Rapid Testosterone Cycling and Chemotherapy for Prostate Cancer: A Way Forward or Return to the Past?

Abstract

Androgen deprivation therapy is the mainstay of treatment for metastatic prostate cancer. Among men with overt metastatic disease, androgen deprivation therapy by either bilateral orchiectomies or chronic treatment with a gonadotropin-releasing hormone agonist achieves responses in the vast majority, with a median response duration is approximately 1 to 2 years. Only rarely does androgen deprivation therapy result in prolonged remission or cure. Docetaxel is the standard first-line chemotherapy for men who develop disease progression despite androgen deprivation therapy. In two randomized controlled trials in men with castrate-resistant prostate cancer, docetaxel improved overall survival compared with treatment with mitoxantrone. For men with castrate-resistant disease, the current standard of care is to continue androgen deprivation therapy indefinitely, based on concerns that testosterone recovery might accelerate disease progression. The strategy of continuous androgen deprivation therapy and the addition of chemotherapy after emergence of hormone-resistant disease contrasts with the current paradigm of sequential hormone therapy and chemotherapy in breast cancer. In metastatic breast cancer, attempts to improve efficacy by combining hormone therapy and chemotherapy began decades ago. Several randomized controlled trials have compared hormone therapy to hormone therapy plus chemotherapy. Most studies report higher response rates for combination therapy; none report a significant improvement in survival. Other randomized controlled trials have compared chemotherapy alone to chemotherapy plus hormone therapy. Most of those studies reported significantly higher response rates for combination therapy but did not carefully evaluate the cumulative response rates for subjects who received sequential chemotherapy followed by hormone therapy at disease progression. None of the studies have reported a significant improvement in overall survival. An Australian study carefully evaluated concurrent and sequential chemotherapy and hormone therapy for metastatic breast cancer. In that study, 339 women with metastatic breast cancer were assigned randomly to one of three groups: tamoxifen, cyclophosphamide and doxorubicin (CA), or concurrent tamoxifen and CA. Women assigned to tamoxifen were treated with salvage chemotherapy at disease progression. The initial response rates to either CA (45%) or concurrent tamoxifen and CA (50%) were significantly higher than tamoxifen alone (22%). With salvage chemotherapy, however, the cumulative response rates were similar for each of the arms. Overall survival was also similar for each of the regimens. The North American Intergroup designed a study (Intergroup 0100/Southwest Oncology Group 8814) in the late 1980s to address the sequencing of hormone therapy and chemotherapy in the adjuvant setting. A total of 1,477 postmenopausal women with estrogen receptor–positive or progesterone receptor–positive nodepositive breast cancer were randomly assigned to tamoxifen alone, tamoxifen plus concurrent cyclophosphamide, doxorubicin, and fluorouracil (CAF), or CAF followed by tamoxifen. The combination of tamoxifen and CAF was superior to tamoxifen alone. Sequential CAF followed by tamoxifen, however, reduced the incidence of recurrence or death by approximately 50% compared with concurrent therapy. Based on these findings, most clinicians have adopted the strategy of administering chemotherapy followed by hormone therapy for the adjuvant treatment of estrogen receptor–positive breast cancer. Notably, other studies in both premenopausal and postmenopausal women have reported no difference between concurrent and sequential tamoxifen and chemotherapy in the adjuvant setting. In preclinical models of breast cancer, estrogens recruit dormant breast cancer cells into the cell cycle. In phase II studies of women with locally advanced or metastatic breast cancer, short-term pretreatment with estrogen before chemotherapy was associated with relatively high response rates. In one study, for example, estrogen priming and chemotherapy were also associated with comparatively long response duration and survival. A randomized controlled trial from the Netherlands, however, demonstrated no benefit from estrogen priming before chemotherapy. In that study, 318 women with stage II/IIIA breast cancer were assigned randomly to fluorouracil, doxorubicin, and cyclophosphamide with or without pretreatment with ethinyl estradiol. After a median follow-up of 6.8 years, there were no significant differences in relapse-free and overall survival between the groups. Similar results were observed in multivariate analyses that adjusted for subject and disease characteristics. The slow growth rate of prostate cancer may partially explain its limited sensitivity to chemotherapy. In the Dunning rat model of prostate cancer, androgen priming induces cell proliferation and increases sensitivity to chemotherapy compared with chemotherapy alone. The strategy of androgen priming to increase the efficacy of chemotherapy in men with prostate cancer was first evaluated more than two decades ago. In 1988, Manni et al reported the results of a small randomized controlled trial of men with castrate-resistant metastatic prostate cancer. A total of 85 men with disease progression despite bilateral orchiectomies were randomly assigned to monthly chemotherapy (CAF) or monthly chemotherapy preceded by three JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 18 JUNE 2