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Controversies in the systemic management of patients with evidence of biochemical failure following radical prostatectomy
CANCER TREATMENT REVIEWS 2002; 28: 189–194 doi: 10.1016/S0305-7372(02)00046-4, available online at http://www.idealibrary.com on
ANTI TUMOUR TREATMENT
Controversies in the systemic management of patients with evidence of biochemical failure following radical prostatectomy Robert Dreicer Department of Hematology–Oncology, and the Urologic Institute, Cleveland Clinic Foundation, Cleveland, OH, USA The management of patients with evidence of a detectable prostate-specific antigen (PSA) following prostatectomy is an increasingly common and difficult issue for patients and clinicians alike. In the setting in which biochemical failure is believed representative of early systemic failure, therapeutic options primarily involve the use of hormonal therapy. Extrapolating results of early vs. delayed hormonal therapy from studies of patients with more advanced prostate cancer is problematic. Antiandrogen monotherapy and intermittent androgen deprivation are increasingly popular approaches, although their ultimate utility remains unproven. This patient subset is an optimal one in which to conduct clinical trials to both define the role of hormonal therapy and to investigate novel, non-hormonal approaches. The most appropriate therapeutic intervention c 2002 Elsevier Science for patients with evidence of biochemical failure following radical prostatectomy remains undefined. s Ltd. All rights reserved.
Key words: PSA recurrence; hormonal therapy.
INTRODUCTION One of the most important consequences of prostatespecific antigen’s (PSA) wide-spread application into clinical practice in the late 1980s, has been a dramatic shift of the prostate cancer disease curve to the left, with significant numbers of patients now being diagnosed with presumed clinically localized disease (1). With the presumption that earlier diagnosis and therapy may result in an increased likelihood of cure, substantial number of patients are undergoing therapy with curative intent (2). In the US, parts of Europe, and around the world significant number of patients will undergo radical prostatectomy as management of localized disease (3,4). Approximately one third of prostate cancer patients with clinically localized disease treated with radical prostatectomy develop evidence of biochemical
Correspondence to: Robert Dreicer, M.D., FACP, Cleveland Clinic Foundation, 9500 Euclid Ave R35, Cleveland, OH 44195, USA, Tel.: +1-216-445-4623; Fax: 1-216-445-2360; E-mail: [email protected]
failure during long-term follow-up (5–8). Thus the down-stream impact of our current prostate cancer screening and therapeutic strategies has created a new subset of prostate cancer patients, those with evidence of disease recurrence, biochemically (PSA) defined, potentially representing thousands of patients/year in the US alone (9,10).
NATURAL HISTORY AND EVALUATION OF PSA RELAPSE The natural history of PSA relapse following radical prostatectomy is poorly understood in part due to the relatively short follow-up available, but more significantly, the confounding effects of salvage radiotherapy and/or hormonal therapy which are administered to a substantial number of patients (11). The limited use of radiation and hormonal therapy in the series reported by Pound et al. makes this the most important report detailing the natural history of biochemical failure following radical
c 2002 ELSEVIER SCIENCE LTD. ALL RIGHTS RESERVED. 0305-7372/02/$ - see front matter s
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prostatectomy. Over a 15-year period, 1997 patients underwent a radical prostatectomy with 304 (15%) subsequently experiencing biochemical failure. Of these 304 patients, 103 (34%) developed metastatic disease. However, none of these patients received hormonal therapy on the basis of an elevated PSA in the absence of clinically evident metastatic disease. The median actuarial time from PSA elevation to metastatic disease was 8 years with the median time to death following development of metastatic disease being approximately 5 years later. Prognostic factors predictive of outcome included the Gleason score on the prostatectomy specimen (high vs. intermediate), time to PSA recurrence (>2 vs. O2 years) and to a lesser extent the PSA doubling time (12). Clinicians evaluating patients with detectable PSA values following radical prostatectomy are faced with the significant challenge of determining whether there is evidence of local vs. systemic relapse. This information would aid in the determination of patients with local recurrence who might be suitable for ‘‘salvage’’ radiotherapy although the utility of this approach is controversial and is beyond the scope of this discussion. In the setting of PSA-only relapse, radionuclide bone scintigraphy and computed tomography (CT) imaging are insufficiently sensitive to distinguish local vs. systemic failure (13,14). The utility of radioimmunoscintigraphy with Indium-111-capromab pendetide to distinguish between local and systemic failures remains controversial. Recent reports suggest sensitivity, specificity and overall accuracy of this study to be in the 75, 86, and 81% range, respectively (15–17). A large study of men with low levels of PSA (0.1–4.0 ng/mL) demonstrated capromab pendetide uptake in 72% of 255 men with 31% of men having evidence of prostatic fossa only uptake (18).
