Urologic Oncology: Seminars and Original Investigations 30 (2012) 3 15

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1 Urologic Oncology: Seminars and Original Investigations 30 (2012) 3 15 Review article The multi-disciplinary management of high-risk prostate cancer Jonathan C. Picard, M.D. a, *, Ali-Reza Golshayan, M.D. b, David T. Marshall, M.D., M.S. c, Krisha J. Opfermann, M.D. c, Thomas E. Keane, M.B.B.Ch., F.R.C.S.I., F.A.C.S. a a Department of Urology, Medical University of South Carolina, Charleston, SC 29425, USA b Division of Hematology and Oncology, Medical University of South Carolina, Charleston, SC 29425, USA c Department of Radiation Oncology, Medical University of South Carolina, Charleston, SC 29425, USA Received 30 June 2009; received in revised form 2 September 2009; accepted 3 September 2009 Abstract Prostate cancer is the most frequently diagnosed cancer and the second most common cause of cancer death in men in the United States. Such men can experience a continuum of disease presentations from indolent to highly aggressive. For physicians who care for these men, a significant challenge has been and continues to be identifying and treating those men with localized cancer who are at a higher risk of dying from their disease. We discuss the risk stratification of patients in order to better identify those patients at higher risk of progression. A comprehensive review of the literature was then performed reviewing the roles of surgery, radiotherapy, hormone therapy, and chemotherapy, as well as combinations of these modalities, in treating these challenging patients. An integrated approach combining local and systemic therapies can be beneficial in the management of high-risk localized prostate cancer. The choice of therapy or combination of therapies is dependant upon many considerations, including patient preference and quality of life aspects. It is becoming clearer that the addition of hormonal therapies or chemotherapies to established therapies, such as radiotherapy or surgery, will have significant benefits. As evidence accumulates regarding the efficacy of these new regimens, our hope is that the challenge of optimizing the management of high-risk prostate cancer will be delivered. However, many important questions remain unresolved regarding the optimal type, combination, timing of therapy, and duration of therapy. Such questions will only be answered with large, well-designed prospective clinical trials Elsevier Inc. All rights reserved. Keywords: High risk prostate cancer; Prostatectomy; Chemotherapy; Radiotherapy; Hormone therapy 1. Introduction Prostate cancer is the most frequently diagnosed cancer and the second most common cause of cancer death in men in the United States [1]. Such men can experience a continuum of disease presentations from indolent to highly aggressive. For physicians who care for these men, a significant challenge has been and continues to be identifying those men with localized cancer who are at a higher risk of dying from their disease. Patients with prostate cancer can be categorized based upon the risk of PSA failure and prostate cancer-specific mortality after definitive therapy. The American Urologic Association has defined patients with high risk as having an initial PSA 20 ng/ml or a Gleason score of 8 10, or clinical stage T2c [2]. The precise * Corresponding author. Tel.: ; fax: address: garfield@ccf.edu (J.C. Picard). definition of high-risk prostate cancer has evolved over time and, therefore, patient inclusion criteria for clinical trials have varied (see Table 1). However, it has been suggested that the risk of biochemical progression is similar regardless of the definition of high-risk prostate cancer used [3]. Although men with low and intermediate-risk prostate cancer have greater than 90% long-term survival, men with high-risk prostate cancer have a 25% of death due to prostate cancer at 5 years [4]. The relative risk of prostate cancer-related mortality in men with high-risk prostate cancer has been estimated to be 14.2 after radical prostatectomy and 14.3 after radiation therapy [5]. There is currently no consensus on the optimal management of patients with high-risk prostate cancer. Single modality treatment with either surgery or radiation results in a progression-free survival of only about 50% [6]. Therefore, it is reasonable to employ more aggressive strategies in such patients. The utilization of a multidisciplinary oncology team allows specialists from different disciplines to collab /$ see front matter 2012 Elsevier Inc. All rights reserved. doi: /j.urolonc

