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Journal of Clinical Oncology, Vol 26, No 18 (June 20), 2008: pp. 2932-2933 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.16.0788
Rapid Testosterone Cycling and Chemotherapy for Prostate Cancer: A Way Forward or Return to the Past?Massachusetts General Hospital Cancer Center, Division of Hematology Oncology, Boston, MA 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.1 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.2,3 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.4 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.5 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.6 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 node-positive breast cancer were randomly assigned to tamoxifen alone, tamoxifen plus concurrent cyclophosphamide, doxorubicin, and fluorouracil (CAF), or CAF followed by tamoxifen.7 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.8,9 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.10 A randomized controlled trial from the Netherlands, however, demonstrated no benefit from estrogen priming before chemotherapy.11 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.12 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 al13 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 days of treatment with the synthetic androgen fluoxymesterone. Response rates and response duration were similar between the groups. Median survival was longer in the control group than in the androgen stimulation group (15 v 10 months; P = .0047). The authors concluded that androgen priming did not improve the efficacy of chemotherapy. In this issue of the Journal of Clinical Oncology, Rathkopf et al14 laudably evaluate rapid androgen cycling in combination with docetaxel for men with advanced prostate cancer. In this well-conducted phase II study, 102 men with progressive prostate cancer and noncastrate testosterone levels were treated with either six cycles of leuprolide, testosterone, and docetaxel (cohort 1) every 4 weeks, or nine cycles of a similar regimen (cohort 2) every 3 weeks. The total duration of gonadotropin-releasing hormone agonist exposure was 24 weeks for cohort 1 and 36 weeks for cohort 2. The primary end point was the proportion of men at 18 months with noncastrate testosterone levels and an undetectable prostate-specific antigen—a proposed surrogate for durable remission.15 Five percent of subjects, all from cohort 2, achieved the primary end point. The median time to disease progression was 13 months. The rate of febrile neutropenia was greater than that previously observed in men with castrate-resistant prostate cancer, likely due to lower docetaxel clearance. This study has several important differences from the approach described by Manni et al13 two decades ago. First, the study excluded men with castrate-resistant prostate cancer to reduce the potential that androgen priming might induce a disease flare. Second, the study used effective chemotherapy—an option unavailable in earlier studies. Lastly, the study evaluated disease outcomes using prostate-specific antigen, rather than less sensitive clinical or radiographic criteria. Does the strategy of rapid androgen cycling and chemotherapy represent a promising way forward in prostate cancer? Based on the low objective response rate and observed toxicity, Rathkopf et al14 do not recommend this regimen for further study. The consistent lack of a survival benefit for combining hormone therapy with chemotherapy in breast cancer appears to provide an important cautionary tale about limitations of similar strategies in prostate cancer. Is there a better way? Recent advances in the molecular biology of prostate cancer may provide some direction. Chromosomal translocations involving the androgen-responsive gene TMPRSS2 and ETS-related transcription factors ERG, ETV1, ETV4, and ETV5, have been identified in 50% to 70% of prostate cancer cases.16,17 Specific translocations in primary tumors have been associated with more advanced disease at diagnosis and greater lethality.18-21 Ongoing research will determine whether these gene rearrangements are associated with response to androgen deprivation therapy. The new biology of prostate cancer may hold the promise of molecular classification, optimal subject selection for clinical trials, and individualized therapy. The potential interplay of hormones and cytotoxic agents is complex, however, and the challenges of evaluating combinations of hormone therapy and chemotherapy will remain daunting even with substantial advances in molecular biology. AUTHOR's DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. ACKNOWLEDGMENTS I thank John Erban, MD, Richard Lee, MD, PhD, and Paula Ryan, MD, PhD, for their thoughtful suggestions and critical review of this manuscript. REFERENCES
