Hormone Therapy for Prostate Cancer: Guidelines versus Clinical Practice

european urology supplements 5 (2006) 362 368 available at www.sciencedirect.com journal homepage: www.europeanurology.com Hormone Therapy for Prostate Cancer: Guidelines versus Clinical Practice Antonio Alcaraz a, *, Pierre Teillac b a Hospital Clinic, University of Barcelona, Barcelona, Spain b Hôpital Saint-Louis, Paris, France Article info Keywords: Clinical practice Guidelines Hormone therapy Prostate cancer Radiation therapy Radical prostatectomy Abstract Objectives: In 2005, the European Association of Urology (EAU) published an update of the EAU guidelines on prostate cancer. This report evaluates whether these guidelines reflect the current therapy standards in daily clinical practice. Methods: An interactive meeting was held comparing the current therapy standards in prostate cancer with the EAU guidelines. This paper contains a summary of the outcomes of this meeting. Results: The EAU guidelines recommend curative therapy for patients diagnosed with localized prostate cancer (T1b T2c). However, for unfit patients with a life expectancy of 5 10 yr and poorly differentiated tumours, the combination of radiotherapy and hormones is recommended. The majority of the delegates (68%) would also recommend combination therapy in the latter. However, 17% would prescribe luteinizing hormone releasing hormone (LHRH) agonist monotherapy for this type of patient. Although radiotherapy in combination with adjuvant hormone therapy is recommended for patients with advanced prostate cancer (T3 T4), only 30% of the delegates agreed. Almost half of the urologists (48%) would prescribe LHRH agonist monotherapy. The patient s age appears to be a major differentiator for urologists to select the most appropriate treatment strategy. Approximately half of the urologists adhered to the guidelines for patients with a biochemical relapse after radical prostatectomy and would recommend radiotherapy. Around one third of the urologists would prescribe LHRH agonist monotherapy. The discussion on defining the moment for initiating LHRH agonist monotherapy remained inconclusive. Different practice patterns were noted for patients with positive nodes and patients with metastatic disease. Conclusions: The EAU guidelines, although followed by a majority of physicians, do not give direction for all patients seen in daily clinical practice. Large variations in practice exist among the participating urologists. # 2006 Elsevier B.V. All rights reserved. * Corresponding author. Hospital Clinic, University of Barcelona, Department of Urology, Villarroel, 170, 08036 Barcelona, Spain. Tel. +34 9322 75545; Fax: +34 9322 75545. E-mail address: aalcaraz@clinic.ub.es (A. Alcaraz). 1569-9056/$ see front matter # 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.eursup.2006.01.001

european urology supplements 5 (2006) 362 368 363 1. Introduction In October 2005, the European Association of Urology (EAU) published the updated guidelines on prostate cancer [1,2]. To discuss whether these guidelines (Table 1) reflect the current therapy standards in daily clinical practice, an interactive session was held during the symposium New Horizons in Urology, Malta, 29 30 October 2005. The symposium was attended by approximately 150 urologists coming from countries throughout Europe. Four specific patient cases were introduced to the audience (Figs. 1 4), followed by an interactive voting session where the delegates had to select their preferred treatment option. The subsequent debate with the audience and 10 experts was chaired by Prof. Teillac and Prof. Alcaraz. The main outcomes from the interactive voting session and the debate, as well as comparisons with Table 1 Summary of the EAU guidelines on primary treatment of prostate cancer [1,2] Stage Treatment Comment T1a Watchful waiting Standard treatment for well-, and moderately differentiated tumours and <10-year life expectancy. In patients with >10-year life expectancy, re-staging with TRUS and biopsy is advised (grade B recommendation) Radical prostatectomy Optional in young patients with a long life expectancy, especially for poorly differentiated tumours (grade B recommendation) Optional in younger patients with a long life expectancy, especially for poorly differentiated tumours. Higher complication risks after TURP, especially with interstitial radiation (grade B recommendation) Not an option (grade A recommendation) Not an option (grade C recommendation) T1b-T2b Watchful waiting Asymptomatic patients with well-, and moderately, differentiated tumours and a life expectancy <10 years. Patients who do not accept treatment-related complications (grade B recommendation) Radical prostatectomy Standard treatment for patients with life expectancy >10 years who accept treatment-related complications (grade A recommendation) Patients with a life expectancy >10 years who accept treatment-related complications. Patients with contraindications for surgery. Unfit patients with 5 10 years of life expectancy and poorly differentiated tumours (combination therapy is recommended; see below) (grade B recommendation) Symptomatic patients who need palliation of symptoms unfit for curative treatment. (grade C recommendation). Antiandrogens are associated with poorer outcome in comparison with watchful waiting and are not recommended (grade A recommendation) Neoadjuvant hormonal therapy (NHT) + radical prostatectomy: no proven benefit (grade A recommendation) NHT + radiotherapy: better local control. No proven survival benefit (grade B recommendation). (3 years) + radiotherapy: better than radiotherapy in poorly differentiated tumours (grade A recommendation) T3-T4 Watchful waiting Option in asymptomatic patients with T3, well-differentiated and moderately differentiated tumours, and a life expectancy <10 years (grade C recommendation) Radical prostatectomy Optional for selected patients with T3a and a life expectancy >10 years (grade C recommendation) T3 with >5 10 years of life expectancy. Dose escalation >70 Gy seems to be of benefit. If this is not available, a combination with hormonal therapy could be recommended (see below) (grade A recommendation) Symptomatic patients, extensive T3-T4, high PSA level (>25 ng/ml), unfit patients. Better than watchful waiting (grade A recommendation) + hormonal seems better than radiotherapy alone (grade A recommendation). NHT + radical prostatectomy: no proven benefit (grade B recommendation) N+, M0 Watchful waiting Asymptomatic patients. Patient driven. May have worse survival (grade C recommendation) Radical prostatectomy No standard option (grade C recommendation) No standard option (grade C recommendation) Standard therapy (grade A recommendation) No standard option. Patient driven (grade B recommendation) M+ Watchful waiting No standard option. May have worse survival/more complications than with immediate hormonal therapy (grade B recommendation) Radical prostatectomy Not an option (grade C recommendation) Not an option (given for cure) (grade C recommendation) Standard therapy. Symptomatic patients should not be denied treatment (grade B recommendation) Not an option (grade C recommendation) TRUS = transrectal ultrasound; TURP = transurethral resection of the prostate. Reprinted from Aus G, Abbou CC, Bolla M, et al. EAU guidelines on prostate cancer. Eur Urol 2005;48:546 551, with permission from the European Association of Urology.

364 european urology supplements 5 (2006) 362 368 Hormone therapy as monotherapy is only recommended for symptomatic patients unfit for curative therapy who need palliation of symptoms. Antiandrogen monotherapy has a poorer outcome than watchful waiting and is not recommended for patients with localized prostate cancer [1,2]. 2.2. Daily clinical practice Fig. 1 The majority of the delegates selected the combination of radiotherapy plus hormone therapy as preferred treatment option for this patient. (a) Localized prostate cancer, specific patient case: 70 yr, T2b, Gleason 7 (4+3) on 6 of 10 cores, PSA level 16 ng/ml, moderate symptoms, unfit for surgery, life expectancy about 10 yr. hormone; HT = hormone therapy. the recommendations from the EAU guidelines are summarized in this paper. 