IMMEDIATE VS DELAYED HORMONAL THERAPY Although it is widely recognized that there is no ‘‘standard of care’’ for the management of patients with biochemical failure (presumption of systemic failure) or with PSA progression following ‘‘salvage’’ radiotherapy, androgen-deprivation therapy is frequently prescribed, especially for patients older than 65 (11). The subject of immediate vs. deferred androgen suppression remains controversial and has significant ramifications for the patient (10). An interesting illustration of the uncertainty surrounding this clinical dilemma is exemplified by the report by Wasson et al. In his survey of practicing urologists, more than half of the urologists who stated that did
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not believe that early hormonal therapy impacted on the survival of locally advanced prostate cancer stated that they still prescribed it to their patients (19). For several decades, interpretation of the results from the two Veterans Administration Co-operative Urological Research Group (VACURG) trials have guided the timing of hormonal therapy in patients with advanced prostate cancer (20,21). Walsh et al. reevaluated the findings from both VACURG I and II in an attempt to clarify the role of early vs delayed hormonal therapy (10). VACURG I was a 4 arm blinded trial, which assigned patients with locally advanced and metastatic prostate cancer to placebo, orchiectomy plus placebo, diesthylstilbestrol (DES) 5 mg daily, or orchiectomy plus DES. Walsh and colleagues concentrated on both the placebo and orchiectomy + placebo arms, arguing that the two DES containing arms were exposed to the confounding effect of increased cardiovascular mortality and a possibility that non-compliance may have influenced outcome. In the two non-DES containing arms, 262 patients with locally advanced (T3-4, M0) disease were assigned to placebo and 266 to orchiectomy. In men with metastatic disease 223 were assigned to placebo and 203 patients to orchiectomy. At 9 years follow-up, there was no difference in disease specific or overall survival suggesting a lack of benefit to early hormonal therapy (10). VACURG II randomized over 1500 patients with locally advanced and metastatic disease into four treatment arms: placebo, 0.2, 1, and 5 mg DES daily. The 5 mg arm was terminated early secondary to increased cardiovascular mortality and interpretation of the results of this study suggested a survival benefit to 1 mg of DES compared to placebo or 0.2 mg. Walsh et al. suggest that due to protocol issues, a significant subset of patients assigned to both the placebo and 0.2 mg DES (a dose that is ineffective for suppressing testosterone) arms never received hormonal therapy calling into question whether in fact the question asked by this study was appropriately addressed (10). The three most widely quoted trials used to extrapolate the role of early hormonal therapy to patients with biochemical failure are the EORTC 22863 (Bolla et al.) the Eastern Cooperative Oncology Group (ECOG) node positive study, and the Medical Research Council (MRC) study in locally advanced and metastatic disease. Bolla et al. randomized 401 patients with either high-grade T1-2, NO or T3/4 any grade patients to radiotherapy alone or with combined androgen ablation for 3 years. At 5 years, the survival of patients receiving hormonal/radiotherapy was 79% vs. 62% for radiotherapy alone (22). Other randomized studies of this approach have demonstrating improvement in local control,
CONTROVERSIES IN THE SYSTEMIC MANAGEMENT OF PATIENTS
disease-free survival and time to metastatic with some subsets of patients demonstrating improvement in overall survival (23,24). The ECOG performed a randomized, prospective study of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes (25). Patients on the treatment arm received goserelin monthly or underwent orchiectomy. Ninety-eight eligible patients were entered and at a median follow-up of 7.1 years, 7 of 47 men who received immediate antiandrogen therapy had died compared with 18 of 51 in the observation group (P ¼ 0:02). The authors concluded that immediate antiandrogen therapy after radical prostatectomy and pelvic lymphadenectomy improves survival and reduces the risk of recurrence in patients with node positive disease. Critics of this study point to the small sample size, the potential imbalance of the arms noting a relatively low cancerspecific survival rate in the control arm compared to historical series, the lack of central pathologic review and