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Long-Term Hormonal Therapy: Who Would Benefit?
EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) 695–700
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Long-Term Hormonal Therapy: Who Would Benefit? Franc¸ois Desgrandchamps * Department of Urology, Saint-Louis Hospital, Paris, France
Article info
Abstract
Keywords: Adjuvant Androgen deprivation Metastatic prostate cancer Orchiectomy Palliative Prostatectomy Survival
Traditionally, the role of hormonal therapy (HT) for prostate cancer (PCa) has been the palliative treatment of advanced and metastatic disease. Recently, advances in the development of androgen-deprivation therapy (ADT) with luteinising hormone-releasing hormone (LHRH) agonists have made LHRH agonists the standard of care for 90% of men with advanced or metastatic PCa. Although the role of ADT is historically well defined, recent studies demonstrate that the treatment of advanced or metastatic PCa with ADT can be tailored to the needs of the patient. This may be achieved by the immediate or deferred initiation of ADT (orchiectomy or LHRH agonist treatment) depending upon the nature of the disease and the patient’s age. Patients who are likely to die of non-PCa-related causes prior to an indication for treatment initiation, for example, may benefit from deferred treatment, which may spare them the burden of treatment-related adverse events. In contrast, patients who are likely to die of PCa-related causes may benefit from immediate treatment because this option may delay disease progression and reduce symptom burden. Additionally, recent studies have shown that prognostic disease markers such as prostate-specific antigen (PSA) and PSA doubling time (PSA DT) can be used as indicators of who may receive the greatest benefit from treatment. Patients with a high baseline PSA level or a short PSA DT (markers of aggressive and/or advanced disease), for example, are more likely to die of disease-related causes than patients with low baseline PSA levels or long PSA DT. Furthermore, recent studies have shown that HT may be used successfully in adjuvant settings for patients in earlier stages of the disease and/or who require radical treatment. This paper reviews which patients can benefit from HT in terms of treatment timing, baseline prognostic indicators, disease stage, and adjuvant use. # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved.
* Tel. +33 1 42 49 96 21; Fax: +33 1 42 49 96 16 E-mail address: [email protected]
1.
Introduction
From the early debates on the optimal dose of diethylstilbesterol and the treatment of asymptomatic versus symptomatic prostate cancer (PCa) in the 1940s to the postmillennium development of long-acting luteinising hormone-releasing hormone (LHRH) agonists, the traditional role of hormonal therapy (HT) for PCa has been the
palliative treatment of metastatic disease via androgen deprivation and the induction of prostate cell apoptosis. In recent years, androgen-deprivation therapy (ADT) with LHRH agonists has been the standard of care for 90% of men with advanced or metastatic PCa [1]. Furthermore, it is now being used increasingly in younger patients with advanced PCa and in those with relapse in prostate-specific antigen (PSA) levels after local therapy [2,3]. In addition to
1569-9056/$ – see front matter # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eursup.2010.08.003
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EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) 695–700
this palliative use in advanced or metastatic PCa, HT is being utilised in the adjuvant setting in patients with earlier stages of disease requiring radical treatment [2,3]. In this paper, we will describe which patients with PCa can benefit from HT, according to disease stage and time of treatment, in terms of immediate versus deferred treatment, PSA levels at diagnosis, and as an adjuvant to radical prostatectomy (RP) or radiation therapy (RT). 2.
Immediate versus deferred hormonal therapy
The current European guidelines for the treatment of PCa [2] support the use of HT for the treatment of both symptomatic and asymptomatic metastatic disease. However, the question of whether it is better to initiate HT in patients with asymptomatic metastatic PCa at diagnosis (immediate treatment) or only when symptoms become present (deferred treatment) has been the subject of much debate. Immediate treatment is given in the hope of delaying symptoms and/or disease progression. Conversely, treatment may be deferred because elderly patients may die of non-PCa-related causes prior to the emergence of PCa symptoms and therefore can be spared the burden of HT-related adverse events (AEs). This debate was answered in part by a study conducted by the Medical Research Council [4] that compared immediate and deferred HT in HT-naı¨ve patients with local PCa considered too advanced for curative treatment (T2–T4) or asymptomatic metastatic PCa. Patients were randomised to receive (1) immediate ADT with either orchiectomy or an LHRH agonist or (2) the same treatment deferred until an indication to commence HT occurred. Death from any cause occurred in significantly more patients (two-tailed p < 0.01) randomised to deferred treatment (77.6%), compared with immediate treatment (69.9%). However, the benefit of immediate treatment was only significant in patients with M0 disease. Similarly, the rate of PCa-related death was significantly lower (two-tailed p < 0.001) with immediate treatment (61.9%), compared with deferred treatment (71.1%), in [(Fig._1)TD$IG]patients with M0 disease (Fig. 1). Distant progression to
metastatic disease was also significantly lower (two-tailed p < 0.001) with immediate treatment (96 cases of progression) in patients with M0 disease, compared with deferred treatment (114 cases of progression). A similar benefit was seen for local progression. Significantly fewer patients (twotailed p < 0.001) treated immediately underwent transurethral RP (TURP) compared with those whose treatment was deferred (65 versus 141 patients). In addition, the incidence of common complications in the immediate treatment group was approximately half that of the deferred treatment group (spinal cord compression, twotailed p < 0.025; ureteric obstruction, two-tailed p < 0.025; extraskeletal metastases, two-tailed p < 0.05). It was also observed that 11% of patients with deferred treatment died from non-PCa-related causes before an indication for treatment arose. The data from this study support the use of immediate treatment with HT. However, the study shows that there are patients, often >70 yr of age, who may not benefit from immediate HT, as they would die from non-PCa-related causes before an indication for initiation of deferred HT occurred. Such patients could be spared the burden of the AEs associated with HT if a deferred treatment regimen was used. The benefits of early versus deferred ADT for the treatment of patients with any stage nonmetastatic PCa not suitable for local treatment with curative intent were also demonstrated by a European Organisation for Research and Treatment of Cancer (EORTC) trial [5]. Patients were randomised to immediate or deferred treatment (until the time of symptomatic disease progression or serious complication) with subcapsular orchiectomy or subcutaneous injections of the LHRH agonist buserelin (6.3 mg) every 2 mo. At the time of analysis, 52.2% of patients receiving ADT and 57.6% of patients receiving deferred ADT had died [5]. The intent-to-treat analysis failed to prove noninferiority for deferred treatment (median overall survival time: 6.5 yr; 95% confidence interval [CI], 5.9–7.2 yr), compared with immediate treatment (median overall survival time: 7.4 yr; 95% CI, 6.6–8.5 yr; noninferiority, p = 0.43) (mortality hazard ratio [HR]: 1.25; 95% CI, 1.05–1.48). Furthermore,
Fig. 1 – Prostate cancer–related deaths with immediate versus delayed treatment in patients with advanced prostate cancer. Reproduced with permission from [4].
