Adjuvant chemotherapy use and outcomes in older women with breast cancer: what have we learned?

In both the basic science and clinical trial worlds it is not uncommon for two or more research groups to make similar discoveries or the same discovery simultaneously, or for two similarly designed clinical trials to obtain similar or the same results. However, this phenomenon is less common in the clinical epidemiology/outcomes research world. As editorial board member/ reviewer (R.A.S.) and associate editor (P.A.G.) of the Journal of Clinical Oncology, we encountered this issue. We felt that the story, its outcomes, and the research and clinical implications would be of interest to the readership. In April 2005, Giordano et al submitted an article addressing temporal changes in adjuvant chemotherapy use in older women, including changing patterns of specific agent use. The article also focused on patient factors associated with the receipt of chemotherapy and with putative toxicities of these agents. The analyses presented relied on the Surveillance, Epidemiology, and End Results (SEER)-Medicare data set, with the strengths of large numbers of cases across 14 geographic sites and over time, and the weaknesses of reliance on administrative claims data (and therefore lack of clinical data) for comorbidity, chemotherapy use, and toxicities. Although the reviewers and editor were enthusiastic about the topic, the lack of linkage of treatment to outcomes and the limitations of the data sources for toxicity information dampened their enthusiasm. A revised article received in June 2005 addressed the relationship between adjuvant chemotherapy treatment and breast cancer-specific and all-cause mortality and deleted the toxicity analyses. However, several remaining concerns of the reviewers led to the request for additional revisions. While these revisions were underway, Elkin et al submitted an article addressing temporal changes in adjuvant chemotherapy use in older women, also focusing on patient factors associated with receipt of chemotherapy, relating receipt of chemotherapy to all-cause mortality. The authors also used propensity scores and sensitivity analysis to address the methodologic challenges of measured and unmeasured confounders in observational studies. The additional strengths associated with these analytic approaches, the fact that the striking similarity between the two articles was a result of the editorial process, and the fact that both articles were simultaneously under review led to the decision to publish them both. The tangible outcomes of this process are found elsewhere in the Journal of Clinical Oncology. To complicate things additionally, while both research groups were finalizing their articles, the Journal of Gerontology: Medical Sciences published a similar paper by Du et al, again based on analyses of the SEER-Medicare data set. For comparative purposes, the key features of all three articles are displayed in Table 1. As might be expected from experienced investigators using the same data, all three groups observed increasing use of adjuvant chemotherapy over time; substantial geographic variation in use (from a low in San Francisco to a high in Hawaii); decreasing use in patients with increasing age and comorbidity; and increasing use in patients with poor prognostic indicators. The varying association of race across studies may well be related to different strategies for socioeconomic status measurement which are known to not be comparable, and differences in tumor characteristics (eg, stage and receptor status) selected for sampling across the three studies. It is the differences in tumor characteristics coupled with differences in outcome that are most likely responsible for the apparent lack of consistency of findings across the three studies. Giordano et al were least restrictive in their initial sampling, including all women with stage I-III disease, both estrogen receptor (ER) –positive and –negative, who received either breastconserving surgery or mastectomy. However, in the end, after stratification by ER and lymph-node status, they identified lymph node–positive, ER–negative patients as the subgroup benefiting from chemotherapy (hazard ratio, 0.72; 95% CI, 0.54 to 0.96). In contrast, Elkin et al restricted their sample to all stage I-III women with ER–negative tumors. Their initial analyses considered both lymph node-positive and lymph node-negative patients, yielding a hazard ratio of 0.85 (95% CI, 0.77 to 0.95). In response to the Giordano paper, analyses restricted to the lymph node-positive group, but with the additional propensity score adjustment, yielded results very similar to those of Giordano: hazard ratio, 0.76; 95% CI, 0.65 to 0.88; suggesting that most of the overall observed effect was restricted to this subgroup. Both sets of investigators observed that the benefits of adjuvant chemotherapy did not vary by age, and specifically were similar for those women younger than 70 years of age versus those 70 years of age or older. This latter finding is of particular importance because the overview of trials JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 24 NUMBER 18 JUNE 2