2 4 J.C. Picard et al. / Urologic Oncology: Seminars and Original Investigations 30 (2012) 3 15 Table 1 Various definitions of high-risk prostate cancer American Urologic Association [2] D Amico definition NCCN definition orate in the best possible care of the individual patient. The treatment chosen is based upon prognostic factors: age, patient co-morbidities, and individual patient preferences. 2. The role of surgery 2.1. Surgery monotherapy PSA 20 ng/ml or GL 8or Stage T2c PSA 20 ng/ml or GL 8or Stage T2c PSA 20 ng/ml or GL 8or Stage T3 or Any 2 of the following: T2b/c, GL 7, PSA 10 GL Gleason score; PSA prostate-specific antigen. Radical prostatectomy represents one of the two most often utilized therapeutic modalities in the treatment of high-risk localized prostate cancer. Radical prostatectomy series from major institutions show 5-year and 10-year freedom from biochemical relapse rates from approximately 30% to 70% and 15 to 60% for high-risk prostate cancer, respectively [7 9]. A recent update on radical prostatectomy monotherapy for T3a prostate cancer by Freedland et al. found that 49% of men at 15 years after surgery had not developed a PSA recurrence. Additionally, in patients with a PSA recurrence, the PSA doubling time was greater than 9 months in nearly half and greater than 15 months in one-third. At 15 years after surgery, only 16% of patients had died of prostate cancer. He argued that radical prostatectomy was a reasonable option for selected high-risk patients. His review also demonstrated that 9% of specimens were down-staged to organ-confined disease after prostatectomy [10]. Prior series found that 24% to 27% of patients were over-staged [11 13]. It has been argued that these patients may have been unnecessarily subjected to the morbidity of additional therapies. Yossepowitch et al. reported their experience in 4,708 men with prostate cancer treated with radical prostatectomy between 1985 and Depending upon the definition of high-risk prostate cancer utilized, patients classified as highrisk were found to have adverse features, such as extracapsular extension (35% 71%), seminal vesicle invasion (10% 33%), and lymph node metastasis (7% 23%). These patients were also found to have an increased likelihood of PSA progression with a hazard ratio of However, he found that between 22% and 63% of these men had organ-confined disease, and 41% to 74% remained progression-free 10 years after surgery alone. He concluded that while some patients at high-risk may harbor systemic disease and relapse after local therapy, a substantial proportion have localized disease and may be cured by surgery alone and spared the morbidity of additional therapies [14] Surgery and hormonal therapy The role of neoadjuvant hormonal therapy has been investigated in multiple prospective trials. Such therapy has been shown to be safe to administer. Patients who have received neoadjuvant androgen deprivation have shown a significant decrease in positive surgical margins and lymph node metastasis, as well as reductions in tumor size and PSA levels [15 17]. However, no trial has been successful in producing a complete pathologic response, and no trial has demonstrated an improvement in the rate of biochemical recurrence or in overall survival [18]. In a recent metaanalysis, neoadjuvant hormonal therapy did not improve progression-free survival or overall survival, but may reduce positive surgical margins and improve local pathologic variables, such as lymph node involvement [19]. Similarly, the meta-analysis found that adjuvant hormonal therapy after radical prostatectomy did not improve overall survival. Although immediate hormonal therapy has demonstrated an improvement in overall survival in patients with gross lymph node involvement, it is not known whether such benefit will translate to those patients with localized disease [20]. Longer follow-up may be required to observe a survival benefit. Therefore, neoadjuvant hormonal therapy prior to radical prostatectomy is not recommended outside of a clinical trial Surgery and adjuvant radiotherapy The utilization of radiation after surgery can significantly reduce the risk of local recurrence in patients with prostate cancer after radical prostatectomy with extra-capsular extension, positive margins, or seminal vesicle involvement. This benefit has been demonstrated in multiple studies [21 23]. At a follow-up of 15 years, local control was significantly better in men who received postoperative radiation (82% vs. 53%, P 0.002) [21]. However, there