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[(Fig._2)TD$IG]
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the survival benefit of immediate ADT remained significant when adjusted for baseline risk factors (age, performance status, voiding symptoms, T stage, tumour grade, PSA 20 ng/ml, TURP, and associated chronic disease) (HR: 1.29; 95% CI, 1.09–1.53). In addition, the cumulative incidences of subjective and objective disease progression after entry were significantly lower ( p < 0.0001 for both end points) in patients receiving immediate treatment versus deferred treatment. Despite these results [5], the comparison of PCa-related deaths between the two treatments was nonsignificant. However, this may have been due to the limited statistical power of the number of PCa-related deaths during the study. A further analysis of this trial [6] revealed that PSA levels and PSA doubling time (PSA DT) can also be used as a guide for timing initiation of ADT for PCa. 3. Hormonal therapy in patients with a high PSA level and/or a short PSA doubling time When the risk of death from PCa-related causes in the EORTC 30891 trial was stratified by baseline PSA level, it was evident that patients with a baseline PSA level >50 ng/ml were at a greater risk than those with a baseline PSA level < 8 ng/ml (Fig. 2; immediate treatment HR: 4.3; 95% CI, 2.1–9.1; p < 0.0001; deferred treatment HR: 3.5; 95% CI, 1.9–6.6; p < 0.0001) [6]. Furthermore, increasing baseline PSA levels were associated with numerically, but not significantly, higher HRs of PCa-related death in deferred versus immediate treatment (PSA 8.1–20 ng/ml, HR: 1.18; 95% CI, 0.67–2.10; PSA 20.1–50 ng/ml, HR: 1.40; 95% CI, 0.79–2.50; PSA >50 ng/ml, HR: 1.44; 95% CI, 0.86–2.41). There was also a significant association ( p < 0.001) between increasing baseline PSA levels and earlier or more frequent initiation of deferred therapy. Additionally, an analysis of the rate of PCa-related death in patients stratified by PSA DT showed that patients with a PSA DT 12 mo were 7.5 times (95% CI, 3.3–17.2) more likely to die of PCa-related causes than patients with a PSA DT < 12 mo (PSA DT 12 mo, 7-yr PCa-mortality: 47.6%; 95% CI, 28.4–70.5%; PSA DT >12 mo, 7-yr PCa-mortality: 11.4%; 95% CI, 4.9–17.9%). Taken collectively, these data indicate that patients with a baseline PSA >50 ng/ml and/or a PSA DT 12 mo may benefit from immediate ADT, whereas patients with a baseline PSA < 50 ng/ml and a PSA DT >12 mo are likely to die of causes unrelated to PCa and may potentially be spared the burden of immediate ADT. 4. Hormonal therapy as an adjuvant to radical prostatectomy The appropriateness of immediate versus deferred ADT (goserelin 3.6 mg monthly or bilateral orchiectomy) in the treatment of patients with node-positive PCa who have undergone RP and pelvic lymphadenectomy was investigated in approximately 100 patients in a multicentre study in the United States [7]. After a median follow-up time of 11.9 yr (range for surviving patients: 9.7–14.5 yr),
Fig. 2 – Baseline prostate-specific antigen (PSA) levels as a prognostic marker of mortality in (A) immediate and (B) deferred treatment. Reprinted from [6], Copyright (2008), with permission from Elsevier.
immediate ADT showed a significant benefit in terms of overall survival (HR: 1.84; 95% CI, 1.01–3.35; p = 004), PCa-specific survival (HR: 4.09; 95% CI, 1.76–9.49; p = 0.0004), and progression-free survival (HR: 3.42; 95% CI, 1.96–5.98; p < 0.0001) (Fig. 3). These data suggest that early ADT benefits patients who have nodal metastases and who have had a prostatectomy and lymphadenectomy. In contrast, results from a retrospective observational study of patients with PSA relapse who had undergone RP [8] demonstrated no significant clinical benefit for early HT (initiated when PSA 5 ng/ml) versus late HT (initiated upon identification of bone metastases) in terms of metastasis-free survival. However, when the patients were stratified by risk, patients with a Gleason score >7 and those with a PSA DT 12 mo received a significant benefit ( p = 0.004) in terms of metastasis-free survival, compared with patients treated with late HT. 5.