the observation that a larger (currently unpublished) EORTC node positive study of early vs. delayed hormonal therapy has at a median follow-up of 6 years failed to demonstrate a impact on cancer specific or overall survival (10). The MRC performed a randomized trial of immediate vs. deferred therapy for advanced prostate cancer (26). Nine-hundred and thirty-eight patients with incurable local (T2-4) or metastatic disease were randomized to deferred treatment (indications for treatment in deferred patients left to individual physician) vs. hormonal therapy with either orchiectomy or LHRH analogue. At the time of the initial report in 1997, 934 patients were evaluable. Patients in the deferred treatment arm had pathologic fractures, spinal cord compressions and ureteral obstruction at twice the rate of patients in the immediate therapy group. In men with locally advanced disease 32% who received early hormonal therapy died of prostate cancer compared to 49% in the deferred therapy group (P < 0:001), with no significant difference in treatment arms for patients with metastatic disease. The initial reported results of this study have been interpreted by some to suggest clear benefit to early application of hormonal therapy. Critics point out that of the additional 54 cancer deaths in the deferred treatment arm, 29 patients (54%) never received hormonal therapy, although MRC investigators have re-analyzed their data and present a compelling argument that the omission of therapy in these 29 patients did not impact on the observed survival advantage (10,27,28). A recent update of the MRC study demonstrates that while disease-specific survival in the immediate treatment arm remains statistically significant, in contrast to the original report, overall
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survival for patients with locally advanced disease receiving immediate therapy is not significantly different than those in the delayed arm (29). Irrespective of the ultimate validity of the findings of the MRC trial, many observers have commented on the limited applicability of the study’s findings to the current management of patients with prostate cancer, especially in the US, given the frequent assessment of patients with PSA and earlier utilization of hormonal therapy, thereby altering the timing of ‘‘delayed’’ hormonal therapy (30).
ANDROGEN DEPRIVATION: SIDE EFFECTS AND IMPACT ON QUALITY OF LIFE Although androgen deprivation has been the standard of care for the management of advanced prostate cancer for 60 years, there is surprisingly little prospective data available to quantitate the frequency and severity of the side effects associated with this therapeutic intervention. Widely appreciated side effects include: loss of libido and potency, hot flushes, fatigue, anemia, loss of muscle mass, weight gain, and depression (31). More recently, development of osteoporosis has been recognized as a potentially serious consequence of long-term androgen-deprivation therapy with mounting evidence demonstrating both a decrease in bone mineral density and increasing risk of fracture (32–34). This latter concern is amplified both by the increasing numbers of patients receiving treatment and the significantly longer duration of hormonal therapy patients with early biochemical failure are likely to require. Although recent studies have suggested potential beneficial therapeutic interventions such as the use of bisphosphonates (35), the added costs and potential toxicity of additional pharmaceutical interventions used to attempt to mitigate the toxicity of androgen deprivation remains a daunting issue. To date there are only a handful of studies in the literature that speak to the impact of androgen deprivation on the quality of life of in patients with primarily biochemical failure. Herr et al. studied a cohort of 144 men with locally advanced prostate cancer or those with PSA relapse after local therapy. Seventy-nine patients opted to receive androgendeprivation therapy consisting of LHRH analogue therapy with our without flutamide or orchiectomy. Compared to the 65 men who opted to not to receive androgen-deprivation hormonally treated men had more fatigue, loss of energy, emotional distress, and a lower overall quality of life (36). This and other currently available reports are compromised by the lack of prospective randomization and small sample
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size. Quality of life assessments attached to ongoing randomized studies may provide additional insight.