2. Localized prostate cancer (T1a T2c) 2.1. EAU guidelines Overall, the EAU guidelines [1,2] recommend radical prostatectomy as standard therapy for young patients (about 55 yr) diagnosed with stage T1b T2 prostate cancer, a life expectancy of >10 yr, fit for surgery, and otherwise healthy (Table 1). However, if the patient does not meet one of the above criteria, he should be offered different radiotherapy schedules. For patients with a diagnosis of low-risk disease (T1a T2a N0, M0, Gleason score 6, and a prostate specific antigen [PSA] level <10 ng/ml), external radiotherapy up to 70 72 Gy is recommended [3]. Intermediate-risk patients (T2b or PSA 10 20 ng/ml or Gleason score 7), however, should receive dose escalation with a dose ranging from 76 to 81 Gy [3 5]. Patients with high-risk disease (T2c or Gleason score >7 or PSA >20 ng/ml), or unfit patients with a life expectancy of 5 10 yr and poorly differentiated tumours, should receive radiotherapy in combination with short-term neoadjuvant and concomitant hormone therapy. Watchful waiting is only recommended in asymptomatic patients with well- and moderately differentiated tumours and a life expectancy of <10 yr. Also, patients who do not accept treatment-related complications may be offered deferred therapy [1,2]. Most delegates agreed that radical therapy is the standard of care for patients diagnosed with localized disease, with age and physical condition as major differentiators between radical prostatectomy and radiation therapy. Most discussion between experts and delegates was related to whether these patients should receive additional hormone therapy, either in a neoadjuvant and/or an adjuvant setting. The majority of the delegates (68%) agreed that the addition of hormone therapy to radiation therapy has proven benefit in localized prostate cancer patients (Fig. 1). Especially high-risk patients (high PSA level and high Gleason score) or patients unfit for surgery will benefit from the addition of hormones. Moreover, 17% of the delegates indicated that they would prescribe luteinizing hormone releasing hormone (LHRH) agonist monotherapy to these patients (Fig. 1). Although the benefits of hormone therapy for high-risk localized prostate cancer have been proven, some questions remain. First, what is the optimal duration of hormone therapy? In the experts opinion, concomitant and adjuvant hormone therapy should be administered for as long as 2 3 yr. Neoadjuvant hormone therapy, on the other hand, should only be administered as short-term therapy (2 6 mo). Second, there is no study available that directly compares the combination of radiotherapy and hormone therapy with hormone therapy alone. As such, it is not clear whether the positive effects achieved by the combination of radiotherapy plus hormone therapy have been the result of both therapies or of hormone therapy alone. To address this question, the Scandinavian Prostate Cancer Study Group (SPCG) has initiated a randomized controlled trial (SPCG 7) enrolling about 880 patients comparing the combination of radiotherapy (at least 70 Gy) and hormone therapy with hormone monotherapy. Results are expected early 2006 (personal communication, P.-A. Abrahamsson, Malmö, Sweden and A. Widmark, Umeå, Sweden). 2.3. EAU guidelines versus daily clinical practice Although the EAU guidelines recommend curative therapy as the preferred treatment option for

european urology supplements 5 (2006) 362 368 365 patients diagnosed with localized disease, both the experts and the delegates of the meeting indicated that they may prefer the additional administration of hormone therapy in some high-risk cases. The experts also felt that the total clinical picture of the patient should be taken into account before deciding on the most appropriate therapy. Unfortunately, no systematic decision models exist today to provide guidance on selecting the most appropriate therapy. 3. Advanced prostate cancer (T3 T4) 3.1. EAU guidelines Watchful waiting is optional in T3 prostate cancer patients with well- or moderately differentiated tumours and a life expectancy <10 yr [1,2]. As radical prostatectomy in locally advanced prostate cancer often leads to incomplete tumour excision, surgery is not recommended in these patients. Nevertheless, good results have been observed in patients with clinical T3a. However, it should be noted that the capability to differentiate T2b-c from T3a tumours is low. If surgery is applied to these patients, it should be followed by immediate postoperative radiation (Table 1) [1,2]. Since the combination of radical prostatectomy and hormone therapy is no longer recommended for patients with locally advanced prostate cancer, combining radiotherapy with hormone therapy is considered to be the standard (Table 1) [6 9]. Short-term neoadjuvant hormone therapy plus radiotherapy is specifically indicated in patients with a low Gleason score (Gleason 2 6) [8]. Onthe other hand, adjuvant hormone therapy following radiotherapy with a duration of 2 3 yr is highly recommended in patients with advanced prostate cancer with a high Gleason score (Gleason 7 10) [9]. Hormone therapy, as monotherapy, delays progression, prevents potentially catastrophic complications, and effectively palliates symptoms. However, as hormone therapy does not prolong survival, it is only recommended in symptomatic patients, unfit for surgery, with extensive T3 T4 and a high PSA level (>25 ng/ml; Table 1) [1,2]. 