Published Ahead of Print on February 16, 2016 as 10.1200/JCO.2015.65.8161 The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2015.65.8161

JOURNAL OF CLINICAL ONCOLOGY

E D I T O R I A L

Big Data, Small Effects Howard S. Hochster, Yale Cancer Center, New Haven, CT Donna Niedzwiecki, Duke University School of Medicine, Durham, NC See accompanying article doi:10.1200/JCO.2015.65.1158

Cheung et al1 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.2 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.3 Other important analyses identified treatment benefits in patients with poor prognostic factors and in the elderly.4,5 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 compared with 6 months 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 1.12.6 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,1 the investigators have analyzed the death rates at 30 days to 6 months 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.7 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 early mortality would 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%, © 2016 by American Society of Clinical Oncology

Downloaded from jco.ascopubs.org on February 21, 2016. For personal use only. No other uses without permission. Copyright © 2016 American Society of Clinical Oncology. All rights reserved.

Copyright 2016 by American Society of Clinical Oncology

1

Editorial

any potential benefit of adjuvant chemotherapy would be substantially mitigated by this risk. However, most clinicians would act on this with clinical judgment and tend to defer treatment in such a case. Although these 6-month mortality statistics are based in fact, and the nomogram may be predictive, this nomogram is of little actual clinical utility when faced with a high-risk patient who has stage III disease. Big data can yield statistically valid small effects, but they are not always useful in the face of clinical reality. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Disclosures provided by the authors are available with this article at www.jco.org. AUTHOR CONTRIBUTIONS

Manuscript writing: All authors Final approval of manuscript: All authors REFERENCES 1. Cheung WY, Renfro LA, Kerr D, et al: Determinants of early mortality among 37,568 patients with colon cancer who participated in 25 clinical trials from the Adjuvant Colon Cancer End Points Database. J Clin Oncol doi:10.1200/JCO.2015.65.1158

2. Renfro LA, Shi Q, Sargent DJ: Mining the ACCENT database: A review and update. Chin Clin Oncol 2:18, 2013 3. Sargent DJ, Wieand HS, Haller DG, et al: Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: Individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol 23:8664-8670, 2005 4. Gill S, Loprinzi CL, Sargent DJ, et al: Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: Who benefits and by how much? J Clin Oncol 22:1797-1806, 2004 5. Sargent DJ, Goldberg RM, Jacobson SD, et al: A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med 345: 1091-1097, 2001 6. Andre´ T, Iveson T, Labianca R, et al: The IDEA (International Duration Evaluation of Adjuvant Chemotherapy) Collaboration: Prospective combined analysis of phase III trials investigating duration of adjuvant therapy with the FOLFOX (FOLFOX4 or modified FOLFOX6) or XELOX (3 versus 6 months) regimen for patients with stage III colon cancer: Trial design and current status. Curr Colorectal Cancer Rep 9:261-269, 2013 7. Alberts SR, Sargent DJ, Nair S, et al: Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: A randomized trial. JAMA 307:1383-1393, 2012

DOI: 10.1200/JCO.2015.65.8161; published online ahead of print at www.jco.org on February 16, 2016.

n n n

2

© 2016 by American Society of Clinical Oncology

JOURNAL OF CLINICAL ONCOLOGY

Downloaded from jco.ascopubs.org on February 21, 2016. For personal use only. No other uses without permission. Copyright © 2016 American Society of Clinical Oncology. All rights reserved.

Editorial

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Big Data, Small Effects The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc. Howard S. Hochster Consulting or Advisory Role: Bayer HealthCare Pharmaceuticals, Boehringer Ingelheim, Genentech, Amgen, Sirtex Medical, Bristol-Myers Squibb Speakers’ Bureau: Genomic Health

www.jco.org

Donna Niedzwiecki No relationship to disclose.

© 2016 by American Society of Clinical Oncology

Downloaded from jco.ascopubs.org on February 21, 2016. For personal use only. No other uses without permission. Copyright © 2016 American Society of Clinical Oncology. All rights reserved.

Big Data, Small Effects.

Big Data, Small Effects. - PDF Download Free
441KB Sizes 0 Downloads 20 Views