Hormonal therapy as an adjuvant to RT
The role of HT as an adjuvant to RT was highlighted in a study of patients with locally advanced (clinical stage T3) PCa who were randomised to treatment with RT alone (total
[(Fig._3)TD$IG]
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Fig. 3 – Immediate versus deferred androgen-deprivation therapy (ADT) in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. CI = confidence interval. Reprinted from [7], Copyright (2006), with permission from Elsevier.
EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) 695–700
[(Fig._4)TD$IG]
699
6. Long-term versus short-term androgendeprivation therapy with radiation therapy
Fig. 4 – Overall survival rates in patients with prostate cancer treated with either radiation therapy (RT) with hormonal therapy (HT) at relapse or with RT with adjuvant HT. Reprinted from [9], Copyright (2005), with permission from Elsevier.
dose: 67–70 Gy), treatment with goserelin (3.6 mg at relapse), or RT with indefinite goserelin (3.6 mg) adjuvant therapy [9]. After 10 yr, patients treated with RT and adjuvant goserelin showed significant benefits in terms of overall survival (49% vs 39%, respectively; p = 0.002), disease-specific mortality (16% vs 22%, respectively; p < 0.0052), and the incidence rate of distant metastases (24% vs 39%, respectively; p < 0.001) (Fig. 4). Furthermore, a benefit of continuing goserelin HT for a period of 2 yr after RT with 2 mo of concomitant goserelin therapy was demonstrated in patients with locally advanced PCa (clinical stage T2c–T4) [10]. With the exception of overall survival, several significant benefits were observed for extended HT, including disease-free survival ( p < 0.0001), disease-specific survival ( p = 0.0042), local progression ( p < 0.0001), and distant metastases ( p < 0.0001). However, a significant improvement in overall survival was noted with additional goserelin HT in patients with a Gleason score 8 ( p = 0.0061). Further support for long-term androgen suppression with LHRH agonists can be taken from the EORTC 22863 trial [11], in which patients with newly diagnosed PCa (T1–2 [World Health Organisation histologic grade 3] or T3–4 [any histologic grade]) were randomly assigned to receive either RT alone or RT in conjunction with immediate LHRH agonist (goserelin) treatment. The assigned treatments involved photonic radiation (once daily for 5 d/wk for a period of 7 wk; recommended exposure: 10 MV) of the whole pelvis (first planning target volume: 50-Gy radiation) and the prostate and seminal vesicles (second planning target volume: 20-Gy radiation). Goserelin (3.6 mg administered subcutaneously every 4 wk) was administered on the first day of pelvic irradiation and continued for 3 yr. Combined treatment provided significantly favourable outcomes, compared with RT alone, for overall survival (5-yr survival: 78% vs 62%; p = 0.0002; HR: 0.51; 95% CI, 0.36–0.73), specific survival (5-yr survival: 94% vs 79%; p = 0.0001; HR: 0.26; 95% CI, 0.15–0.44), and clinical disease-free survival (5-yr survival: 74% vs 40%; p < 0.0001; HR: 0.34; 95% CI, 0.26–0.46), among other end points.
Although there is a wealth of supportive evidence for the use of long-term (2 yr) ADT in conjunction with RT versus RT alone for the treatment of PCa, the use of long-term ADT is associated with numerous AEs. The risk of some of these AEs may be reduced with the replacement of long-term ADT with short-term ADT (6 mo), which has also been shown to improve outcomes in patients with localised PCa [12]. This hypothesis was tested in a study by the EORTC [13] that investigated the overall survival rates of patients with locally advanced PCa (stage T1c–T2a-b N1–2 M0 or stage T2c–T4 N0–2 M0) who were treated with RT in conjunction with either short- or long-term ADT with a LHRH agonist. All patients received treatment with photonic radiation (once daily for 5 d/wk for a period of 7 wk; recommended exposure: 10 MV) of the whole pelvis (first planning target volume: 50 Gy radiation) and the prostate and seminal vesicles (second planning target volume: 20 Gy radiation) in conjunction with an LHRH agonist (initiated on the first day of irradiation) for a period of 6 mo (short-term therapy). Patients who were randomised to receive long-term treatment were then subsequently treated with the LHRH agonist for a further 2.5 yr. Long-term treatment with an LHRH agonist provided favourable outcomes, compared with short-term therapy, for overall survival (5-yr overall mortality: 15.2% [95% CI, 12.1–18.9] vs 19.0% [95% CI, 15.5–23.0]; HR: 1.42; upper 95.71% CI, 1.79; noninferiority, p = 0.65]), PCa-specific survival (5-yr, HR: 1.71; 95% CI, 1.14–2.57; log-rank p = 0.002), PCa-specific mortality (5-yr: 3.2% [95% CI, 1.6–4.8] vs 4.7% [95% CI, 2.7–6.7]), and mortality unrelated to PCa (5-yr: 7.4% [95% CI, 5.0–9.9] vs 9.0% [95% CI, 6.3–11.7]; HR: 1.3; 95% CI, 0.98–1.2). These results indicate that short-term androgen suppression is inferior to long-term androgen suppression when combined with RT. The efficacy of RT in combination with HT for the treatment of patients with high-risk PCa was also demonstrated in an open, randomised phase 3 study by the Scandinavian Prostate Cancer Group and the Swedish Association for Urological Oncology [14]. Patients with high-risk PCa (T1b–T2, G2–G3, or T3; PSA 70 ng/ml; N0 