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Radiation Endocrine Action in Prostate Cancer

Royal Marsden Hospital Surrey, United Kingdom

To the Editor:We congratulate Kestin et al at William Beaumont Hospital on their matched-pair analysis of conformal high-dose-rate brachytherapy boost versus external-beam radiation therapy alone for locally advanced prostate cancer reported in the Journal of Clinical Oncology.¹

Their study compared combined treatment with pelvic external-beam radiotherapy and brachytherapy boost with external-beam radiotherapy to the prostate only. No patients received endocrine therapy by orchidectomy or drug treatment. The study showed a lower prostate specific antigen (PSA) nadir and improved biochemical control in subsequent years for the patients who received combined treatment. Many possible reasons for this effect are discussed in the article. We suggest that unintended endocrine treatment might be a further factor to be considered in interpreting these data.

Endocrine treatment has an increasing role in the treatment of localized prostate cancer. Randomized trials show that actuarial 5-year local and biochemical control rates, freedom from distant metastasis, and disease-free survival are improved by hormone therapy (level of evidence, 1Aii).^2-4 Immediate endocrine therapy seems to be more effective than delayed therapy.⁵

In William Beaumont Hospital, patients in the combined-treatment group received external-beam radiotherapy to the whole pelvis using 10-MV or 18-MV photons by a four-field planned beam arrangement to a median dose of 46 Gy. Although the testes are usually outside the direct radiotherapy beams, they receive a significant radiotherapy dose by internal scatter within the patient by this technique. The scattered testicular dose is significantly higher than that from the smaller beams used for external-beam radiotherapy to the prostate alone, as used in the alternative matched-pair series.⁶ Estimates suggest doses of more than 10 Gy may be observed. Doses of 2 Gy or higher have been shown to affect testicular Leydig cell function.⁷

Leydig cells are situated in the interstitium of the testis between seminiferous tubules. They are stimulated by luteinizing hormone to synthesize androgens. Leydig cells were believed historically to be radioresistant compared with cells of the seminiferous tubules. This was from observations that radiotherapy had little effect on Leydig cell populations on histologic examination of irradiated testes.

The United States Atomic Energy Commission study treated the testes of healthy men with radiotherapy to between 0.8 Gy and 6 Gy. They found significant Leydig cell dysfunction with reduced testosterone levels and raised luteinizing hormone levels after low-dose radiotherapy.⁸

Techniques similar to those used in the William Beaumont Hospital study have used external-beam radiotherapy to the whole pelvis with a four-field planned beam arrangement for patients with prostate cancer, and testes dose has been measured by lithium fluoride dosimetry. In one study of 59 patients, testes doses were measured as 4.5 Gy to 6 Gy, equivalent to between 5% and 8% of the pelvic tumor dose.⁹ In a second study, scattered dose to the testes was measured without shielding in 20 patients and hormone levels were measured before and after radiotherapy (3 to 60 months). In some cases, the testicular dose was more than 10 Gy. Longlasting Leydig cell dysfunction was seen with a dose-dependent relationship. Testosterone concentrations were reduced significantly at 1 week as well as 3 months after treatment.¹⁰ In a third study of 78 men undergoing therapeutic orchidectomy for prostate cancer, 35 patients had received prior radiotherapy, including 35 Gy to the pelvis using a similar four-field technique. No patient had received prior hormone therapy. Testicular atrophy was more common in radiotherapy patients compared with nonirradiated patients (71% v 28%) (P < .001), and atrophy was more prominent in specimens from older patients and those obtained at longer intervals after pelvic radiotherapy.¹¹

Unintended endocrine therapy may occur after pelvic radiotherapy. It would be a possible consequence of the more successful treatment technique used in the William Beaumont Hospital matched-pair analysis of conformal high-dose-rate brachytherapy boost versus external-beam radiation therapy alone for locally advanced prostate cancer.

REFERENCES

1. Kestin LL, Martinez AA, Stromberg JS, et al: Matched-pair analysis of conformal high-dose-rate brachytherapy boost versus external-beam radiation therapy alone for locally advanced prostate cancer. J Clin Oncol 18: 2869-2880, 2000[Abstract/Free Full Text]

2. Pilepich MV, Caplan R, Byhardt RW, et al: Phase III trial of androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate treated with definitive radiotherapy: Report of Radiation Therapy Oncology Group protocol 85-31. J Clin Oncol 15: 1013-1021, 1997[Abstract/Free Full Text]

3. Pilepich MV, Krall JM, Al-Sarraf M, et al: Androgen deprivation with radiation therapy compared with radiation therapy alone for locally advanced prostatic carcinoma: A randomized comparative trial of the Radiation Therapy Oncology Group. Urology 45: 616-623, 1995[Medline]

4. Bolla M, Gonzalez D, Warde P, et al: Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 337: 295-300, 1997[Abstract/Free Full Text]

5. Medical Research Council Prostate Cancer Working Party Investigators Group: Immediate versus deferred treatment for advanced prostatic cancer: Initial results of the Medical Research Council trial. Br J Urol 79: 235-246, 1997[Medline]

6. Amies C, Mamegham H, Rose A, et al: Testicular doses in definitive radiation therapy for localised prostate cancer. Int J Radiat Oncol Biol Phys 32: 839-846, 1995[Medline]

7. Shapiro E, Kinsella TJ, Makuch RW, et al: Effects of fractionated irradiation of endocrine aspects of testicular function. J Clin Oncol 3: 1232-1239, 1985[Abstract/Free Full Text]