ALTERNATIVE ANDROGEN-DEPRIVATION APPROACHES Given the side effect profile of androgen-deprivation therapy, there is an understandable desire to have it both ways, i.e. to provide potentially life-prolonging therapy with improved quality of life. Two therapeutic strategies that have attracted substantial attention are antiandrogen monotherapy and intermittent androgen deprivation. Hormonal monotherapy using non-steroidal antiandrogens represents a potentially attractive alternative approach to standard testicular androgen suppression for the management of early biochemical failure. In comparison to castration, antiandrogens such as bicalutamide have a significantly better toxicity profile, with more preserved sexual interest and physical capacity and a lower incidence of hot flushes (37). Of the available antiandrogens, monotherapy with bicalutamide (150 mg) has been most extensively studied. Iversen et al. compared bicalutamide at 150 mg/day vs. either orchiectomy or LHRH analogue monotherapy in patients with locally advanced (T3/4) or metastatic prostate cancer. A total of 1453 patients were randomized in two studies and were pooled for analysis. Patients receiving bicalutamide had significant advantages over patients receiving castration for both sexual interest and physical capacity. Bicalutamide monotherapy provided a similar survival outcome to castration for patients with locally advanced disease, however castration provided a 6 week survival benefit in comparison to bicalutamide-treated patients with metastatic disease (38,39). A recent meta-analysis evaluating single-therapy androgen suppression in men with advanced prostate cancer concluded ‘‘survival rates may be somewhat lower if a non-steroidal antiandrogen is used as monotherapy (40).’’ Intermittent androgen deprivation represents another therapeutic strategy to deliver hormonal therapy in patients with biochemical failure with an improved toxicity profile (41). Based upon in vitro and animal model evidence suggesting that intermittent replacement of androgens may result in a delay to development of androgen insensitivity (42,43) various investigators have reported relatively small clinical experiences with this approach (44,45). Grossfeld et al. reported their experience with intermittent hormonal therapy in 61 patients with rising PSA values without clinical apparent metastatic disease (46). Patients received from one
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to five treatment cycles (median two), with a median cycle length of 14 months. Patients spent an average of 45% of the time-off hormonal therapy, but the time off therapy decreased with each successive treatment cycle. With an average follow-up of 30 months, 5 patients (8.1%) demonstrated progressive disease. Although conceptually attractive, there is currently no prospective evidence demonstrating that the intermittent approach is either equivalent or superior to standard hormonal therapy in terms of survival. The South West Oncology Group (SWOG) is currently leading an Intergroup trial (S9346) of continuous vs. intermittent hormonal therapy in patients with advanced metastatic prostate cancer that will hopefully provide evidence either supporting or refuting this management strategy.
INVESTIGATIONAL OPTIONS Irrespective of the debate regarding early vs. delayed hormonal therapy for biochemical failure, there is no argument that hormonal therapy administered in this setting is at best a temporizing measure even if it provides a modest survival advantage. Given that this patient subset has no clear standard of care and the typical patient is anxious and motivated it would seem to represent an ideal group in which to conduct clinical trials of non-hormonal options. When examined closer however, confounding issues present unique challenges. One obvious problem is the definition of the optimal PSA level that ultimately translates into clinically evident disease. Although this issue is most problematic for patients undergoing radiotherapy there is still limited data and no consensus in patients treated with radical prostatectomy (47,48). An additional critical issue is the utility and reliability of PSA, especially at relatively low levels to be used as a response parameter. (49,50). From a pragmatic perspective, the investigational therapy proposed must not be either unduly toxic or cumbersome to administer as we are dealing with a patient population that is asymptomatic (at least physically) and many continue to work or have active lifestyles. Among the agents currently undergoing evaluation is exisulind a selective, apoptotic antineoplastic drug. Goluboff et al. performed a small phase III trial in 96 men with increasing PSA after radical prostatectomy (51). Patients were randomized to receive placebo or 250 mg. exisulind twice daily for 12 months. Compared with placebo, exisulind significantly suppressed the increase in PSA in all patients (P ¼ 0:017) and the median PSA doubling time was lengthened in high risk patients on exisulind
CONTROVERSIES IN THE SYSTEMIC MANAGEMENT OF PATIENTS
(2.12 month increase) compared with those on placebo (3.37 month decrease, P ¼ 0:048). Therapy was well tolerated and additional evaluation of this agent is ongoing. Other studies including vaccine trials and other targeted therapy agents are ongoing.
CONCLUSIONS Patients presenting with biochemical failure after prostatectomy represent a vexing challenge to urologists, medical and radiation oncologists. The patients feel well, they know that despite aggressive local therapy they may not be cured and they are understandably anxious. The role of hormonal therapy in this setting remains unclear and the impact of androgen deprivation on individual patients quality of life is not insignificant. Extrapolating the results of the ECOG node positive study and the MRC studies to earlier disease stages is problematic. The use of antiandrogen monotherapy or intermittent androgen deprivation in this setting (therapies not yet demonstrated to be as effective as conventional androgen deprivation) adds additional uncertainty. Motivated patients should be offered entry onto ongoing clinical trials. For the majority of patients for whom clinical trial entry is either not feasible or desired a liberal application of the art of medicine, including a practical discussion of the limited current body of evidence, the side effect profile and potential impact on quality of life of hormonal therapy must be the starting point for a difficult decision process.