M0) received ADT treatment with an LHRH agonist (leuprorelin, 3.75 mg/mo or 11.25 mg every 3 mo) for a period of 3 mo. Subsequently, patients randomised to ADT treatment combined with RT received standard threedimensional conformal RT to the prostate and the seminal vesicles (first planning target volume: 50 Gy) with a sequential boost (20 Gy) to the prostate (second planning volume, total minimum dose: 70 Gy). The 7-yr incidence rate of PCa-specific mortality was 9.9% (95% CI, 7.1–12.8%) in patients treated with HT only and 6.3% (95% CI, 3.9–8.6%) in patients who received HT plus RT (treatment difference: 3.7%; 95% CI, 0.0–7.4%). The corresponding rates after 10 yr were 23.9% (95% CI, 18.4–29.4%) and 11.9% (95% CI, 7.4– 16.5%) with a between-treatment difference of 12.0% and showed a significant relative risk of 0.44 (95% CI,
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0.30–0.66; p < 0.001) in favour of combined treatment. Similarly, the rate of overall mortality after 7 and 10 yr was higher in patients treated with HT only (20.1% [95% CI, 16.2–23.9%] and 39.4% [95% CI, 33.0–45.7%], respectively), compared with patients who received HT and RT in combination (16.5% [95% CI, 12.9–20.1%] and 29.6% [95% CI, 23.3–36.0%], respectively). This resulted in a significantly lower ( p = 0.004) relative risk of overall mortality after 10 yr of follow-up (HR: 0.68; 95% CI, 0.52–0.89) with combined treatment versus HT alone. Combined treatment, compared with HT alone, also significantly reduced ( p < 0.001) the probability of 10-yr follow-up PSA recurrence (HR: 0.16; 95% CI, 0.12–0.20). These data clearly demonstrate the benefits of RT in combination with HT in patients with nonmetastatic locally advanced or prostate-confined PCa with aggressive pathology.
References [1] Boccon-Gibod L, Hammerer P, Madersbacher S, Mottet N, PrayerGaletti T, Tunn U. The role of intermittent androgen deprivation in prostate cancer. BJU Int 2007;100:738–43. [2] Heidenreich A, Bolla M, Joniau S, et al. Guidelines on prostate cancer. European Association of Urology Web site. http://www. uroweb.org/fileadmin/tx_eauguidelines/2009/Full/Prostate_Cancer. pdf. Updated 2009. Accessed July 12, 2010. [3] Tunn U. Can intermittent hormone therapy fulfil its promise? Eur Urol Suppl 2008;7:752–7. [4] The 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 1997;79:235–46. [5] Studer UE, Whelan P, Albrecht W, et al. Immediate or deferred androgen deprivation for patients with prostate cancer not suitable for local treatment with curative intent: European Organisation for Research and Treatment of Cancer (EORTC) trial 30891. J Clin Oncol 2006;24:1868–76.
7.
Conclusions
These studies demonstrate that specific populations of patients with PCa will benefit differently from HT. A patient can benefit from ADT in two ways, either through an improvement in disease control or through an increase in survival. Practically all metastatic patients will benefit from ADT, but a population of nonmetastatic patients can also expect a benefit. Patients with a PSA >50 ng/ml or between 8 and 50 ng/ml and PSA DT < 12 mo will benefit from ADT alone. ADT can also bring a benefit to patients either when combined with surgery—in node-positive patients or with a PSA relapse in patients with Gleason sum >7 and or PSA DT < 12 mo—or in combination with RT in locally advanced or high-risk patients.
[6] Studer UE, Collette L, Whelan P, et al. Using PSA to guide timing of androgen deprivation in patients with T0-4 N0-2 M0 prostate cancer not suitable for local curative treatment (EORTC 30891). Eur Urol 2008;53:941–9. [7] Messing EM, Manola J, Yao J, et al. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate
cancer
after
radical
prostatectomy
and
pelvic
lymphadenectomy. Lancet Oncol 2006;7:472–9. [8] Moul JW, Wu H, Sun L, et al. Early versus delayed hormonal therapy for prostate specific antigen only recurrence of prostate cancer after radical prostatectomy. J Urol 2004;171:1141–7. [9] Pilepich MV, Winter K, Lawton CA, et al. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma—longterm results of phase III RTOG 85-31. Int J Radiat Oncol Biol Phys 2005;61:1285–90. [10] Horwitz EM, Bae K, Hanks GE, et al. Ten-year follow-up of radiation therapy oncology group protocol 92-02: a phase III trial of the duration of elective androgen deprivation in locally advanced
Conflicts of interest Professor Desgrandchamps received an honorarium for speaking at Orion Pharma’s symposium at the European Association of Urology (EAU) annual congress. The honorarium was governed by the EAU committee.
prostate cancer. J Clin Oncol 2008;26:2497–504. [11] Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002;360:103–6. [12] Roach III M, Bae K, Speight J, et al. Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610.
Funding support Orion Pharma supported medical writing services for the preparation and review of this supplement. Medical writing services provided by David Candlish and Andrew Stead (inScience Communications, a Wolters Kluwer business).
J Clin Oncol 2008;26:585–91. [13] Bolla M, de Reijke TM, Van Tienhoven G, et al. Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med 2009;360:2516–27. [14] Widmark A, Klepp O, Solberg A, et al. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/ SFUO-3): an open randomised phase III trial. Lancet 2009;373:301–8.
