Adjuvant Chemotherapy for Elderly Women With Hormone Receptor-Positive Breast Cancer: An Old(er) Problem (2004)

Since the mid-1980s, mortality as a result of breast cancer has been declining in the Western world, due in part to the widespread application of adjuvant systemic therapy. However, for the most part, clinical trials have failed to address the benefit of adjuvant chemotherapy in elderly women. The few efforts to do so have involved what appear to be better tolerated, yet— one hopes— efficacious treatments. In this issue of the Journal of Clinical Oncology, Fargeot et al from the French Adjuvant Study Group (FASOG) report results of a prospective, randomized clinical trial of weekly adjuvant epirubicin compared to no postoperative chemotherapy for estrogen receptor (ER) -positive, node-positive patients over the age of 65 years, all of whom also received tamoxifen, either alone or concurrent with and following epirubicin. The investigators observed a modest but statistically significant improvement in disease-free survival, but no improvement in overall survival for the epirubicin-treated patients. Although this study represents a victory in accruing patients older than 65 years to a prospective chemotherapy trial, one must question whether these benefits are clinically meaningful. Retrospective subgroup analyses of early randomized trials of adjuvant chemotherapy compared to observation alone suggested that older women gain proportionally less benefit than younger women. Subsequently, the Oxford Worldwide Overview of adjuvant systemic therapy demonstrated a stepwise reduction in relative efficacy of adjuvant chemotherapy with advancing age by decade. Several hypotheses have been proposed to explain these observations, including shorter expected life span in general, differential reductions in delivered dose, and possible differences in tumor biology resulting in reduced sensitivity to chemotherapy in elderly patients. Examination of each of these possibilities provides little further insight. The significant survival benefit from adjuvant tamoxifen, even in older women, speaks against the argument that comorbidity and mortality from other causes prevent prolongation of survival due to suppression of breast cancer. Reductions in chemotherapy dose might play a role, since the elderly represent a special population of patients for whom concurrent morbidity could lead to decreased tolerance of toxic regimens. Some investigators have reported higher toxicities from chemotherapy in the elderly, but several studies have suggested that, with careful selection and with certain caveats, fit elderly women tolerate chemotherapy as well as their younger counterparts. Alternatively, the elderly may have tumors that are biologically less responsive to chemotherapy. Studies have demonstrated that untreated and treated prognoses differ by age, as do biologic factors that are known to be important in both prognosis and prediction for systemic therapy in general. Of these, increased expression of ER in older women is the most consistently observed difference. This observation would obviously lead to higher rates of benefit from endocrine therapy, but ER expression alone may also decrease chemosensitivity. Nonetheless, in addition to the present study by Fargeot et al, other large cooperative groups have also reported statistically significant improvement in outcomes in postmenopausal women with the use of chemotherapy plus tamoxifen compared to tamoxifen alone. Of interest, two of these studies—National Surgical Adjuvant Bowel and Breast Project B-16 and Southwest Oncology Group Intergroup 8814—employed doxorubicin-based regimens, raising the possibility that perhaps anthracycline therapy might be more effective in the elderly, hormone-responsive patient than JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 23 DECEMBER 1 2004