Our primary aim was to determine the degree of 5-year overall survival benefit conferred by adjuvant chemotherapy on patients with stage II colon cancer having poor prognostic features. Although these characteristics do distinguish a subgroup of stage II patients with worse survival than the rest of the stage II cohort, they do not predict measurable mortality benefit from chemotherapy in this study population. Our sample size in this analysis of Medicare beneficiaries allows us to detect, if present, a 2% absolute difference in 5-year survival attributable to chemotherapy; our lack of statistical significance implies that any benefit that exists is quite small. Interestingly, chemotherapy use does not differ between stage II patients with or without poor prognostic features, suggesting that these are not central to the treatment decision.
Our analysis has several important advantages over prior investigations. In contrast to prior trials that predominantly recruited patients with stage III disease, our study population has sufficient power to detect clinically significant differences in survival for patients with stage II disease, addressing concerns about inadequate sample size. In addition, this is the only study to date that specifically examines the subgroup of stage II patients with poor prognostic features, thereby addressing the population heterogeneity that was thought to confound prior conclusions of minimal survival benefit.1–10,12,15
The median age of colon cancer diagnosis is 70 years, yet many older adults were explicitly excluded from randomized chemotherapy trials or were otherwise deemed ineligible as a result of age-related comorbidity, provider bias, or patient preference.1–10
Our study population importantly presents a more real-world age distribution (68% over age 75 years at diagnosis) and includes patients with greater levels of comorbidity and risk than typically allowed in randomized trials, facilitating better generalizability to the population of senior adults.32
These factors, particularly our inclusion of older individuals and those with shorter postoperative survival compared with the Schrag studies, may explain the relatively low utilization of chemotherapy identified in our analysis, even among stage III patients.13
This investigation uses existing data to address a research question that would require substantial resources and time to answer through a randomized trial. Limitations to our study include our inability to investigate the role of two known poor prognostic features, preoperative CEA and lymphovascular invasion, as these characteristics are not available within the SEER-Medicare database. These features may represent more locally advanced disease, but it is unclear how they influence the likelihood of chemotherapy receipt and any subsequent survival benefit. Although our models included several important patient- and disease-related variables, administrative data lack direct measurement of factors that may influence treatment assignment, such as patient preferences or provider care patterns. There is some suggestion that chemotherapy administration is related to provider practice: Hershman et al33
found that among elderly women with breast cancer, chemotherapy was more commonly received by those treated by younger private-practice oncologists. Although these factors may influence treatment receipt, their relationship to survival is unknown. Finally, our study examines only Medicare beneficiaries age 66 years and older at the time of diagnosis, limiting its applicability to younger patients with colon cancer, such as those with familial syndromes. However, because more than 60% of colorectal cancer diagnoses are made in the 65-years-and-older population, our findings are likely appropriate for the majority of patients with colon cancer.32
This study retrospectively examines the use of chemotherapy as identified through Medicare claims data using a “one claim” algorithm.22,23
This creates a heterogeneous population in which some patients received a substandard duration of therapy for unrecorded reasons, possibly including patient/provider preference or adverse effects, whereas other patients receive a complete course. We speculate that those patients who stop chemotherapy early may have other features related to poor survival (older age, comorbid conditions, and so on), and that the inclusion of both subsets of patients within a single analysis group likely leads to a reduction in the survival benefit observed with chemotherapy. However, the “none versus any” approach used to assign treatment status provides a window into the effectiveness of chemotherapy in real world practice, in which an individual's likelihood of completing the treatment course is not known at the outset of the study. We also note that chemotherapeutic recommendations have changed since the time period of this analysis, and many patients in our study population likely did not receive oxaliplatin, thus limiting the applicability of our results to today's standard regimens. Further investigation into patient characteristics predicting therapy completion, the influence of chemotherapy duration on survival, and the benefit of oxaliplatin in practice may be warranted.
The poor prognostic features considered in this analysis and described in published guidelines represent an imprecise clinical mechanism for identifying patients with high-risk stage II colon cancer. Recently, high-frequency DNA microsatellite instability from mismatch repair defects has emerged as an important predictor of better prognosis as well as resistance to fluorouracil therapy.12,34–37
Older patients may also demonstrate increased prevalence of a methylator phenotype (CIMP), which may be correlated with higher disease stages and sporadic cases of microsatellite instability.38,39
These and other histologic and genetic factors are the subject of investigation in ongoing basic science and prospective clinical trials that may identify any subset of stage II patients for whom chemotherapy offers significant survival benefit.40
In conclusion, we find that patients with stage II colon cancer, even those with any of six identified poor prognostic features, do not have a significant survival benefit from chemotherapy. Given the frequent use of chemotherapy in this generalizable population of older adults, this suggests that, in practice, many patients may be receiving chemotherapy with a disadvantageous risk-benefit ratio. Given the statistical power of this study, clinicians may wish to counsel high-risk older adults with colon cancer that any possible survival benefit is likely less than 2% at 5 years.