherapy in colon cancer should be initiated earlier rather than later, but, in real practice, the initiation of adjuvant chemotherapy in colon cancer is often delayed [13, 14].

There is no direct and high-quality evidence regarding the importance of the timing of adjuvant chemotherapy in colon cancer. Although two meta-analyses demonstrated that delays in the initiation of adjuvant chemotherapy were detrimental to survival in colorectal cancer [15, 16], these meta-analyses included both rectal and colon cancer, and it was thus not clear whether the conclusions could be applied to the treatment of colon cancer because of the biological differences between colon cancer and rectal cancer. To date, few retrospective studies evaluated the impact of the timing of adjuvant chemotherapy on survival in colon cancer, and the results were inconsistent [17‐23]. Moreover, the relevant postoperative complications that cause delays in adjuvant chemotherapy are unknown.

Therefore, this population-based study was conducted to assess the impact of the timing of adjuvant chemotherapy on survival in stage III colon cancer and to assess whether postoperative complications were associated with the timing of adjuvant chemotherapy.

There is no evidence about the optimal time to initiate adjuvant chemotherapy after surgical resection, or whether there is an ideal timing for adjuvant therapy after which treatment benefit decreases. This population-based study based on the SEER-Medicare databases was conducted to evaluate the relationship between the timing of adjuvant chemotherapy and survival in stage III colon cancer. The results indicated that adjuvant chemotherapy that was initiated within 5–8 weeks after surgery did not increase the risk of mortality compared with chemotherapy initiated at ≤4 weeks after surgery, and the initiation of adjuvant chemotherapy within 8 weeks after surgery was thus feasible. However, adjuvant chemotherapy after 8 weeks of surgery was significantly associated with worse OS. The survival benefit of adjuvant chemotherapy became statistically insignificant when chemotherapy was initiated after 21 weeks compared with the non-chemotherapy group, thus, adjuvant chemotherapy might be still useful even with a delay of approximately 5 months (Fig. 3). Our results indicated that the survival benefits of the FOLFOX/CapeOX chemotherapy regimen within 5–8 weeks and ≤4 weeks were similar, and chemotherapy initiated ≥19 weeks did not have a significant OS benefit compared with the non-chemotherapy group.

The favorable effect of adjuvant chemotherapy on survival primarily involves the eradication of residual disease and micrometastases. However, the relationship between the timing of adjuvant chemotherapy and survival is unclear. Several studies reported that primary tumor removal could accelerate angiogenesis and growth of residual disease and micrometastases by releasing growth-stimulating factors and promoting immunosuppression [3‐7]; thus, a delay in adjuvant chemotherapy might favor tumor angiogenesis and growth, and a long delay could lead to tumor recurrence or metastasis and a consequent failure to achieve the curative potential of adjuvant chemotherapy. Furthermore, Goldie et al. suggested that the drug sensitivity of a tumor was related to the spontaneous mutation rate toward phenotypic drug resistance, which was a function of time [33]. Moreover, the mathematical model by Harless et al. demonstrated that the effectiveness of chemotherapy was inversely proportional to the tumor burden that had to be eradicated, which, in turn, was a function of the time of the initiation of chemotherapy after surgery [8]. Therefore, the survival benefit of adjuvant chemotherapy was time-dependent. Studies have also reported that delayed chemotherapy might reflect poor patient and disease characteristics and increase comorbidity, which would be associated with poor prognoses [13, 34].

