Testosterone Replacement for Hypogonadism After Treatment of Early Prostate Cancer With Brachytherapy

Transcription

1 536 Testosterone Replacement for Hypogonadism After Treatment of Early Prostate Cancer With Brachytherapy Michael F. Sarosdy, MD South Texas Urology and Urologic Oncology, San Antonio, Texas. BACKGROUND. Controversy and a notable paucity of published clinical data best characterize the current knowledge of testosterone-replacement therapy (TRT) for hypogonadism after treatment for early, localized prostate cancer. The objective of this study was to assess the risk of biochemical failure with TRT after treatment of early prostate cancer with permanent transperineal brachytherapy with or without external beam therapy in patients with low serum levels of testosterone and clinical symptoms of hypogonadism. METHODS. Patients who underwent prostate brachytherapy from 1996 to 2004 and received subsequent TRT for symptomatic hypogonadism were reviewed to detail cancer characteristics and treatment as well as pre- and post-trt serum testosterone and prostate-specific antigen (PSA) values. RESULTS. Thirty-one men received TRT after prostate brachytherapy for 0.5 to 8.5 years (median, 4.5 years), with a follow-up that ranged from 1.5 years to 9.0 years (median, 5.0 years) postbrachytherapy. TRT was started from 0.5 years to 4.5 years (median, 2.0 years) after brachytherapy. Serum total testosterone levels ranged from 30 ng/dl to 255 ng/dl (median, 188 ng/dl) before TRT and rose to 365 ng/dl to 1373 ng/dl (median, 498 ng/dl) on TRT. Transient rises in PSA were observed in 1 patient. The most recent PSA level was <0.1 ng/ml in 23 patients (74.2%), <0.5 ng/ml in 30 patients (96.7%), and <1 ng/ml in 31 patients (100%). No patients stopped TRT because of cancer recurrence or documented cancer progression. CONCLUSIONS. For patients with low serum testosterone levels and symptoms of hypogonadism, TRT may be used with caution and close follow-up after prostate brachytherapy. Cancer 2007;109: Ó 2006 American Cancer Society. Presented in abstract form at the Annual Meeting of the American Urological Association, Atlanta, Georgia, May 20 25, Dr. Sarosdy has served as an investigator and consultant with the Mentor Corporation (now Coloplast). Address for reprints: Michael F. Sarosdy, MD, South Texas Urology and Urologic Oncology, 4499 Medical Drive, Suite 218, San Antonio, TX 78229; Fax: (210) ; urodoc@ satx.rr.com Received September 6, 2006; revision received November 2, 2006; accepted November 10, KEYWORDS: testosterone replacement, prostate cancer, hypogonadism, brachytherapy. Since the pioneering and Nobel Prize-winning studies of Huggins and Hodges nearly 60 years ago, the link between testosterone and prostate cancer has been detailed extensively. 1 Androgen blockade, whether surgical or medical, in many forms, is the mainstay of treatment of advanced prostate cancer for palliative purposes, with significant side effects. 2 Among American males, testosterone deficiency is common yet often is insidious in onset. The incidence of hypogonadism increases with age, although it is diagnosed increasingly in younger men because of growing physician and patient awareness and increased testing of serum testosterone levels. 3 Increased knowledge of the role of testosterone in normal male metabolic processes, as well as the ª 2006 American Cancer Society DOI /cncr Published online 20 December 2006 in Wiley InterScience (

2 Testosterone Replacement in Prostate CA/Sarosdy 537 derangements associated with endogenous hypogonadism, makes treatment of this condition appropriate in some patients. Although there is controversy regarding the benefits and risks of testosterone replacement therapy (TRT) in males who are not believed to have prostate cancer, there is even more controversy over the potential of TRT in males who have received previous treatment for prostate cancer. 4,5 Whereas many men with hypogonadism and prostate cancer are not symptomatic, some who are symptomatic may desire TRT. However, hypogonadal men who have undergone potentially curative and successful treatment for localized prostate cancer face a conundrum regarding potential TRT. Men with normal testosterone levels are not castrated if they have no evidence of disease after radical surgery or irradiation. Yet, TRT after prostatectomy is considered controversial at best and contraindicated by some. TRT after brachytherapy, with the prostate still in vivo, may be more angst provoking. Unfortunately, there is a paucity of data regarding TRT in men who receive previous treatment for prostate cancer, limited to 2 published reports totaling 17 patients with median follow-up of 2 years after radical prostatectomy. 