3.2. Daily clinical practice As Fig. 2 indicates, the delegates opinions are divided between LHRH agonist monotherapy (48%) and the combination of hormone therapy and radiation therapy (30%). According to the experts, the major differentiator between both treatment Fig. 2 LHRH agonists seem to be the preferred treatment option for this patient. (b) Advanced prostate cancer, specific patient case: 74 yr, T3b, N0, M0, Gleason 8 (4+4) on 8/10 cores, PSA level 20 ng/ml, moderate symptoms, unfit for surgery, life expectancy about 5 10 yr. hormone; HT = hormone therapy. options is the patient s age. Young patients (about 55 yr) have different needs and priorities than older patients (about 75 yr). Survival is much more important in younger patients than in older patients, whereas preserving quality of life (QOL) is the most important treatment factor for older patients. Most younger patients will receive radiation therapy in combination with hormone therapy, whereas older patients will receive hormone monotherapy. Most experts base their opinion on the study by Bolla et al. [6] stating that radiotherapy plus at least 3 yr of adjuvant hormone therapy is better than radiotherapy alone. Overall, the agreed recommendation for young patients with advanced disease is radiotherapy administered in a high dose (about 78 Gy) plus concomitant and adjuvant addition of hormone therapy for about 3 yr. The experts also indicated that radical prostatectomy is the most aggressive (and perhaps the only) therapy option for young patients diagnosed with a very aggressive tumour. As those patients are expected to have positive surgical margins, postoperative radiation therapy or hormone therapy in an adjuvant setting is, in their opinion, highly recommended. 3.3. EAU guidelines versus daily clinical practice Both the recommendations in the EAU guidelines and the delegates practice patterns matched in the sense that radiotherapy in combination with at least 3 yr of adjuvant hormone therapy is the

366 european urology supplements 5 (2006) 362 368 preferred treatment option for advanced disease. However, although the EAU guidelines do not take the patient s age into account, the delegates indicated that radiotherapy plus adjuvant hormone therapy is mainly for younger patients. Older patients should be offered hormone monotherapy. However, since studies directly comparing the combination of radiation and hormone therapy with hormone monotherapy are lacking, no firm conclusions can be made with regard to standard of care in these patients. 4. Biochemical failure after radical therapy 4.1. EAU guidelines About 27 53% of all patients undergoing radical therapy (radiation therapy or radical prostatectomy) will develop local or distant recurrence within 10 yr after initial therapy [10 12]. Following a study by Pound et al. [13] who demonstrated that no patient followed for >5 yr developed any recurrence without a concomitant PSA rise, treatment failure is currently defined as a rising PSA level after radical therapy. The EAU guidelines define recurrent prostate cancer as follows: Following radical prostatectomy, two consecutive PSA values 0.2 ng/ml represent recurrent cancer. Following radiation therapy, three consecutive increasing PSA values above a previous nadir represent recurrent cancer [1,2]. Once recurrent prostate cancer has been diagnosed, determining whether the recurrence has developed at local or at distant sites is of major importance. Local failure after radical prostatectomy can be predicted with an 80% probability by a PSA increase >3 yr after surgery, a PSA doubling time (PSA DT) 11 mo, Gleason score 6, stage pt3a pn0, ptxr1. On the opposite, distant failure after radical prostatectomy is predicted by a PSA increase <1 yr after surgery, a short PSA DT (4 6 mo), Gleason score 8 10, stage pt3b, ptxpn1. After radiation therapy, a late and slowly rising PSA level is a sign of local failure. A prostate biopsy demonstrating malignant cells after 18 mo following initial radiotherapy, and no evidence of metastatic spread on computer