No Pain, No Gain: A Fallacy So Far
Authors: William J. Gradishar
Journal: Journal of Clinical Oncology (2014)

The notion that toxicity related to treatment can be a surrogate for treatment efficacy has long been embedded in the psyche of patients. We are frequently confronted with the question of whether the therapy we have recommended is aggressive—not infrequently a path the patient desires, even if it means more adverse events. Oncologists have also often been attracted to this approach to treatment, believing that a bad disease needs to be treated aggressively, and again this often relates to the adverse events that a patient may experience. However, this philosophy has not always proven to be correct. For example, in the realm of breast cancer therapeutics, extensive radical surgeries (eg, Halsted radical mastectomies and regional nodal dissections) have been largely abandoned as evidence from randomized trials revealed that far less breast surgery, radiation therapy, and minimal axillary nodal sampling results in equivalent clinical outcomes: breast preservation with far less morbidity. Similarly, not so long ago, the enthusiasm for high-dose chemotherapy and autologous stem-cell transplantation as treatment for both early-stage and advanced-stage breast cancer led to a nationwide proliferation of programs offering such treatments for patients. The conviction that this form of therapy was so much more effective than standard systemic therapy delayed the completion of randomized clinical trials by many years; and those trials ultimately proved that high-dose chemotherapy did not offer an advantage over standard-dose systemic therapy. Multiple other examples in breast cancer and other malignancies can be offered as evidence that toxicity of a therapy does not necessarily correspond in a meaningful way to the likelihood of clinical benefit. The article by Stearns et al that accompanies this editorial shows no relationship between the effectiveness of adjuvant anastrozole and the development of either vasomotor or musculoskeletal symptoms. Much of the toxicity that systemic therapy confers to a patient is the result of collateral damage—nontargeted effects to normal tissue that may, or may not, share specific features of the target cancer cell. The idea that specific toxicities from an anticancer agent may be a surrogate for efficacy has gained traction in recent years. For example, an acne-form skin rash is an extremely common adverse effect of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), such as gefitinib or erlotinib, occurring in up to 66% of patients with non–small-cell lung cancer (NSCLC). A meta-analysis of clinical trials evaluating EGFR-TKIs as treatment for NSCLC have shown that the development of a skin rash is a marker for response to the EGFRTKI and also predictive of better progression-free survival and overall survival compared with those who do not develop such a rash. EGFR is important in both skin biology and NSCLC. EGFR-TKIs seem to interact with basal keratinocytes, which results in the rash that may be an outward manifestation of a similar effect occurring in tumor tissue. The use of tamoxifen as adjuvant therapy for early-stage breast cancer can now be recommended as monotherapy for 5 years, for 2 to 3 years to be followed by an aromatase inhibitor (AI) to complete 5 years, or as long as 10 years in women deemed to have a significant ongoing risk of recurrence who remain premenopausal or are not candidates for treatment with an aromatase inhibitor. Any medication that must be taken daily for years can be a challenge for both the patient and the physician. Extensive research has shown that compliance is a major issue with longer durations of therapy and that rates of compliance are influenced by many factors including age, education, and the magnitude of the insurance copay that a patient must contribute. Although physicians have reported confidence in medication compliance by their patients, evidence suggests otherwise. Hot flushes have been suggested as a surrogate for tamoxifen efficacy. The underlying explanation purported to support this observation is that women who are more able to metabolize tamoxifen to its active metabolite, endoxifen, will be those experiencing more hot flushes. By extension, those women unable to metabolize tamoxifen as effectively, resulting in less endoxifen and fewer hot flushes, would be those predicted to have less benefit from tamoxifen and greater numbers of recurrences. The basic concept was that occurrence of hot flushes was hypothesized to predict which patients were likely to be extensive metabolizers (EM) compared with those less able to metabolize tamoxifen (intermediate metabolizers [IM] or poor metabolizers [PM]). In the Women’s Healthy Eating and Living (WHEL) study, a nutritional intervention study, Mortimer et al reported on 1,551 patients with early-stage breast cancer who were enrolled and randomly assigned to the no dietary intervention group. At baseline, 56% of these women were taking tamoxifen, and of those, 78% reported hot flushes. After 7.3 years of follow-up, patients who reported hot flushes at baseline were less likely to develop a recurrence (12.9% v 21%) compared with those without hot flushes at baseline. This observation was a stronger predictor of recurrence compared with patient age, hormone receptor status, or disease stage. Although no one was eager to tell a woman hot flushes were a good thing, these results suggested that perhaps the occurrence of hot flushes could be a poor man’s assay for CYP2D6 genotype. However, CYP2D6 testing has had its share of controversy. Despite early results that suggested the ability of CYP2D6 testing to predict which patients were most likely to benefit from tamoxifen (EM), subsequent work on several large, mature data sets have failed to confirm the early findings, and most show no association between JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 3 JANUARY 2