4,5 A literature review reveals that no reports of TRT after brachytherapy exist. To assess the risk of biochemical failure or prostate cancer recurrence in patients who undergo TRT after prostate brachytherapy, a large, single urologic oncologist s experience was reviewed. Herein, I report a large series of TRT in men after treatment for prostate cancer using brachytherapy and with more extensive follow-up. MATERIALS AND METHODS Data from men who underwent transperineal, lowdose-rate, permanent brachytherapy or seed implantation for early-stage prostate cancer by a single urologic oncologist from July 1996 to December 2004 were reviewed from a prospectively maintained database. Assessment included disease characteristics and serum prostate-specific antigen (PSA) value at diagnosis, length of follow-up, and all subsequent PSA values. Cancer treatment-related details were noted, including whether brachytherapy was used alone or in combination with external beam therapy and whether or not patients received temporary adjuvant androgen blockade. When the latter was used, it was accomplished with lutenizing hormone-releasing hormone (LHRH) agonist (leuprolide acetate or goserelin) either alone or in combination with nonsteroidal antiandrogen (bicalutamide) for a maximum of 12 months. TRT was initiated 6 months from the time of implantation after it was confirmed that the total serum testosterone level was <300 ng/dl on repeated morning assays in combination with symptoms of hot flashes, severe anergy, depression, fatigue, and erectile dysfunction and/or decreased libido. TRT was continued only in men who manifested a beneficial clinical response. The choice of pharmacologic agent for TRT was left to each individual patient, although most patients initially received injections (testosterone cyprionate 200 mg) to avoid issues of variable absorption of transdermal products. Subsequently, patients were switched to other compounds according to their preference. All patients were staged according to the TNM classification system. 6 Informed verbal discussion and consent was documented in all patients. Followup consisted of semiannual visits for 5 years after implantation and annual visits thereafter. At each visit, patients underwent physical examination and measurement of serum PSA and total testosterone. Prior to June 2004, all PSA and testosterone assays were done at commercial or hospital laboratories; after that, a point-of-care, in-office assay (Qualigen) was used for most determinations. Assessment did not include measurements of free testosterone or sex-binding globulin, routine complete blood counts, calculation of body mass index, or standardized, validated quality-of-life (QOL) measures. RESULTS Thirty-six of 715 men (5.0%) who were treated consecutively between July 1996 and December 2004 have received or are receiving TRT after brachytherapy. Five patients received from 1 to 3 months of TRT, which was stopped after they achieved no perceived symptomatic benefit, not because of any rise in PSA, because PSA was not measured during that short interval, and those men did not demonstrate any subsequent rises in PSA. Thirty-one patients have received or are receiving long-term TRT and form the basis of this analysis. Men ranged in age from 51 years to 79 years (median, 65 years) at the time of brachytherapy. The prostate cancer disease characteristics at the time of diagnosis and treatments are detailed in Table 1. The median serum PSA level was 5.3 ng/ml, the single most common Gleason score was 6 in 19 of 31 men (61.3%), and the most frequent clinical stage was T1c in 20 of 31 men (64.5%). Twenty patients underwent brachytherapy implantation alone, and the remaining 11 patients underwent brachytherapy implantation combined with external-beam radiotherapy. Tran-

3 538 CANCER February 1, 2007 / Volume 109 / Number 3 TABLE 1 Disease Characteristics and Treatment of Patients on Testosterone Replacement After Brachytherapy Characteristic No. of patients PSA, ng/ml Range Median 5.3 Gleason score /9 3 Clinical tumor classification T1b 1 T1c 20 T2a 8 T2b 2 Cancer treatment Brachytherapy 20 Brachytherapy and EBT 11 Brachytherapy with or without EBT 14 combined with androgen blockade PSA indicates prostate-specific antigen; EBT, external beam radiotherapy. TABLE 2 Testosterone Levels and Duration of Follow-up Variable Range Median Testosterone, ng/dl Pre-TRT On TRT Duration, y TRT Follow-up TRT indicates testosterone-replacement therapy. TABLE 3 Most Recent Prostate-specific Antigen Level in 31 Men on Testosterone-replacement Therapy From 1.5 Years to 9.0 Years After Brachytherapy PSA, ng/ml No. of patients (%) < (74.2) < (96.7) < (100) PSA indicates prostate-specific antigen. sient androgen blockade for shrinkage or for highrisk disease was received for 8 to 12 months by 14 patients. The preblockade serum testosterone level was available in only 3 patients and was <300 ng/dl in all 3. Whether or not the other 11 patients failed to recover or had endogenously low testosterone levels prior to blockade is unknown. TRT was initiated from 0.5 years to 4.25 years (median, 2.0 years) after brachytherapy; and, in the 14 men who had received transient androgen blockade, TRT was initiated from 0.5 years to 3.0 years (median, 2.0 years) after the LHRH agonist had been stopped. Pre-TRT serum testosterone levels ranged from 30 ng/dl to 255 ng/dl (median, 188 ng/dl) (Table 2). The duration of TRT in all 31 patients ranged from 0.5 years to 8.5 years (median, 4.5 years). The maximal serum testosterone level on TRT ranged from 356 ng/dl to 1373 ng/dl (median, 498 ng/dl). Follow-up after brachytherapy implantation ranged from 1.5 years to 9.0 years (median, 5.0 years). PSA values have declined steadily from the time of implantation, and only 3 patients have had a transient PSA rise or bounce that already had resumed a declining course prior to initiation of TRT. Only 1 