Big Data, Small Effects.

Cheung et al from the Adjuvant Colon Cancer End Points (ACCENT) collaboration report on the risk of early death at 6 months in patients receiving adjuvant colon cancer treatment in the article accompanying this editorial. A key feature of this publication is the ACCENT database itself. With the use of an amalgamated database involving 37,568 individual patient-level records in 25 adjuvant colon cancer trials conducted between 1977 and 2008, the ACCENT collaboration provides a major tool for asking questions such as risk of early mortality, with an incidence of less than 2%. It is only with a database this large that such questions can be answered with statistical significance. How did investigators from the US Cooperative Groups (now National Clinical Trials Network), Canada, France, Italy, and the United Kingdom come to contribute to this remarkable tool? It has been through the persistence of key investigators and their continual ability to curate and incorporate additional studies. The ACCENT group is commended for their foresight in initiating and maintaining this collaborative effort. The ACCENT database is a valuable resource and has several strengths, including the large number of patients randomly assigned and treated according to protocol, the comparability of the patient data across studies, and the use of clinical trial data beyond its initial purpose. The ACCENT group has published extensively on important topics relevant to patient care and clinical trials design. The most important work coming out of this collaboration is the demonstration that 3-year disease-free survival is predictive of 5-year overall survival and the acceptance of this earlier end point by the US Food and Drug Administration and European Medicines Agency. Other important analyses identified treatment benefits in patients with poor prognostic factors and in the elderly. An outgrowth of the ACCENT collaboration is the ongoing, prospective, International Duration Evaluation of Adjuvant Chemotherapy (IDEA) Collaboration to test the noninferiority of 3 months comparedwith 6months of adjuvant infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CapeOx). A sample size of 10,000 patients is required to test this hypothesis with sufficient power for an upper limit noninferiority margin of hazard ratio 1.12. It is only such international cooperation in compiling patient-level data across trials that permits the scientific community to answer questions that cannot feasibly be answered in one trial, in this case a stringent noninferiority question. In the study by Cheung et al, the investigators have analyzed the death rates at 30 days to 6months and found 540 patients (1.4%)with death at the 6-month time point. By univariate and multivariate analysis, known prognostic factors such as age, performance status, tumor stage and grade, as well as decade of treatment were identified. A nomogram was developed that could predict probability of early death at 6 months and was validated using an independent data set from North Central Cancer Treatment Group study N0147, assessing adjuvant FOLFOX with or without cetuximab. Overall, 40% of those dying at 6 months had recurrent disease, which conveys a considerably higher risk for death at 6 months. This recurrence percentage was more than double for stage III compared with stage II and varied by decade, suggesting a role for detection bias of occult metastatic disease. However, it should be noted that for surgery alone, the 6-month mortality was 2%, consistent with the fact that the excess mortality is not due to chemotherapy toxicity. The choice of 6-month mortality rate as the primary end point appears arbitrary. Results at 30, 60, and 90 days were also described, but the number of deaths at each of these cut points was approximately half or fewer than the number of deaths by 6 months. In addition, data on cause of death were not available. Risk of death due to disease progression (40%) is included in the total risk. As stated above, death within 6 months among patients randomly assigned to surgery alone, 2,313 patients, cannot be attributed to chemotherapy. Early mortality in this surgery-alone patient subset (2%)may be due to surgical complications or disease progression. The majority of studies randomly assigned patients to chemotherapy regimens, most likely postsurgery. These patients appear to have a different risk profile. The association of older age and poor performance status with early treatment failure may also reflect the impact of comorbidities. Thus, risk is heterogeneous, and this heterogeneity should be considered when interpreting the risk estimate. In this nomogram, early death can be predicted by age, performance status, grade, tumor stage, lymph node ratio (LNR), and decade of treatment. The decade of treatment is factored in but not helpful for current patients. The risk for an elderly patient with high LNR may be at least double the risk of early death compared with a younger patient who has no nodes, but it is still quite small. As discussed in the article, the risk of early death for a patient who is elderly with a high LNR is determined to be 2.9%. Conversely, the risk of living beyond 6 months would therefore be more than 97%. Furthermore, with a risk of recurrence as high as 50% (for N2c disease), the increase in earlymortalitywould be far outweighed by the potential benefit of adjuvant FOLFOX chemotherapy. Therefore, in most cases, this nomogram is statistically correct but not relevant to clinical practice. However, in the case of an elderly high-risk patient with stage II disease, where the risk of early death might be 2% to 3%,