8. Rowley MJ, Leach DR, Warner GA, et al: Effect of graded doses of ionizing radiation on the human testis. Radiat Res 59: 665-678, 1974[Medline]

9. Grigsby PW, Perez CA: The effects of external beam radiotherapy on endocrine function in patients with carcinoma of the prostate. J Urol 135: 726-727, 1986[Medline]

10. Tomic R, Bergman B, Damber JE, et al: Effects of external radiation therapy for cancer of the prostate on the serum concentrations of testosterone, follicle-stimulating hormone, luteinizing hormone and prolactin. J Urol 130: 287-289, 1983[Medline]

11. Daniell HW, Tam EW: Testicular atrophy in therapeutic orchiectomy specimens from men with prostate carcinoma: Association with prior prostate bed radiation and older age. Cancer 83: 1174-1179, 1998[Medline]

Response

William Beaumont Hospital Royal Oak, MI

In Reply:We sincerely thank Dr Beitler and Drs Cornes and Shahidi for taking the time to address important issues regarding our article.¹ As Beitler implies, high-dose-rate (HDR) brachytherapy clearly offers some enticing radiobiologic and technical advantages. Recent studies have indicated a relatively low alpha:beta ratio in prostate cancer for which hypofractionated HDR brachytherapy would seem ideal.^2,3 In fact, we have also begun a prospective study evaluating the use of HDR brachytherapy alone (as monotherapy) for the treatment of low-risk prostate cancer. Since 1999, we have already treated 43 patients using this technique. The preliminary report is currently in press.⁴

Although we believe that the HDR brachytherapy boost is primarily responsible for the improved outcome in our study, treatment of the pelvis in the implant group versus the prostate only in the external-beam radiation therapy (EBRT)-alone group may be a confounding factor, as pointed out in our Discussion. The use of pelvic fields in the treatment of prostate cancer has remained controversial for many years. Although the majority of studies have not demonstrated improved outcome with treating the whole pelvis, some studies have indicated a potential benefit in certain subgroups with high-risk prostate cancer.⁵ Although a scattered dose to the testicles could possibly cause a reduction in androgen levels, we are confident that slight hormonal changes were not responsible for the difference in outcome between the two treatment groups. According to the thorough study cited by Cornes and Shahidi, the distance from the testis to the lower field border is the most important factor influencing testicular dose.⁶ The second most important factor is the number of port films obtained. In our study, regardless of whether a whole-pelvis or prostate-only field was used, the inferior field edge was identical for the two treatment groups (1.5 cm inferior to the urethral cone). In addition, port films were consistently acquired at a rate of one film per week per treatment field. Based on the data from Amies et al,⁶ approximately 0.7 Gy (0.025 Gy x 28 port films) was delivered to the testes via filming for the prostate-only patients, versus 0.5 Gy (0.025 Gy x 20 port films) for the pelvis group. Most importantly, variation in field size is only a minor factor influencing testicular dose. According to the data published by Amies et al, an 8-cm equivalent-square field contributed approximately 1.4% of the relative dose at isocenter to the testicles, versus 2.2% for a 15-cm equivalent-square field. Extrapolating this data for our study, this would mean a testicular dose of 0.93 Gy (0.014 x 66.6 Gy) in the prostate-only group versus 1.01 Gy (0.022 x 46.0 Gy) in the pelvis group. Combining this with the dose received from port films, the prostate-only group received a total of 1.63 Gy, versus 1.51 Gy for the pelvis group. Thus, the prostate-only patients may have received more testicular dose than the pelvis patients in our study. Furthermore, while some studies have indicated reduced androgen levels after testicular radiation, we know of no data demonstrating that the resultant minor fluctuation in hormonal levels translated into an improved clinical outcome. We realize that there is a considerable error margin and a wide range in the estimation of testicular dose from EBRT. Regardless, we are relatively certain that the clinical impact of testicular dose in our matched-pair analysis is negligible. It seems a bit more plausible that the additional 29 Gy (median) in total dose to the prostate (equivalent dose in 2-Gy fractions based on an alpha:beta ratio of 1.5 Gy) was the primary reason for improved outcome with an HDR brachytherapy boost.

REFERENCES

1. Kestin LL, Martinez AA, Stromberg JS, et al: A matched-pair analysis of conformal high-dose-rate brachytherapy boost versus external-beam radiation therapy alone for locally advanced prostate cancer. J Clin Oncol 18: 2869-2880, 2000

2. Brenner DJ, Hall EJ: Fractionation and protraction of radiotherapy of prostate carcinoma. Int J Radiat Oncol Biol Phys 43: 1095-1101, 1999[Medline]

3. Brenner DJ: Toward optimal external-beam fractionation for prostate cancer. Int J Radiat Oncol Biol Phys 48: 315-316, 2000[Medline]

4. Martinez AA, Pataki I, Edmundson G, et al: Phase II prospective study of the use of conformal high dose rate brachytherapy as monotherapy for the treatment of favorable stage prostate cancer: A feasibility report. Int J Radiat Oncol Biol Phys (in press)

5. Stock RG, Ferrari AC, Stone NN: Does pelvic irradiation play a role in the management of prostate cancer? Oncology (Huntingt) 12: 1467-1472, 1998[Medline]

6. Amies CJ, Mameghan H, Rose A, et al: Testicular doses in definitive radiation therapy for localized prostate cancer. Int J Radiat Oncol Biol Phys 32: 839-846, 1995

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Cornes, P. G. S. Articles by Martinez, A. A. Search for Related Content PubMed PubMed Citation Articles by Cornes, P. G. S. Articles by Martinez, A. A. Social Bookmarking                            What's this?