Our spline-based HR model revealed that the efficacies of adjuvant chemotherapy within 5–8 weeks and ≤4 weeks were similar, although the minimum risk of mortality was achieved at 4 weeks after surgery. Bos et al. demonstrated that adjuvant chemotherapy within 5–6 weeks or 7–8 weeks after surgery did not decrease OS compared to the initiation of chemotherapy within 4 weeks, and the start of chemotherapy 8 weeks after surgery was associated with a decreased OS [35]. In clinical practice, it is important to note that the toxicity of chemotherapy may be maximized due to poor immune and performance statuses after surgery, and thus, initiating chemotherapy early may cause severe chemotherapy-related adverse events and even death [36]. Therefore, an additional survival benefit of excess-early adjuvant chemotherapy may be difficult to detect because of the severe adverse events caused by chemotherapy. The initiation of adjuvant chemotherapy within 8 weeks after surgery was feasible. However, adjuvant chemotherapy that was initiated ≥21 weeks after surgery did not have a significant survival OS benefit compared with the non-chemotherapy group, and conversely, this delay may cause additional chemotherapy-related adverse events. Further studies are needed to explore the optimal timing for adjuvant chemotherapy, for example, identifying the time at which the survival benefit from chemotherapy maximally outweighs the risks of chemotherapy-related adverse events and death.

Several studies reported that patient and disease characteristics, including older age, low income, and high comorbidity, were associated with delayed adjuvant chemotherapy [13, 34]. Cheung et al. reported that the determinants of delayed adjuvant chemotherapy might be primarily influenced by their relationships with the postoperative complications that ultimately resulted in chemotherapy delay, and these complications seemed to be a more important driver for chemotherapy delay [37]. Therefore, the relationship between postoperative complications and delayed adjuvant chemotherapy was evaluated, and the results indicated that patients with postoperative complications had a significantly higher risk of delayed adjuvant chemotherapy (p < 0.05). Specifically, cardiac arrest, ostomy infection, shock, and septicemia had strong influences on delayed chemotherapy and caused delays of 4–11 weeks. Moreover, disruption of the operation wound, peritonitis, fistula of the gastrointestinal tract, acute renal failure, postoperative infection, intestinal perforation, acute myocardial infarction, and stroke could cause delays of 2–3 weeks. These results were expected because patients with severe postoperative complications were likely to require more time for recovery. Therefore, multidisciplinary treatment strategies are needed to reduce postoperative complications and promote timely adjuvant chemotherapy.

This study has limitations. First, this was a retrospective SEER-Medicare study, and thus the potential for confounding based on patient selection could not be completely eliminated. Second, the data on the patient/disease characteristics and treatments were obtained from a fee-for-service insurance database. Some clinical variables were not available, and the presence of other important confounding factors could not be discarded. Third, the use of adjuvant chemotherapy may decrease in older patients mainly because older patients are more likely to have high comorbidity and poor performance statuses, and oncologists may be less willing to use adjuvant chemotherapy [38, 39]. In our study, the results demonstrated that the use of adjuvant chemotherapy was common in older patients with stage III colon cancer (9722/18,491, 52.6%), and adjuvant chemotherapy significantly improved the prognoses compared with the non-chemotherapy group. Additionally, several studies have also demonstrated that older patients with stage III colon cancer gain a significant survival benefit from adjuvant chemotherapy [40‐43]. Therefore, further large-scale, high-quality studies are needed to evaluate the interactions of age and the timing of adjuvant chemotherapy with survival in stage III colon cancer. Fourth, disease-free survival was also an appropriate measure for assessing the survival benefit of adjuvant chemotherapy; however, disease-free survival could not be evaluated because the data on disease-free survival was not available in the SEER-Medicare database. Further studies are required to investigate the impact of the timing of adjuvant chemotherapy on disease-free survival. Moreover, it was not feasible to conduct a randomized controlled trial to specifically address the impact of the timing of adjuvant chemotherapy on survival in colon cancer. Thus, larger-scale and well-designed retrospective studies are needed to explore the optimal timing of adjuvant chemotherapy after surgical resection.

The survival benefits of adjuvant chemotherapy within 5–8 weeks and ≤4 weeks were similar, and thus, initiation of adjuvant chemotherapy within 8 weeks in patients with stage III colon cancer was feasible. Adjuvant chemotherapy 8 weeks after surgical resection was significantly associated with worse OS. However, adjuvant chemotherapy might still be useful even with a delay of approximately 5 months, although the survival benefit was reduced. Additionally, postoperative complications were significantly associated with the delayed initiation of adjuvant chemotherapy in patients with stage III colon cancer.