were no improvements in the rates of distant metastasis, progression free survival or overall survival. A randomized prospective multi-institutional clinical trial (SWOG 8794) was opened to determine whether adjuvant radiotherapy improved metastasis-free survival in patients with pt3 N0 prostate cancer [24]. Eligible patients were required to have extracapsular extension, positive seminal vesicles, or positive surgical margins. Patients were randomized to receive Gy of external beam radiotherapy to the prostatic fossa within 16 weeks of radical prostatectomy or to observation. The study was opened in 1988 and completed accrual of 425 men in The results were not presented until a median follow-up of 10.6 years. Adjuvant radiotherapy improved metastasis-free survival

3 J.C. Picard et al. / Urologic Oncology: Seminars and Original Investigations 30 (2012) (35.5% vs. 43.1%; P 0.06), median PSA relapse-free survival (10.3 years vs. 3.1 years; P 0.001), and median recurrence-free survival (13.8 years vs. 9.9 years; P 0.001) compared with observation alone. However, at that time, there was no significant difference in overall survival. It should be noted that 33% of men assigned to observation received radiation at the time of disease failure. Adverse side effects were more common in the radiotherapy arm compared with the observation arm. The rates of rectal complications, urethral stricture, and total urinary incontinence were 3.3% vs. 0%, 17.8% vs. 9.5%, and 6.5% vs. 2.8% for the adjuvant radiation therapy vs. observation arms, respectively. In a subgroup analysis, patients who had a postoperative detectable PSA and then received adjuvant therapy were more likely to have PSA progression at 10 years compared with those patients who had a postoperative undetectable PSA (73% vs. 42%). Although this may suggest that patients who benefit most from adjuvant radiotherapy are those who have an undetectable PSA after surgery, such a hypothesis will require confirmation in larger clinical trials. A recent update of SWOG 8794 revealed a statistically significant benefit in overall survival at 15-years (47% vs.37%, P 0.053) [25]. In a similar fashion, the EORTC trial enrolled over 1,000 men with high-risk prostate cancer to undergo 60 Gy of radiotherapy after undergoing radical prostatectomy or observation [26]. After a median follow-up of 5 years, men who had been treated with radiotherapy had improved biochemical progression-free survival (74% vs. 53%; P ), clinical progression-free survival (85% vs. 77.5%; P ), and a lower rate of loco-regional failure (P ). A German study (ARO 9602) has reported similar improvements in progression-free survival [27]. Therefore, in 3 prospective randomized trials, the use of adjuvant radiotherapy has been shown to significantly improve 5-year progression-free survival by about 20%. The SWOG study shows a statistically significant benefit in overall survival after a median follow-up of 11 years. This is compelling evidence for the efficacy of adjuvant radiation therapy in patients with high-risk prostate cancer Surgery and chemotherapy Surgery and neoadjuvant chemotherapy Neoadjuvant chemotherapy in several cancers can decrease tumor bulk, down-stage tumors, and target micrometastases; recurrence rates are thereby reduced after definitive local treatment. Neoadjuvant chemotherapy permits histologic analysis of the response to systemic treatment after examination of tissue postoperatively, as well as enabling the assessment of biological end points and of chemosensitivity of cancer cells to an agent. Such trials can be performed in a relatively timely and cost-effective manner. There have been multiple phase II trials evaluating the benefit of chemotherapy prior to radical prostatectomy using mitoxantrone, docetaxel, and estramustine-based regimens (see Table 2). Several groups have tested the efficacy of single agent docetaxel chemotherapy prior to radical prostatectomy. Neoadjuvant docetaxel was well-tolerated with reported PSA decreases of 50% or greater in 24% to 58% of patients [28,29]. In a Canadian phase II study, 72 men with high-risk prostate cancer were treated with combined androgen deprivation and docetaxel 35 mg/m 2 weekly for 6 of 8 weeks for 3 doses [30]. Sixty-four patients underwent radical prostatectomy and lymphadenectomy within 2 weeks of the last dose of docetaxel. The median PSA decreased by 98.4%. Two patients had a complete pathologic response and 16 patients had a tumor volume of 5% in prostatectomy specimens. At a median follow-up of 42.7 months, 30% had