patient has had any rises in PSA after TRT, followed by declines. The most recent serum PSA levels were <0.1 ng/ml in 23 patients (74.2%), <0.5 ng/ml in 30 patients (96.7%), and <1.0 ng/ml in all 31 patients (100%) (Table 3). All 7 patients with PSA levels between 0.1 ng/ml and 0.5 ng/ml are <3 years postimplantation, had a steadily declining PSA both before and after the initiation of TRT, and their most recent PSA was their nadir since brachytherapy. The 1 patient who had a PSA >0.5 ng/ml is 5 years postimplantation and has not undergone prostatic biopsies or other studies to exclude recurrence. No patient has stopped TRT because of a possible or confirmed recurrence or progression of prostate cancer. DISCUSSION Prostate cancer is very common, in that nearly 250,000 men are diagnosed annually in the United States alone, and the majority have early-stage, localized disease. 7 Based on the frequency of low testosterone and symptoms of hypogonadism in men with early prostate cancer and on the high rate of success with treatment for early prostate cancer, clinicians frequently may encounter patients with prostate cancer who may seek treatment for relief of those symptoms. The current data appear to indicate that TRT after brachytherapy treatment for early-stage prostate cancer may be performed safely in selected and carefully monitored patients. The cornerstone of TRT after prostate cancer treatment is the underlying success of the primary cancer treatment in controlling the cancer. Multiple series indicate that brachytherapy with or without

4 Testosterone Replacement in Prostate CA/Sarosdy 539 external radiation provides a high rate of freedom from biochemical failure at 5 years and 10 years, at least equivalent to radical prostatectomy In those reports, biochemical failure is noted in from 10% to 25% of patients by 5 years posttreatment. The high rate of success in biochemical control of patients in the current report, despite TRT, appears to be consistent with the rates in patients who undergo brachytherapy or radical prostatectomy at multiple centers. It is possible that the current report s apparent success may reflect small numbers or short follow-up, although 50% of patients have been followed from 5 years to 9 years postbrachytherapy. It should be noted that patients who were considered for TRT were not selected after an arbitrary, lengthy time (eg, 5 years) to avoid administering TRT to patients who may have demonstrated biochemical failure to brachytherapy prior to the initiation of TRT. In addition, the disease characteristics at diagnosis closely reflect the range of early-stage prostate cancer, and the majority of patients in this study had stage T1c tumors and a Gleason score of 6; however, 10 patients (32%) had palpable, stage T2 tumors, and 9 patients (29%) had a Gleason score >6. Unlike after surgery, when PSA should rapidly drop to undetectable levels, after brachytherapy implantation, it has been well documented that PSA levels decline in all patients over 24 months to 36 months before a PSA nadir has been reached and that an upward bounce in the PSA level may occur during this decline in nearly 25% of patients. 9,11,14,15 The observation of a slight bounce in PSA in 3 of 31 patients that was resolving by the time TRT was initiated in the current series reinforces the approach of delaying TRT to 18 months after implantation, so that the bounce phenomenon is not interpreted as secondary to TRT. Two reports recently detailed the absence of biochemical recurrence with TRT in smaller numbers of patients after radical prostatectomy. 4,5 The current report confirms that, with even more substantial follow-up, TRT also may be safe and practical after brachytherapy for prostate cancer. Although this report is observational and is not the product of a randomized clinical trial, the results seem to add substantially to the current clinical data; and, together, these reports may serve to generate hypothesis-testing, prospective clinical studies. Much of the concern over the risks of TRT relative to prostate cancer is based on limited published data and anxiety over the known link between prostate cancer and testosterone. 3,16 In the preface to an Institute of Medicine (IOM) report of the research on testosterone therapy, the chairman reported that the committee noted a paucity of randomized, controlled clinical trials, in particular among middle-aged or older men. 17 The IOM committee concluded that a standardized clinical definition of hypogonadism does not exist, that clinical data do not clearly support either the efficacy or safety of TRT in older men, and that small clinical trials designed to define efficacy in older men should be completed and, if positive, followed by larger trials in middle-aged men. In the meantime, the committee indicated that testosterone therapy is appropriate only for the FDAapproved indication: treatment of hypogonadism. 