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Long-Term Hormonal Therapy: Who Would Benefit? Franc¸ois Desgrandchamps * Department of Urology, Saint-Louis Hospital, Paris, France
Article info
Abstract
Keywords: Adjuvant Androgen deprivation Metastatic prostate cancer Orchiectomy Palliative Prostatectomy Survival
Traditionally, the role of hormonal therapy (HT) for prostate cancer (PCa) has been the palliative treatment of advanced and metastatic disease. Recently, advances in the development of androgen-deprivation therapy (ADT) with luteinising hormone-releasing hormone (LHRH) agonists have made LHRH agonists the standard of care for 90% of men with advanced or metastatic PCa. Although the role of ADT is historically well defined, recent studies demonstrate that the treatment of advanced or metastatic PCa with ADT can be tailored to the needs of the patient. This may be achieved by the immediate or deferred initiation of ADT (orchiectomy or LHRH agonist treatment) depending upon the nature of the disease and the patient’s age. Patients who are likely to die of non-PCa-related causes prior to an indication for treatment initiation, for example, may benefit from deferred treatment, which may spare them the burden of treatment-related adverse events. In contrast, patients who are likely to die of PCa-related causes may benefit from immediate treatment because this option may delay disease progression and reduce symptom burden. Additionally, recent studies have shown that prognostic disease markers such as prostate-specific antigen (PSA) and PSA doubling time (PSA DT) can be used as indicators of who may receive the greatest benefit from treatment. Patients with a high baseline PSA level or a short PSA DT (markers of aggressive and/or advanced disease), for example, are more likely to die of disease-related causes than patients with low baseline PSA levels or long PSA DT. Furthermore, recent studies have shown that HT may be used successfully in adjuvant settings for patients in earlier stages of the disease and/or who require radical treatment. This paper reviews which patients can benefit from HT in terms of treatment timing, baseline prognostic indicators, disease stage, and adjuvant use. # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved.
* Tel. +33 1 42 49 96 21; Fax: +33 1 42 49 96 16 E-mail address: [email protected]
1.
Introduction
From the early debates on the optimal dose of diethylstilbesterol and the treatment of asymptomatic versus symptomatic prostate cancer (PCa) in the 1940s to the postmillennium development of long-acting luteinising hormone-releasing hormone (LHRH) agonists, the traditional role of hormonal therapy (HT) for PCa has been the
palliative treatment of metastatic disease via androgen deprivation and the induction of prostate cell apoptosis. In recent years, androgen-deprivation therapy (ADT) with LHRH agonists has been the standard of care for 90% of men with advanced or metastatic PCa [1]. Furthermore, it is now being used increasingly in younger patients with advanced PCa and in those with relapse in prostate-specific antigen (PSA) levels after local therapy [2,3]. In addition to
1569-9056/$ – see front matter # 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eursup.2010.08.003
696
EUROPEAN UROLOGY SUPPLEMENTS 9 (2010) 695–700
this palliative use in advanced or metastatic PCa, HT is being utilised in the adjuvant setting in patients with earlier stages of disease requiring radical treatment [2,3]. In this paper, we will describe which patients with PCa can benefit from HT, according to disease stage and time of treatment, in terms of immediate versus deferred treatment, PSA levels at diagnosis, and as an adjuvant to radical prostatectomy (RP) or radiation therapy (RT). 2.
Immediate versus deferred hormonal therapy
The current European guidelines for the treatment of PCa [2] support the use of HT for the treatment of both symptomatic and asymptomatic metastatic disease. However, the question of whether it is better to initiate HT in patients with asymptomatic metastatic PCa at diagnosis (immediate treatment) or only when symptoms become present (deferred treatment) has been the subject of much debate. Immediate treatment is given in the hope of delaying symptoms and/or disease progression. Conversely, treatment may be deferred because elderly patients may die of non-PCa-related causes prior to the emergence of PCa symptoms and therefore can be spared the burden of HT-related adverse events (AEs). This debate was answered in part by a study conducted by the Medical Research Council [4] that compared immediate and deferred HT in HT-naı¨ve patients with local PCa considered too advanced for curative treatment (T2–T4) or asymptomatic metastatic PCa. Patients were randomised to receive (1) immediate ADT with either orchiectomy or an LHRH agonist or (2) the same treatment deferred until an indication to commence HT occurred. Death from any cause occurred in significantly more patients (two-tailed p < 0.01) randomised to deferred treatment (77.6%), compared with immediate treatment (69.9%). However, the benefit of immediate treatment was only significant in patients with M0 disease. Similarly, the rate of PCa-related death was significantly lower (two-tailed p < 0.001) with immediate treatment (61.9%), compared with deferred treatment (71.1%), in [(Fig._1)TD$IG]patients with M0 disease (Fig. 1). Distant progression to
metastatic disease was also significantly lower (two-tailed p < 0.001) with immediate treatment (96 cases of progression) in patients with M0 disease, compared with deferred treatment (114 cases of progression). A similar benefit was seen for local progression. Significantly fewer patients (twotailed p < 0.001) treated immediately underwent transurethral RP (TURP) compared with those whose treatment was deferred (65 versus 141 patients). In addition, the incidence of common complications in the immediate treatment group was approximately half that of the deferred treatment group (spinal cord compression, twotailed p < 0.025; ureteric obstruction, two-tailed p < 0.025; extraskeletal metastases, two-tailed p < 0.05). It was also observed that 11% of patients with deferred treatment died from non-PCa-related causes before an indication for treatment arose. The data from this study support the use of immediate treatment with HT. However, the study shows that there are patients, often >70 yr of age, who may not benefit from immediate HT, as they would die from non-PCa-related causes before an indication for initiation of deferred HT occurred. Such patients could be spared the burden of the AEs associated with HT if a deferred treatment regimen was used. The benefits of early versus deferred ADT for the treatment of patients with any stage nonmetastatic PCa not suitable for local treatment with curative intent were also demonstrated by a European Organisation for Research and Treatment of Cancer (EORTC) trial [5]. Patients were randomised to immediate or deferred treatment (until the time of symptomatic disease progression or serious complication) with subcapsular orchiectomy or subcutaneous injections of the LHRH agonist buserelin (6.3 mg) every 2 mo. At the time of analysis, 52.2% of patients receiving ADT and 57.6% of patients receiving deferred ADT had died [5]. The intent-to-treat analysis failed to prove noninferiority for deferred treatment (median overall survival time: 6.5 yr; 95% confidence interval [CI], 5.9–7.2 yr), compared with immediate treatment (median overall survival time: 7.4 yr; 95% CI, 6.6–8.5 yr; noninferiority, p = 0.43) (mortality hazard ratio [HR]: 1.25; 95% CI, 1.05–1.48). Furthermore,
Fig. 1 – Prostate cancer–related deaths with immediate versus delayed treatment in patients with advanced prostate cancer. Reproduced with permission from [4].