a PSA recurrence. The use of estramustine-based neoadjuvant regimens has been shown to result in an undetectable PSA in approximately 50% of patients and decrease tumor volume. However, such regimens may be associated with significant toxicities including thromboembolic disease [31 33]. The combination of docetaxel and estramustine has been used in this patient population, with acceptable levels of toxicity and disease-free survival [34,35]. As a result, the CALGB has sponsored a randomized study of neoadjuvant chemotherapy and androgen deprivation therapy Table 2 Selected trials of neoadjuvant chemotherapy prior to radical prostatectomy in patients with high-risk prostate cancer Treatment regimen Number of patients Follow-up time (median, range) Disease-free survival Pettaway 2000 [28] Ketoconazole, Doxorubicin, Vinblastine, Estranustine, months (9 18) 60% LHRH agonist, Antiandrogen Clark 2001 [27] Estramustane, Etoposide months (5 20) 78% Hussain 2003 [30] Docetaxel, Estramustine months (9 18) 71% Dreicer 2004 [23] Docetaxel months (1.5 36) 71% Febbo 2005 [24] Docetaxel months (4.5 40) 44% Prayer-Galetti 2007 [29] Docetaxel, Estramustine, LHRH agonist months (30 64) 42% Chi 2008 [25] Docetaxel, LHRH agonist, Antiandrogen months (26 66) 70% Vuky 2009 [32] Docetaxel, Gefintinib months (10 42) 66% Mathew 2009 [33] Docetaxel, Imatinib, LHRH agonist months 53%

4 6 J.C. Picard et al. / Urologic Oncology: Seminars and Original Investigations 30 (2012) 3 15 prior to radical prostatectomy vs. immediate radical prostatectomy (CALGB )[36]. It is planned to accrue 750 patients who have a 60% or less chance of being disease-free 5 years after surgery. Patients are randomized to either prostatectomy alone or to receive 70 mg/m 2 docetaxel every 21 days for 6 cycles followed by radical prostatectomy. The primary end-point was to determine whether chemotherapy decreases 5-year biochemical recurrence compared with radical prostatectomy alone. The use of novel agents in this setting has also been investigated. Vuky and colleagues gave 31 men with highrisk prostate cancer neoadjuvant docetaxel and the tyrosine kinase inhibitor, gefitinib [37]. This combination appeared to be well tolerated, but did not result in any pathologic complete responses. Mathew et al. investigated the addition of imatinib to docetaxel and androgen deprivation in the neoadjuvant setting [38]. Imatinib is an inhibitor of platelet derived growth factor receptor (PDGFR). It is known that PDGFR is expressed in high-grade prostate adenocarcinoma and bone metastases. It was hypothesized that the combination of inhibition of PDGFR, cytotoxic chemotherapy, and hormonal therapy would improve progression-free survival. Unfortunately, although the therapy was feasible, no significant improvements in outcomes were observed. Several trials employing anti-angiogenic agents are currently underway, including thalidomide, bevacizumab, CCI-799, RAD 001, and sunitinib. In addition, other novel agents such as vorinostat, sirolimus, ixabepilone, degarelix, anti- CTLA-4 antibody, and sipuleucel are being investigated in the neoadjuvant setting. It remains unclear whether there is any advantage to neoadjuvant chemotherapy. To date, no trial has appeared to improve postoperative pathologic outcomes. It is hoped that current trials under study will be shown to be advantageous. It is important to remember that the current standards of care for neoadjuvant chemotherapy in other tumor types were established only after the completion of large studies of patients followed for many years Surgery and adjuvant chemotherapy Adjuvant chemotherapy after definitive local therapy has become a standard of care in many solid tumors. This evolved from the benefit of cytotoxic agents in metastatic disease, which was then demonstrated to improve survival in the adjuvant setting. However, the current standard of care for adjuvant chemotherapy was established only after the completion of many large studies of patients followed for years. Unfortunately to date, no study has definitively demonstrated the benefit of adjuvant chemotherapy in prostate cancer. In a randomized study, 93 men with locally advanced or metastatic prostate cancer undergoing hormonal therapy were treated with or without mitoxantrone [39]. Only 38 men had localized disease and no definitive local treatment was given. However, in those men with localized disease, the median survival was longer in the mitoxantrone arm (80 months vs. 36 months, P 0.04). In a phase II trial, 77 men with high-risk prostate cancer were treated