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ANTI TUMOUR TREATMENT
Controversies in the systemic management of patients with evidence of biochemical failure following radical prostatectomy Robert Dreicer Department of Hematology–Oncology, and the Urologic Institute, Cleveland Clinic Foundation, Cleveland, OH, USA The management of patients with evidence of a detectable prostate-specific antigen (PSA) following prostatectomy is an increasingly common and difficult issue for patients and clinicians alike. In the setting in which biochemical failure is believed representative of early systemic failure, therapeutic options primarily involve the use of hormonal therapy. Extrapolating results of early vs. delayed hormonal therapy from studies of patients with more advanced prostate cancer is problematic. Antiandrogen monotherapy and intermittent androgen deprivation are increasingly popular approaches, although their ultimate utility remains unproven. This patient subset is an optimal one in which to conduct clinical trials to both define the role of hormonal therapy and to investigate novel, non-hormonal approaches. The most appropriate therapeutic intervention c 2002 Elsevier Science for patients with evidence of biochemical failure following radical prostatectomy remains undefined. s Ltd. All rights reserved.
Key words: PSA recurrence; hormonal therapy.
INTRODUCTION One of the most important consequences of prostatespecific antigen’s (PSA) wide-spread application into clinical practice in the late 1980s, has been a dramatic shift of the prostate cancer disease curve to the left, with significant numbers of patients now being diagnosed with presumed clinically localized disease (1). With the presumption that earlier diagnosis and therapy may result in an increased likelihood of cure, substantial number of patients are undergoing therapy with curative intent (2). In the US, parts of Europe, and around the world significant number of patients will undergo radical prostatectomy as management of localized disease (3,4). Approximately one third of prostate cancer patients with clinically localized disease treated with radical prostatectomy develop evidence of biochemical
Correspondence to: Robert Dreicer, M.D., FACP, Cleveland Clinic Foundation, 9500 Euclid Ave R35, Cleveland, OH 44195, USA, Tel.: +1-216-445-4623; Fax: 1-216-445-2360; E-mail: [email protected]
failure during long-term follow-up (5–8). Thus the down-stream impact of our current prostate cancer screening and therapeutic strategies has created a new subset of prostate cancer patients, those with evidence of disease recurrence, biochemically (PSA) defined, potentially representing thousands of patients/year in the US alone (9,10).
NATURAL HISTORY AND EVALUATION OF PSA RELAPSE The natural history of PSA relapse following radical prostatectomy is poorly understood in part due to the relatively short follow-up available, but more significantly, the confounding effects of salvage radiotherapy and/or hormonal therapy which are administered to a substantial number of patients (11). The limited use of radiation and hormonal therapy in the series reported by Pound et al. makes this the most important report detailing the natural history of biochemical failure following radical
c 2002 ELSEVIER SCIENCE LTD. ALL RIGHTS RESERVED. 0305-7372/02/$ - see front matter s
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prostatectomy. Over a 15-year period, 1997 patients underwent a radical prostatectomy with 304 (15%) subsequently experiencing biochemical failure. Of these 304 patients, 103 (34%) developed metastatic disease. However, none of these patients received hormonal therapy on the basis of an elevated PSA in the absence of clinically evident metastatic disease. The median actuarial time from PSA elevation to metastatic disease was 8 years with the median time to death following development of metastatic disease being approximately 5 years later. Prognostic factors predictive of outcome included the Gleason score on the prostatectomy specimen (high vs. intermediate), time to PSA recurrence (>2 vs. O2 years) and to a lesser extent the PSA doubling time (12). Clinicians evaluating patients with detectable PSA values following radical prostatectomy are faced with the significant challenge of determining whether there is evidence of local vs. systemic relapse. This information would aid in the determination of patients with local recurrence who might be suitable for ‘‘salvage’’ radiotherapy although the utility of this approach is controversial and is beyond the scope of this discussion. In the setting of PSA-only relapse, radionuclide bone scintigraphy and computed tomography (CT) imaging are insufficiently sensitive to distinguish local vs. systemic failure (13,14). The utility of radioimmunoscintigraphy with Indium-111-capromab pendetide to distinguish between local and systemic failures remains controversial. Recent reports suggest sensitivity, specificity and overall accuracy of this study to be in the 75, 86, and 81% range, respectively (15–17). A large study of men with low levels of PSA (0.1–4.0 ng/mL) demonstrated capromab pendetide uptake in 72% of 255 men with 31% of men having evidence of prostatic fossa only uptake (18).