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the survival benefit of immediate ADT remained significant when adjusted for baseline risk factors (age, performance status, voiding symptoms, T stage, tumour grade, PSA 20 ng/ml, TURP, and associated chronic disease) (HR: 1.29; 95% CI, 1.09–1.53). In addition, the cumulative incidences of subjective and objective disease progression after entry were significantly lower ( p < 0.0001 for both end points) in patients receiving immediate treatment versus deferred treatment. Despite these results [5], the comparison of PCa-related deaths between the two treatments was nonsignificant. However, this may have been due to the limited statistical power of the number of PCa-related deaths during the study. A further analysis of this trial [6] revealed that PSA levels and PSA doubling time (PSA DT) can also be used as a guide for timing initiation of ADT for PCa. 3. Hormonal therapy in patients with a high PSA level and/or a short PSA doubling time When the risk of death from PCa-related causes in the EORTC 30891 trial was stratified by baseline PSA level, it was evident that patients with a baseline PSA level >50 ng/ml were at a greater risk than those with a baseline PSA level < 8 ng/ml (Fig. 2; immediate treatment HR: 4.3; 95% CI, 2.1–9.1; p < 0.0001; deferred treatment HR: 3.5; 95% CI, 1.9–6.6; p < 0.0001) [6]. Furthermore, increasing baseline PSA levels were associated with numerically, but not significantly, higher HRs of PCa-related death in deferred versus immediate treatment (PSA 8.1–20 ng/ml, HR: 1.18; 95% CI, 0.67–2.10; PSA 20.1–50 ng/ml, HR: 1.40; 95% CI, 0.79–2.50; PSA >50 ng/ml, HR: 1.44; 95% CI, 0.86–2.41). There was also a significant association ( p < 0.001) between increasing baseline PSA levels and earlier or more frequent initiation of deferred therapy. Additionally, an analysis of the rate of PCa-related death in patients stratified by PSA DT showed that patients with a PSA DT 12 mo were 7.5 times (95% CI, 3.3–17.2) more likely to die of PCa-related causes than patients with a PSA DT < 12 mo (PSA DT 12 mo, 7-yr PCa-mortality: 47.6%; 95% CI, 28.4–70.5%; PSA DT >12 mo, 7-yr PCa-mortality: 11.4%; 95% CI, 4.9–17.9%). Taken collectively, these data indicate that patients with a baseline PSA >50 ng/ml and/or a PSA DT 12 mo may benefit from immediate ADT, whereas patients with a baseline PSA < 50 ng/ml and a PSA DT >12 mo are likely to die of causes unrelated to PCa and may potentially be spared the burden of immediate ADT. 4. Hormonal therapy as an adjuvant to radical prostatectomy The appropriateness of immediate versus deferred ADT (goserelin 3.6 mg monthly or bilateral orchiectomy) in the treatment of patients with node-positive PCa who have undergone RP and pelvic lymphadenectomy was investigated in approximately 100 patients in a multicentre study in the United States [7]. After a median follow-up time of 11.9 yr (range for surviving patients: 9.7–14.5 yr),
Fig. 2 – Baseline prostate-specific antigen (PSA) levels as a prognostic marker of mortality in (A) immediate and (B) deferred treatment. Reprinted from [6], Copyright (2008), with permission from Elsevier.
immediate ADT showed a significant benefit in terms of overall survival (HR: 1.84; 95% CI, 1.01–3.35; p = 004), PCa-specific survival (HR: 4.09; 95% CI, 1.76–9.49; p = 0.0004), and progression-free survival (HR: 3.42; 95% CI, 1.96–5.98; p < 0.0001) (Fig. 3). These data suggest that early ADT benefits patients who have nodal metastases and who have had a prostatectomy and lymphadenectomy. In contrast, results from a retrospective observational study of patients with PSA relapse who had undergone RP [8] demonstrated no significant clinical benefit for early HT (initiated when PSA 5 ng/ml) versus late HT (initiated upon identification of bone metastases) in terms of metastasis-free survival. However, when the patients were stratified by risk, patients with a Gleason score >7 and those with a PSA DT 12 mo received a significant benefit ( p = 0.004) in terms of metastasis-free survival, compared with patients treated with late HT. 5.