tomography (CT)/ magnetic resonance imaging (MRI) and bone scintigraphy should exclude distant failure [1,2]. The recommended therapy for local recurrence after radical prostatectomy is salvage radiation therapy (64 66 Gy) before the PSA level has risen >1.5 ng/ml. Carefully selected patients suffering from local recurrence after initial radiation therapy might be candidates for salvage radical prostatectomy. However, due to the high risk of complications, Fig. 3 The majority of the delegates indicated that radiotherapy, closely followed by LHRH agonists, is the preferred treatment option for this patient suffering from biochemical recurrence after initial prostatectomy. (c) Second-line therapy, specific patient case: 68 yr, PSA relapse 4 yr after initial radical prostatectomy (pt2a, PSA 7 ng/ml, Gleason 6), PSA DT of 15 mo. hormone. patients might be offered watchful waiting with possible hormone therapy later on [1,2]. Early hormone therapy might be of benefit in delaying progression and possibly achieving survival benefit in patients diagnosed with distant failure after initial curative therapy [1,2]. 4.2. Daily clinical practice The experts unanimously agreed that both PSA level and PSA DT are the most important predictors to distinguish between local and distant recurrence. Overall, when a patient is diagnosed with low PSA levels after radical prostatectomy and a long PSA DT (both indicative for local recurrence), radiation therapy of at least 64 Gy is the preferred treatment for 49% of the urologists (Fig. 3). As mentioned in the paper by Klotz [14], PSA DT is the major predictor of progression. Patients diagnosed withapsadtof>2 yr have a probability of about 1% of dying from prostate cancer without receiving any treatment [4]. As a consequence, many experts agreed that if the patient has a long PSA DT, active surveillance is the best treatment option, especially with regard to preserving the patient s QOL. Currently, the patient s QOL has gained a lot of interest. Most studies discussed in the EAU guidelines [1,2] are old(er) studies that only focused on survival outcomes. Nevertheless, QOL is an important element in patients with biochemical recurrence. Therefore, new studies should investigate QOL elements together with survival.

european urology supplements 5 (2006) 362 368 367 About one third of the delegates (31%; Fig. 3) preferred to treat patients with biochemical failure after radical therapy with LHRH agonist monotherapy to avoid treatment-related side effects of salvage radiotherapy and to improve the patient s QOL. 4.3. EAU guidelines versus daily clinical practice Both the experts and the delegates follow the EAU guidelines with respect to salvage radiotherapy after initial radical prostatectomy. However, they also stated that the EAU guidelines only discuss the importance of survival but forget the patient s QOL. Because the emphasis of biochemical recurrence therapy in daily clinical practice is currently not only on survival but also on QOL, LHRH agonist monotherapy is increasingly used for patients with recurrent disease. 5. Positive nodes/metastatic disease (N+/M+) 5.1. EAU guidelines In case of clinical node positive disease, the guidelines recommend hormone therapy to palliate symptoms, to defer progression to a symptomatic stage, and to prolong progression-free and overall survival (Table 1) [1,2]. Also patients diagnosed with metastatic disease will benefit from early hormone therapy (Table 1) [1,2]. Watchful waiting is recommended only for asymptomatic metastatic patients not willing to suffer from treatment-related side effects. 5.2. Daily clinical practice As seen in Fig. 4, most delegates would administer the combination of LHRH agonists with an additional antiandrogen (combined androgen blockade [CAB], 44%) or LHRH agonist monotherapy (39%). However, as combination therapy shows no benefit and an increased number of side effects compared to hormone monotherapy, LHRH agonist monotherapy seems to be the preferred treatment option [15,16]. 