IMMEDIATE VS DELAYED HORMONAL THERAPY Although it is widely recognized that there is no ‘‘standard of care’’ for the management of patients with biochemical failure (presumption of systemic failure) or with PSA progression following ‘‘salvage’’ radiotherapy, androgen-deprivation therapy is frequently prescribed, especially for patients older than 65 (11). The subject of immediate vs. deferred androgen suppression remains controversial and has significant ramifications for the patient (10). An interesting illustration of the uncertainty surrounding this clinical dilemma is exemplified by the report by Wasson et al. In his survey of practicing urologists, more than half of the urologists who stated that did
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not believe that early hormonal therapy impacted on the survival of locally advanced prostate cancer stated that they still prescribed it to their patients (19). For several decades, interpretation of the results from the two Veterans Administration Co-operative Urological Research Group (VACURG) trials have guided the timing of hormonal therapy in patients with advanced prostate cancer (20,21). Walsh et al. reevaluated the findings from both VACURG I and II in an attempt to clarify the role of early vs delayed hormonal therapy (10). VACURG I was a 4 arm blinded trial, which assigned patients with locally advanced and metastatic prostate cancer to placebo, orchiectomy plus placebo, diesthylstilbestrol (DES) 5 mg daily, or orchiectomy plus DES. Walsh and colleagues concentrated on both the placebo and orchiectomy + placebo arms, arguing that the two DES containing arms were exposed to the confounding effect of increased cardiovascular mortality and a possibility that non-compliance may have influenced outcome. In the two non-DES containing arms, 262 patients with locally advanced (T3-4, M0) disease were assigned to placebo and 266 to orchiectomy. In men with metastatic disease 223 were assigned to placebo and 203 patients to orchiectomy. At 9 years follow-up, there was no difference in disease specific or overall survival suggesting a lack of benefit to early hormonal therapy (10). VACURG II randomized over 1500 patients with locally advanced and metastatic disease into four treatment arms: placebo, 0.2, 1, and 5 mg DES daily. The 5 mg arm was terminated early secondary to increased cardiovascular mortality and interpretation of the results of this study suggested a survival benefit to 1 mg of DES compared to placebo or 0.2 mg. Walsh et al. suggest that due to protocol issues, a significant subset of patients assigned to both the placebo and 0.2 mg DES (a dose that is ineffective for suppressing testosterone) arms never received hormonal therapy calling into question whether in fact the question asked by this study was appropriately addressed (10). The three most widely quoted trials used to extrapolate the role of early hormonal therapy to patients with biochemical failure are the EORTC 22863 (Bolla et al.) the Eastern Cooperative Oncology Group (ECOG) node positive study, and the Medical Research Council (MRC) study in locally advanced and metastatic disease. Bolla et al. randomized 401 patients with either high-grade T1-2, NO or T3/4 any grade patients to radiotherapy alone or with combined androgen ablation for 3 years. At 5 years, the survival of patients receiving hormonal/radiotherapy was 79% vs. 62% for radiotherapy alone (22). Other randomized studies of this approach have demonstrating improvement in local control,
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disease-free survival and time to metastatic with some subsets of patients demonstrating improvement in overall survival (23,24). The ECOG performed a randomized, prospective study of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes (25). Patients on the treatment arm received goserelin monthly or underwent orchiectomy. Ninety-eight eligible patients were entered and at a median follow-up of 7.1 years, 7 of 47 men who received immediate antiandrogen therapy had died compared with 18 of 51 in the observation group (P ¼ 0:02). The authors concluded that immediate antiandrogen therapy after radical prostatectomy and pelvic lymphadenectomy improves survival and reduces the risk of recurrence in patients with node positive disease. Critics of this study point to the small sample size, the potential imbalance of the arms noting a relatively low cancerspecific survival rate in the control arm compared to historical series, the lack of central pathologic review and