Hormonal therapy as an adjuvant to RT
The role of HT as an adjuvant to RT was highlighted in a study of patients with locally advanced (clinical stage T3) PCa who were randomised to treatment with RT alone (total
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Fig. 3 – Immediate versus deferred androgen-deprivation therapy (ADT) in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. CI = confidence interval. Reprinted from [7], Copyright (2006), with permission from Elsevier.
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6. Long-term versus short-term androgendeprivation therapy with radiation therapy
Fig. 4 – Overall survival rates in patients with prostate cancer treated with either radiation therapy (RT) with hormonal therapy (HT) at relapse or with RT with adjuvant HT. Reprinted from [9], Copyright (2005), with permission from Elsevier.
dose: 67–70 Gy), treatment with goserelin (3.6 mg at relapse), or RT with indefinite goserelin (3.6 mg) adjuvant therapy [9]. After 10 yr, patients treated with RT and adjuvant goserelin showed significant benefits in terms of overall survival (49% vs 39%, respectively; p = 0.002), disease-specific mortality (16% vs 22%, respectively; p < 0.0052), and the incidence rate of distant metastases (24% vs 39%, respectively; p < 0.001) (Fig. 4). Furthermore, a benefit of continuing goserelin HT for a period of 2 yr after RT with 2 mo of concomitant goserelin therapy was demonstrated in patients with locally advanced PCa (clinical stage T2c–T4) [10]. With the exception of overall survival, several significant benefits were observed for extended HT, including disease-free survival ( p < 0.0001), disease-specific survival ( p = 0.0042), local progression ( p < 0.0001), and distant metastases ( p < 0.0001). However, a significant improvement in overall survival was noted with additional goserelin HT in patients with a Gleason score 8 ( p = 0.0061). Further support for long-term androgen suppression with LHRH agonists can be taken from the EORTC 22863 trial [11], in which patients with newly diagnosed PCa (T1–2 [World Health Organisation histologic grade 3] or T3–4 [any histologic grade]) were randomly assigned to receive either RT alone or RT in conjunction with immediate LHRH agonist (goserelin) treatment. The assigned treatments involved photonic radiation (once daily for 5 d/wk for a period of 7 wk; recommended exposure: 10 MV) of the whole pelvis (first planning target volume: 50-Gy radiation) and the prostate and seminal vesicles (second planning target volume: 20-Gy radiation). Goserelin (3.6 mg administered subcutaneously every 4 wk) was administered on the first day of pelvic irradiation and continued for 3 yr. Combined treatment provided significantly favourable outcomes, compared with RT alone, for overall survival (5-yr survival: 78% vs 62%; p = 0.0002; HR: 0.51; 95% CI, 0.36–0.73), specific survival (5-yr survival: 94% vs 79%; p = 0.0001; HR: 0.26; 95% CI, 0.15–0.44), and clinical disease-free survival (5-yr survival: 74% vs 40%; p < 0.0001; HR: 0.34; 95% CI, 0.26–0.46), among other end points.
Although there is a wealth of supportive evidence for the use of long-term (2 yr) ADT in conjunction with RT versus RT alone for the treatment of PCa, the use of long-term ADT is associated with numerous AEs. The risk of some of these AEs may be reduced with the replacement of long-term ADT with short-term ADT (6 mo), which has also been shown to improve outcomes in patients with localised PCa [12]. This hypothesis was tested in a study by the EORTC [13] that investigated the overall survival rates of patients with locally advanced PCa (stage T1c–T2a-b N1–2 M0 or stage T2c–T4 N0–2 M0) who were treated with RT in conjunction with either short- or long-term ADT with a LHRH agonist. All patients received treatment with photonic radiation (once daily for 5 d/wk for a period of 7 wk; recommended exposure: 10 MV) of the whole pelvis (first planning target volume: 50 Gy radiation) and the prostate and seminal vesicles (second planning target volume: 20 Gy radiation) in conjunction with an LHRH agonist (initiated on the first day of irradiation) for a period of 6 mo (short-term therapy). Patients who were randomised to receive long-term treatment were then subsequently treated with the LHRH agonist for a further 2.5 yr. Long-term treatment with an LHRH agonist provided favourable outcomes, compared with short-term therapy, for overall survival (5-yr overall mortality: 15.2% [95% CI, 12.1–18.9] vs 19.0% [95% CI, 15.5–23.0]; HR: 1.42; upper 95.71% CI, 1.79; noninferiority, p = 0.65]), PCa-specific survival (5-yr, HR: 1.71; 95% CI, 1.14–2.57; log-rank p = 0.002), PCa-specific mortality (5-yr: 3.2% [95% CI, 1.6–4.8] vs 4.7% [95% CI, 2.7–6.7]), and mortality unrelated to PCa (5-yr: 7.4% [95% CI, 5.0–9.9] vs 9.0% [95% CI, 6.3–11.7]; HR: 1.3; 95% CI, 0.98–1.2). These results indicate that short-term androgen suppression is inferior to long-term androgen suppression when combined with RT. The efficacy of RT in combination with HT for the treatment of patients with high-risk PCa was also demonstrated in an open, randomised phase 3 study by the Scandinavian Prostate Cancer Group and the Swedish Association for Urological Oncology [14]. Patients with high-risk PCa (T1b–T2, G2–G3, or T3; PSA 70 ng/ml; N0 M0) received ADT treatment