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Journal of Clinical Oncology, Vol 23, No 24 (August 20), 2005: pp. 5846 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.01.7657
In Reply:National Cancer Research Institute; and the University of Genoa, Genoa, Italy We appreciate the comments of Thönnessen and Wenz concerning our recent article1 and agree with the fact that prophylactic radiotherapy could be a reasonable alternative to manage bicalutamide-induced gynecomastia. However, our colleagues have probably missed the conclusions of our work, which clearly discourage the use of anastrozole, and rather support the use of tamoxifen. Thönnessen and Wenz raised some concerns about the tolerability and safety of long-term treatment with tamoxifen in these patients with prostate cancer. Indeed the number of patients enrolled onto our study is small and the median follow-up time is relatively short (ie, 12 months). However, there was no significant difference in the incidence, type, and severity of adverse events between the group of patients assigned to placebo and those patients who were given tamoxifen (37.5% v 35.1%, respectively). The percentages of serious adverse events also were comparable (11% v 14%). Moreover, tamoxifen had no detrimental effect on sexual interest or functioning in our study, nor on the other domains of the quality of life (QoL) questionnaires1; in particular, there was no evidence of an adverse impact on mood or depression (Table 1).
Although we did not investigate this aspect specifically, it is not clear why the addition of tamoxifen should interfere with the known protective effect of bicalutamide monotherapy on bone mineral density and resorption,2 as this treatment does not interfere with bicalutamide pharmacodynamics, and in particular with total and free-testosterone circulating levels.1 Concerning the efficacy of radiotherapy, we reviewed in detail the articles cited by Thönnessen and Wenz in support of this treatment modality.3-10 These articles report on different series, including patients receiving different hormonal manipulations and applying the use of different doses and schedules radiation on different irradiation fields. The great majority of these studies are retrospective and do not include a sham-control arm. Therefore, we focused our attention on only the two large prospective trials reporting on the value of prophylactic breast irradiation to prevent gynecomastia and mastalgia induced by monotherapy with pure antiandrogens. The study by Tyrrel et al3 was a randomized, sham-controlled, double-blind, parallel-group multicenter trial involving 106 men assigned to bicalutamide monotherapy. In this study, the incidence of gynecomastia was 85% in the sham-controlled group (a rate that was comparable with the incidence rate in the placebo group in our study), compared with 52% in the radiotherapy group; this difference was statistically significant. However, the incidence rate in the intervention group in this study was much higher than in the tamoxifen group in our study (52% v 10%, respectively). Moreover, the effect of radiotherapy in this study appeared to be most pronounced during the first 6 months.3 In contrast with what we observed in our study, in which tamoxifen did significantly lower the incidence of breast pain too, there was no difference in breast pain incidence in the Tyrrell et al study between the two groups (radiotherapy v sham radiotherapy, 83% v 91%; P = .22). Comparable results were achieved by Widmark et al,9 who also reported a relatively poor effect of prior breast irradiation on flutamide-induced breast tenderness (radiotherapy versus sham radiotherapy group, 64% v 85%) despite noting a significant reduction in the incidence of gynecomastia at 1-year follow-up (radiotherapy v sham radiotherapy group, 28% v 71%). Finally, although it is true that in these studies no long-term sequelae have been reported on prophylactic radiotherapy, it is also true that most of the patients receiving prophylactic breast irradiation in the previous studies did not survive long enough to develop such consequences. Indeed, the use of radiotherapy to manage pubertal gynecomastia has been reported to be associated with an increased risk of breast cancer.11 This possibility should be taken into account in the younger patients who receive antiandrogen monotherapy as an adjuvant following local treatment and who are expected to benefit from a long period of survival. In contrast, it is possible, and is now being tested, that lower doses of tamoxifen or an intermittent scheduling, as suggested by the study reported by Saltzein et al,12 might work as well, limiting the exposure to this antiestrogen. In conclusion, though direct comparisons are still missing, from indirect comparison of available trials it appears that tamoxifen is probably more effective than radiotherapy in preventing both gynecomastia and breast pain during treatment with bicalutamide without increasing the adverse effects induced by antiandrogen monotherapy or interfering with patients’ sexual functioning or QoL. Authors’ Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed discription of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000–99,000 (C)
REFERENCES
1. Boccardo F, Rubagotti A, Battaglia M, et al: Evaluation of tamoxifen and anastrozole in the prevention of gynecomastia and breast pain induced by bicalutamide monotherapy of prostate cancer. J Clin Oncol 23:808-815, 2005
2. Smith MR, Goode M, Zietman AL, et al: Bicalutamide monotherapy versus leuprolide monotherapy for prostate cancer: Effects on bone mineral density and body composition. J Clin Oncol 22:2546-2553, 2004 3. Tyrrell CJ, Payne H, Tammela TL, et al: Prophylactic breast irradiation with a single dose of electron beam (10 Gy) significantly reduces the incidence of bicalutamide-induced gynecomastia. Int J Radiat Oncol Biol Phys 60:476-483, 2004[Medline] 4. Dicker AP: The safety and tolerability of low-dose irradiation for the management of gynecomastia caused by antiandrogen monotherapy. Lancet Oncol 4:30-36, 2003[CrossRef][Medline] 5. Chou JL, Easley JD, Feldmeier JJ, et al: Effective radiotherapy in palliating mammalgia associated with gynecomastia after DES therapy. Int J Radiat Oncolo Biol Phys 15:749-751, 1988 6. Fass D, Steinfeld A, Brown J, et al: Radiotherapeutic prophylaxis of estrogen-induced gynecomastia: A study of late sequela. Int J Radiat Oncol Biol Phys 12:407-408, 1986[Medline] 7. Prezioso D, Piccirillo G, Galasso R, et al: Gynecomastia due to hormone therapy for advanced prostate cancer: A report of ten surgically treated cases and a review of treatment options. Tumori 90:410-415, 2004[Medline] 8. Metzger H, Junker A, Voss AC: Irradiation of breast glands as prophylactic treatment of estrogen-induced gynecomastia in patients with prostate carcinomas [in German]. Strahlentherapie 156:102-104, 1980[Medline] 9. Widmark A, Fossa SD, Lundmo P, et al: Does prophylactic breast irradiation prevent antiandrogen-induced gynecomastia? Evaluation of 253 patients in the randomized Scandinavian trial SPCG/SFUO-3. Urology 61:145-151, 2003[Medline] 10. Waterfall NB, Glaser MG: A study of the effects of radiation on prevention of gynecomastia due to oestrogen therapy. Clin Oncol 5:257-260, 1979[Medline] 11. Lowell DM, Martineau RG, Luria SB: Carcinoma of the male breast following radiation: Report of a case occurring 35 years after radiation therapy of unilateral prepubertal gynecomastia. Cancer 22:585-586, 1968[Medline] 12. Saltzstein D, Cantwell A, Sieber P, et al: Prophylactic tamoxifen significantly reduces the incidence of bicalutamide-induced gynecomastia and breast pain. BJU Int 90:120-121, 2002 (suppl 2) Related Correspondence
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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$100,000 (N/R) Not Required