1. Sharifi N, Gulley JL, Dahut WL: Androgen deprivation therapy for prostate cancer. JAMA 294:238-244, 2005 2. Petrylak DP, Tangen CM, Hussain MH, et al: Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 351:1513-1520, 2004 3. Tannock IF, de Wit R, Berry WR, et al: Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351:1502-1512, 2004 4. Loblaw DA, Mendelson DS, Talcott JA, et al: American Society of Clinical Oncology recommendations for the initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer. J Clin Oncol 22:2927-2941, 2004 5. Pritchard KI: Combining endocrine agents with chemotherapy: Which patients and what sequence? Cancer 112:718-722, 2007 6. A randomized trial in postmenopausal patients with advanced breast cancer comparing endocrine and cytotoxic therapy given sequentially or in combination. The Australian and New Zealand Breast Cancer Trials Group, Clinical Oncological Society of Australia. J Clin Oncol 4:186-193, 1986[Abstract] 7. Albain K, Green S, Ravdin P: Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: Initial results from Intergroup trial 0100 (SWOG-8814). Proc Amer Soc Clin Oncol 21:37a, 2002 (abstr 143) 8. Pico C, Martin M, Jara C, et al: Epirubicin-cyclophosphamide adjuvant chemotherapy plus tamoxifen administered concurrently versus sequentially: Randomized phase III trial in postmenopausal node-positive breast cancer patients: A GEICAM 9401 study. Ann Oncol 15:79-87, 2004 9. Del Mastro L, Dozin B, Aitini E, et al: Timing of adjuvant chemotherapy and tamoxifen in women with breast cancer: Findings from two consecutive trials of Gruppo Oncologico Nord-Ovest-Mammella Intergruppo (GONO-MIG) Group. Ann Oncol 19:299-307, 2008 10. Lippman ME, Cassidy J, Wesley M, et al: A randomized attempt to increase the efficacy of cytotoxic chemotherapy in metastatic breast cancer by hormonal synchronization. J Clin Oncol 2:28-36, 1984[Abstract] 11. Bontenbal M, van Putten WL, Burghouts JT, et al: Value of estrogenic recruitment before chemotherapy: First randomized trial in primary breast cancer. J Clin Oncol 18:734-742, 2000 12. English HF, Heitjan DF, Lancaster S, et al: Beneficial effects of androgen-primed chemotherapy in the Dunning R3327 G model of prostatic cancer. Cancer Res 51:1760-1765, 1991 13. Manni A, Bartholomew M, Caplan R, et al: Androgen priming and chemotherapy in advanced prostate cancer: Evaluation of determinants of clinical outcome. J Clin Oncol 6:1456-1466, 1988 14. Rathkopf D, Carducci MA, Morris MJ, et al: Phase II trial of docetaxel with rapid androgen cycling for progressive noncastrate prostate cancer. J Clin Oncol 26:2959-2965, 2008 15. Beekman K, Morris M, Slovin S, et al: Androgen deprivation for minimal metastatic disease: Threshold for achieving undetectable prostate-specific antigen. Urology 65:947-952, 2005[CrossRef][Medline] 16. Tomlins SA, Rhodes DR, Perner S, et al: Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310:644-648, 2005 17. Helgeson BE, Tomlins SA, Shah N, et al: Characterization of TMPRSS2:ETV5 and SLC45A3:ETV5 gene fusions in prostate cancer. Cancer Res 68:73-80, 2008 18. Perner S, Demichelis F, Beroukhim R, et al: TMPRSS2:ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer. Cancer Res 66:8337-8341, 2006 19. Demichelis F, Fall K, Perner S, et al: TMPRSS2:ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort. Oncogene 26:4596-4599, 2007[CrossRef][Medline] 20. Mehra R, Han B, Tomlins SA, et al: Heterogeneity of TMPRSS2 gene rearrangements in multifocal prostate adenocarcinoma: Molecular evidence for an independent group of diseases. Cancer Res 67:7991-7995, 2007 21. Attard G, Clark J, Ambroisine L, et al: Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer. Oncogene 27:253-263, 2008[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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