with an LHRH agonist (leuprorelin, 3.75 mg/mo or 11.25 mg every 3 mo) for a period of 3 mo. Subsequently, patients randomised to ADT treatment combined with RT received standard threedimensional conformal RT to the prostate and the seminal vesicles (first planning target volume: 50 Gy) with a sequential boost (20 Gy) to the prostate (second planning volume, total minimum dose: 70 Gy). The 7-yr incidence rate of PCa-specific mortality was 9.9% (95% CI, 7.1–12.8%) in patients treated with HT only and 6.3% (95% CI, 3.9–8.6%) in patients who received HT plus RT (treatment difference: 3.7%; 95% CI, 0.0–7.4%). The corresponding rates after 10 yr were 23.9% (95% CI, 18.4–29.4%) and 11.9% (95% CI, 7.4– 16.5%) with a between-treatment difference of 12.0% and showed a significant relative risk of 0.44 (95% CI,
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0.30–0.66; p < 0.001) in favour of combined treatment. Similarly, the rate of overall mortality after 7 and 10 yr was higher in patients treated with HT only (20.1% [95% CI, 16.2–23.9%] and 39.4% [95% CI, 33.0–45.7%], respectively), compared with patients who received HT and RT in combination (16.5% [95% CI, 12.9–20.1%] and 29.6% [95% CI, 23.3–36.0%], respectively). This resulted in a significantly lower ( p = 0.004) relative risk of overall mortality after 10 yr of follow-up (HR: 0.68; 95% CI, 0.52–0.89) with combined treatment versus HT alone. Combined treatment, compared with HT alone, also significantly reduced ( p < 0.001) the probability of 10-yr follow-up PSA recurrence (HR: 0.16; 95% CI, 0.12–0.20). These data clearly demonstrate the benefits of RT in combination with HT in patients with nonmetastatic locally advanced or prostate-confined PCa with aggressive pathology.
References [1] Boccon-Gibod L, Hammerer P, Madersbacher S, Mottet N, PrayerGaletti T, Tunn U. The role of intermittent androgen deprivation in prostate cancer. BJU Int 2007;100:738–43. [2] Heidenreich A, Bolla M, Joniau S, et al. Guidelines on prostate cancer. European Association of Urology Web site. http://www. uroweb.org/fileadmin/tx_eauguidelines/2009/Full/Prostate_Cancer. pdf. Updated 2009. Accessed July 12, 2010. [3] Tunn U. Can intermittent hormone therapy fulfil its promise? Eur Urol Suppl 2008;7:752–7. [4] The 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 1997;79:235–46. [5] Studer UE, Whelan P, Albrecht W, et al. Immediate or deferred androgen deprivation for patients with prostate cancer not suitable for local treatment with curative intent: European Organisation for Research and Treatment of Cancer (EORTC) trial 30891. J Clin Oncol 2006;24:1868–76.
7.
Conclusions
These studies demonstrate that specific populations of patients with PCa will benefit differently from HT. A patient can benefit from ADT in two ways, either through an improvement in disease control or through an increase in survival. Practically all metastatic patients will benefit from ADT, but a population of nonmetastatic patients can also expect a benefit. Patients with a PSA >50 ng/ml or between 8 and 50 ng/ml and PSA DT < 12 mo will benefit from ADT alone. ADT can also bring a benefit to patients either when combined with surgery—in node-positive patients or with a PSA relapse in patients with Gleason sum >7 and or PSA DT < 12 mo—or in combination with RT in locally advanced or high-risk patients.
[6] Studer UE, Collette L, Whelan P, et al. Using PSA to guide timing of androgen deprivation in patients with T0-4 N0-2 M0 prostate cancer not suitable for local curative treatment (EORTC 30891). Eur Urol 2008;53:941–9. [7] Messing EM, Manola J, Yao J, et al. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate
cancer
after
radical
prostatectomy
and
pelvic
lymphadenectomy. Lancet Oncol 2006;7:472–9. [8] Moul JW, Wu H, Sun L, et al. Early versus delayed hormonal therapy for prostate specific antigen only recurrence of prostate cancer after radical prostatectomy. J Urol 2004;171:1141–7. [9] Pilepich MV, Winter K, Lawton CA, et al. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma—longterm results of phase III RTOG 85-31. Int J Radiat Oncol Biol Phys 2005;61:1285–90. [10] Horwitz EM, Bae K, Hanks GE, et al. Ten-year follow-up of radiation therapy oncology group protocol 92-02: a phase III trial of the duration of elective androgen deprivation in locally advanced
Conflicts of interest Professor Desgrandchamps received an honorarium for speaking at Orion Pharma’s symposium at the European Association of Urology (EAU) annual congress. The honorarium was governed by the EAU committee.
prostate cancer. J Clin Oncol 2008;26:2497–504. [11] Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002;360:103–6. [12] Roach III M, Bae K, Speight J, et al. Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610.
Funding support Orion Pharma supported medical writing services for the preparation and review of this supplement. Medical writing services provided by David Candlish and Andrew Stead (inScience Communications, a Wolters Kluwer business).
J Clin Oncol 2008;26:585–91. [13] Bolla M, de Reijke TM, Van Tienhoven G, et al. Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med 2009;360:2516–27. [14] Widmark A, Klepp O, Solberg A, et al. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/ SFUO-3): an open randomised phase III trial. Lancet 2009;373:301–8.