the observation that a larger (currently unpublished) EORTC node positive study of early vs. delayed hormonal therapy has at a median follow-up of 6 years failed to demonstrate a impact on cancer specific or overall survival (10). The MRC performed a randomized trial of immediate vs. deferred therapy for advanced prostate cancer (26). Nine-hundred and thirty-eight patients with incurable local (T2-4) or metastatic disease were randomized to deferred treatment (indications for treatment in deferred patients left to individual physician) vs. hormonal therapy with either orchiectomy or LHRH analogue. At the time of the initial report in 1997, 934 patients were evaluable. Patients in the deferred treatment arm had pathologic fractures, spinal cord compressions and ureteral obstruction at twice the rate of patients in the immediate therapy group. In men with locally advanced disease 32% who received early hormonal therapy died of prostate cancer compared to 49% in the deferred therapy group (P < 0:001), with no significant difference in treatment arms for patients with metastatic disease. The initial reported results of this study have been interpreted by some to suggest clear benefit to early application of hormonal therapy. Critics point out that of the additional 54 cancer deaths in the deferred treatment arm, 29 patients (54%) never received hormonal therapy, although MRC investigators have re-analyzed their data and present a compelling argument that the omission of therapy in these 29 patients did not impact on the observed survival advantage (10,27,28). A recent update of the MRC study demonstrates that while disease-specific survival in the immediate treatment arm remains statistically significant, in contrast to the original report, overall
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survival for patients with locally advanced disease receiving immediate therapy is not significantly different than those in the delayed arm (29). Irrespective of the ultimate validity of the findings of the MRC trial, many observers have commented on the limited applicability of the study’s findings to the current management of patients with prostate cancer, especially in the US, given the frequent assessment of patients with PSA and earlier utilization of hormonal therapy, thereby altering the timing of ‘‘delayed’’ hormonal therapy (30).
ANDROGEN DEPRIVATION: SIDE EFFECTS AND IMPACT ON QUALITY OF LIFE Although androgen deprivation has been the standard of care for the management of advanced prostate cancer for 60 years, there is surprisingly little prospective data available to quantitate the frequency and severity of the side effects associated with this therapeutic intervention. Widely appreciated side effects include: loss of libido and potency, hot flushes, fatigue, anemia, loss of muscle mass, weight gain, and depression (31). More recently, development of osteoporosis has been recognized as a potentially serious consequence of long-term androgen-deprivation therapy with mounting evidence demonstrating both a decrease in bone mineral density and increasing risk of fracture (32–34). This latter concern is amplified both by the increasing numbers of patients receiving treatment and the significantly longer duration of hormonal therapy patients with early biochemical failure are likely to require. Although recent studies have suggested potential beneficial therapeutic interventions such as the use of bisphosphonates (35), the added costs and potential toxicity of additional pharmaceutical interventions used to attempt to mitigate the toxicity of androgen deprivation remains a daunting issue. To date there are only a handful of studies in the literature that speak to the impact of androgen deprivation on the quality of life of in patients with primarily biochemical failure. Herr et al. studied a cohort of 144 men with locally advanced prostate cancer or those with PSA relapse after local therapy. Seventy-nine patients opted to receive androgendeprivation therapy consisting of LHRH analogue therapy with our without flutamide or orchiectomy. Compared to the 65 men who opted to not to receive androgen-deprivation hormonally treated men had more fatigue, loss of energy, emotional distress, and a lower overall quality of life (36). This and other currently available reports are compromised by the lack of prospective randomization and small sample
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size. Quality of life assessments attached to ongoing randomized studies may provide additional insight.