5.3. EAU guidelines versus daily clinical practice Both the EAU guidelines and the attendees indicate that patients diagnosed with either node-positive and/or metastatic disease (or both) should receive hormone therapy. However, the debate remains inconclusive whether LHRH agonist monotherapy or CAB is the preferred treatment option. Fig. 4 Both LHRH agonists and combined androgen blockade seem to be the preferred treatment options for this specific patient. (d) Positive nodes, specific patient case: 74 yr, 7 of 10 cores positive on biopsy, nodes >2 cm on computed tomography scan, N+, Mx, Gleason 7 (4+3), PSA 32 ng/ml, mild symptoms. hormone; CAB = combined androgen blockade. In conclusion, although there is agreement on the administration of hormone therapy, there is a high practice variation related to the type of hormone therapy. 6. Conclusions The interactive voting sessions and the subsequent debate highlighted the differences between the recommendations in the EAU guidelines and clinical practice patterns. The recommendations in the EAU guidelines are largely based on results from randomized, clinical trials, the gold standard for evidence-based medicine. However, there are not enough randomized, controlled trials in the field of prostate cancer to answer all clinical questions in sufficient detail to apply to the wide range of patients seen in everyday clinical practice. This is because randomized, controlled clinical trials have strict inclusion and exclusion criteria and therefore exclude many patients who are commonly treated in clinical practice. Although robust evidence-based medicine about the benefits of many therapies in specific patients is often lacking, physicians nonetheless make treatment decisions every day based also on their clinical experience. On the other hand, an overload of information is currently available on many aspects of prostate cancer management. It has become virtually impossible to assimilate all these data for clinicians in clinical practice. It can be concluded that the EAU guidelines are a useful tool to achieve appropriate care in prostate

368 european urology supplements 5 (2006) 362 368 cancer management, but unfortunately, they are insufficient to provide direction for a number of patients seen in clinical practice. Continued medical education by experts remains critical to try to achieve that goal. References [1] Aus G, Abbou CC, Bolla M, et al. EAU guidelines on prostate cancer. Eur Urol 2005;48:546 51. [2] Aus G, Abbou CC, Bolla M, et al. EAU guidelines on prostate cancer. Updated full version, http://www.uroweb.org, March 2005. [3] Hanks GE, Hanlon AL, Schultheiss TE, et al. Dose escalation with 3D conformal treatment: five year outcomes, treatment optimization, and future directions. Int J Radiat Oncol Biol Phys 1998;41:501 10. [4] Leibel SA, Zelefsky MJ, Kutcher GJ, et al. The biological basis and clinical application of three-dimensional conformal external beam radiation therapy in carcinoma of the prostate. Semin Oncol 1994;21:580 97. [5] Zelefsky MJ, Leibel SA, Gaudin PB, et al. Dose escalation with three-dimensional conformal radiation therapy affects the outcome in prostate cancer. Int J Radiat Oncol Biol Phys 1998;41:491 500. [6] 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 8. [7] Hanks GE, Pajak TF, Porter A, et al. Phase III trial of longterm adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation Therapy Oncology Group Protocol 92-02. J Clin Oncol 2003;21: 3972 8. [8] Pilepich MV, Winter K, John MJ, et al. Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys 2001;50:1243 52. [9] Pilepich MV, Winter K, Lawton CA, et al. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma long-term results of phase III RTOG 85-31. Int J Radiat Oncol Biol Phys 2005;61:1285 90. [10] Bott SR. Management of recurrent disease after radical prostatectomy. Prostate Cancer Prostatic Dis 2004;7:211 6. [11] Grossfeld GD, Stier DM, Flanders SC, et al. Use of second treatment following definitive local therapy for prostate cancer: data from the capsure database. J Urol 1998;160: 1398 404. [12] Partin AW, Pearson JD, Landis PK, et al. Evaluation of serum prostate-specific antigen velocity after radical prostatectomy to distinguish local recurrence from distant metastases. Urology 1994;43:649 59. [13] Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999; 281:1591 7. [14] Klotz L. Active surveillance with selective delayed intervention using PSA doubling time for good risk prostate cancer. Eur Urol 2005;47:16 21. [15] Prostate Cancer Trialists Collaborative Group. Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Lancet 2000;355:1491 8. [16] Samson DJ, Seidenfeld J, Schmitt B, et al. Systematic review and meta-analysis of monotherapy compared with combined androgen blockade for patients with advanced prostate carcinoma. Cancer 2002;95:361 76.