17 That group did not address the issue of TRT in men who were treated previously for prostate cancer; in fact, the 2 prior reports on TRT after radical prostatectomy were published after the IOM report. Investigators generally have skirted the issue of TRT among patients with prostate cancer and have approached it obliquely, by reporting other endpoints, such as new prostate cancers detected or changes in serum PSA while patients without cancer are on TRT. Gaylis et al. detailed 20 patients who were diagnosed with prostate cancer while they were receiving TRT for hypogonadism, but those authors did not report incidence or compare their findings with age-matched controls who did not receive TRT. 18 Calof et al., in their meta-analysis of 19 of 417 TRT reports that met their inclusion criteria, failed to find a significant increase in high PSA levels (>4 ng/ ml), prostate biopsies, or prostate cancer in men undergoing TRT compared with controls. 19 El-Sakka et al. reported no significant change in PSA levels with 12 months of TRT in 187 men who were treated for erectile dysfunction and hypogonadism, whereas Gerstenbluth et al. did note an increase in mean PSA levels from 1.86 ng/ml to 2.82 ng/ml in 54 similar patients without cancer. 20,21 Rhoden and Morgentaler studied a group of patients who they believed were at high risk for prostate cancer because of the histologic findings of highgrade prostatic intraepithelial neoplasia (PIN) on cancer-negative biopsies who subsequently received TRT for 1 year. 22 Those authors did not find a greater rise in PSA or an increased finding of prostate cancer in men with PIN compared with men who did not have PIN on prior biopsy. In addition, in a large review, Morgentaler cited no increase in the risk of prostate cancer in clinical trials of TRT, in longitudinal population-based studies, or in similar high-risk patients. 23 The long-term benefits of TRT relative to sexual function, mood, body mass, and bone mineral density have been outlined well by Wang et al. 24 It should be noted that the 31 patients on TRT in the current study represent only 5% of the patients

5 540 CANCER February 1, 2007 / Volume 109 / Number 3 who underwent brachytherapy during the same period, indicating that many more patients with prostate cancer may have low testosterone levels but may not desire to undergo TRT, even though potential TRT has been discussed and offered to them. Some of the reasons for this may be the lack of published data and the resulting confusion and anxiety and the lack of perceived guidance. This was stated specifically by 3 of the 5 patients who stopped TRT after they obtained no or minimal perceived benefit from a short course of TRT. It also is worth noting that, although QOL indices were not measured, the objective of TRT in these patients was relief of hypogonadal symptoms, not simply restoration of testosterone to higher levels. In the early years, this was largely in response to patient insistence and was agreed to by the author with some trepidation. The observation that 31 of 36 patients (86.1%) who received any TRT have continued it for a median of 4.5 years and for as long as 8.5 years is clear testimony to the improved QOL experienced by these patients. Clearly, most patients who have failed on treatment for early-stage prostate cancer in virtually all previous reports have done so without TRT, and patients on TRT also can be expected to fail, depending on the adequacy of their primary cancer treatment and disease stage. It is conjectural whether or not raising testosterone levels from low to normal would have any negative impact. Castrate levels of total serum testosterone <20 ng/dl have been considered the standard in medical castration. 25 The pre-trt testosterone levels of from 30 ng/dl to 255 ng/dl among the patients in the current report would not be considered low enough for the purposes of anticancer medical castration. Furthermore, it has not been demonstrated that such low levels would not be enough to fuel the recurrence or progression of prostate cancer in the face of less than adequate primary treatment of the localized cancer. Finally, there is no question that prospective, randomized trials would be useful in addressing more completely the issue of TRT after any treatment for early-stage, localized prostate cancer. However, the apparent absence of progression in this report indicates that a randomized Phase III trial would require thousands of patients, a very long duration to reach valid statistical endpoints, and extremely high costs. In conclusion, the current report indicates that TRT may be used with caution and close follow-up in hypogonadal patients after they receive prostate brachytherapy for localized, early-stage prostate cancer. Assessment of baseline testosterone should be considered critical among men with early-stage prostate cancer, especially those who may undergo transient androgen blockade as part of their cancer treatment. Blanket statements that TRT is contraindicated after treatment for early-stage prostate cancer do not appear to be supported by these data. Given the significant, long-term metabolic derangements and significant symptoms in some hypogonadal patients, TRT may be considered in select patients who appear to have been treated successfully for early-stage, localized prostate cancer. REFERENCES 1. Huggins C, Hodges CV. The effects of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1941;1: Klotz L. Combined androgen blockade: an update. Urol Clin North Am. 2006;33: , v vi. 3. Snyder PJ. Hypogonadism in elderly men what to do until the evidence comes. N Engl J Med. 2004;350: Kaufman JM, Graydon RJ. 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