ALTERNATIVE ANDROGEN-DEPRIVATION APPROACHES Given the side effect profile of androgen-deprivation therapy, there is an understandable desire to have it both ways, i.e. to provide potentially life-prolonging therapy with improved quality of life. Two therapeutic strategies that have attracted substantial attention are antiandrogen monotherapy and intermittent androgen deprivation. Hormonal monotherapy using non-steroidal antiandrogens represents a potentially attractive alternative approach to standard testicular androgen suppression for the management of early biochemical failure. In comparison to castration, antiandrogens such as bicalutamide have a significantly better toxicity profile, with more preserved sexual interest and physical capacity and a lower incidence of hot flushes (37). Of the available antiandrogens, monotherapy with bicalutamide (150 mg) has been most extensively studied. Iversen et al. compared bicalutamide at 150 mg/day vs. either orchiectomy or LHRH analogue monotherapy in patients with locally advanced (T3/4) or metastatic prostate cancer. A total of 1453 patients were randomized in two studies and were pooled for analysis. Patients receiving bicalutamide had significant advantages over patients receiving castration for both sexual interest and physical capacity. Bicalutamide monotherapy provided a similar survival outcome to castration for patients with locally advanced disease, however castration provided a 6 week survival benefit in comparison to bicalutamide-treated patients with metastatic disease (38,39). A recent meta-analysis evaluating single-therapy androgen suppression in men with advanced prostate cancer concluded ‘‘survival rates may be somewhat lower if a non-steroidal antiandrogen is used as monotherapy (40).’’ Intermittent androgen deprivation represents another therapeutic strategy to deliver hormonal therapy in patients with biochemical failure with an improved toxicity profile (41). Based upon in vitro and animal model evidence suggesting that intermittent replacement of androgens may result in a delay to development of androgen insensitivity (42,43) various investigators have reported relatively small clinical experiences with this approach (44,45). Grossfeld et al. reported their experience with intermittent hormonal therapy in 61 patients with rising PSA values without clinical apparent metastatic disease (46). Patients received from one
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to five treatment cycles (median two), with a median cycle length of 14 months. Patients spent an average of 45% of the time-off hormonal therapy, but the time off therapy decreased with each successive treatment cycle. With an average follow-up of 30 months, 5 patients (8.1%) demonstrated progressive disease. Although conceptually attractive, there is currently no prospective evidence demonstrating that the intermittent approach is either equivalent or superior to standard hormonal therapy in terms of survival. The South West Oncology Group (SWOG) is currently leading an Intergroup trial (S9346) of continuous vs. intermittent hormonal therapy in patients with advanced metastatic prostate cancer that will hopefully provide evidence either supporting or refuting this management strategy.
INVESTIGATIONAL OPTIONS Irrespective of the debate regarding early vs. delayed hormonal therapy for biochemical failure, there is no argument that hormonal therapy administered in this setting is at best a temporizing measure even if it provides a modest survival advantage. Given that this patient subset has no clear standard of care and the typical patient is anxious and motivated it would seem to represent an ideal group in which to conduct clinical trials of non-hormonal options. When examined closer however, confounding issues present unique challenges. One obvious problem is the definition of the optimal PSA level that ultimately translates into clinically evident disease. Although this issue is most problematic for patients undergoing radiotherapy there is still limited data and no consensus in patients treated with radical prostatectomy (47,48). An additional critical issue is the utility and reliability of PSA, especially at relatively low levels to be used as a response parameter. (49,50). From a pragmatic perspective, the investigational therapy proposed must not be either unduly toxic or cumbersome to administer as we are dealing with a patient population that is asymptomatic (at least physically) and many continue to work or have active lifestyles. Among the agents currently undergoing evaluation is exisulind a selective, apoptotic antineoplastic drug. Goluboff et al. performed a small phase III trial in 96 men with increasing PSA after radical prostatectomy (51). Patients were randomized to receive placebo or 250 mg. exisulind twice daily for 12 months. Compared with placebo, exisulind significantly suppressed the increase in PSA in all patients (P ¼ 0:017) and the median PSA doubling time was lengthened in high risk patients on exisulind
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(2.12 month increase) compared with those on placebo (3.37 month decrease, P ¼ 0:048). Therapy was well tolerated and additional evaluation of this agent is ongoing. Other studies including vaccine trials and other targeted therapy agents are ongoing.
CONCLUSIONS Patients presenting with biochemical failure after prostatectomy represent a vexing challenge to urologists, medical and radiation oncologists. The patients feel well, they know that despite aggressive local therapy they may not be cured and they are understandably anxious. The role of hormonal therapy in this setting remains unclear and the impact of androgen deprivation on individual patients quality of life is not insignificant. Extrapolating the results of the ECOG node positive study and the MRC studies to earlier disease stages is problematic. The use of antiandrogen monotherapy or intermittent androgen deprivation in this setting (therapies not yet demonstrated to be as effective as conventional androgen deprivation) adds additional uncertainty. Motivated patients should be offered entry onto ongoing clinical trials. For the majority of patients for whom clinical trial entry is either not feasible or desired a liberal application of the art of medicine, including a practical discussion of the limited current body of evidence, the side effect profile and potential impact on quality of life of hormonal therapy must be the starting point for a difficult decision process.
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