with 6 cycles of docetaxel 35 mg/m 2 weekly following radical prostatectomy [40]. At a median of 29 months of follow-up, 60.5% of patients had disease progression, and 7 patients were deceased. The expected progression-free survival was 10 months, since 99% of patients had non-organ-confined disease, 56% had Gleason score 8, 65% had positive surgical margins, 65% had seminal vesicle involvement, and 38% had lymph node involvement. The observed median progression-free survival was 15.7 months, an encouraging finding. Grades 3 and 4 toxicities occurred in 26% and 4% of patients, respectively. Adjuvant docetaxel in patients with high-risk prostate cancer was further evaluated in the TAX 3501 phase III trial. The study planned to enroll over 2,000 men after radical prostatectomy and randomize patients to either immediate or deferred androgen deprivation for 18 months with or without 6 cycles of docetaxel. The primary endpoint is progression-free survival. Unfortunately, the trial was closed prematurely prior to completing enrollment, which may limit its usefulness. A randomized phase III study (SWOG 9921) enrolled men with high-risk prostate cancer to androgen deprivation therapy for 2 years with or without 6 cycles of mitoxantrone after radical prostatectomy [41]. The primary endpoint was overall survival and planned accrual was for 1,360 patients over 10 years. However, in January 2007, after enrolling only 983 men, the trial was closed to further accrual after 3 cases of acute myelogenous leukemia were reported in the mitoxantrone treatment arm. Patients continue to be observed and a report of the results is awaited. The U.S. Department of Veteran Affairs is also conducting a phase III trial of adjuvant docetaxel after prostatectomy. High-risk patients will be allocated to receive either 18 weeks of docetaxel or observation. Accrual is expected to be 636 patients, and the primary endpoint is progression-free survival Surgery, hormonal therapy, chemotherapy, and radiotherapy Docetaxel is also finding a place in clinical trials investigating the benefits of combining the drug with androgen deprivation and radiotherapy in the post-prostatectomy setting for high-risk patients. Investigators at the University of California Norris Comprehensive Cancer Center have initiated a trial combining 3-D conformal radiotherapy to 66 Gy with total androgen blockade and weekly docetaxel at 20 mg/m 2 in post-prostatectomy patients ( gov/show/nct ). Similar trials are being considered by other groups in order to combine the local control benefits of radiotherapy and the systemic control benefits of hormonal therapy and chemotherapy.

5 J.C. Picard et al. / Urologic Oncology: Seminars and Original Investigations 30 (2012) Table 3 Selected trials of hormonal and radiation combination therapy Treatment regimen Number of patients Median follow-up time Disease-free survival Crook J et al. [43] Neoadvuvant 8 vs. 3 months of flutamide and goserelin followed by radiotherapy Lawton CA et al. [44] Radiotherapy followed by indefinite goserelin vs. Radiotherapy alone followed by hormones at relapse Pilepich MV et al. [45] Neoadjuvant (2 months) and concurrent goserelin and flutamide with radiotherapy (total 112 days) vs. radiotherapy alone Bolla M et al. [46] Concurent and adjuvant goserelin with radiotherapy (total 3 years) vs. radiotherapy alone Hanks, GE et al. [47] Neoadjuvant (2 months), concurrent (2 months), and adjuvant (2 years) goserelin and flutamide plus radiotherapy vs. neoadjuvant (2 months) and concurrent (2 months) goserelin and flutamide plus radiotherapy D Amico AV et al. [48] Neoadjuvant (2 months), concurrent (2 months) and adjuvant (2 months) LHRH agonist and flutamide plus radiotherapy vs. radiotherapy alone years 5-year 71% vs. 42% years 8-year 36% vs. 25% years 8-year 33% vs. 21% months 5-year 85% vs. 48% years 5-year 46% vs. 28% years 5-year 82% vs. 57% 3. The role of radiotherapy 3.1. Radiotherapy monotherapy Radiotherapy represents the second of the 2 major therapeutic modalities for localized high-risk prostate cancer. Radiotherapy and radical prostatectomy monotherapies have not been directly compared in modern series. The methods differ in toxicity profiles but, overall, appear to have similar long-term survival. Single modality therapy with either surgery or radiotherapy has a low rate of success for high-risk prostate cancer. Similar to the results from radical prostatectomy, outcomes with radiotherapy alone are poor. Results from the radiotherapy-alone arms of radiation therapy oncology group (RTOG) and show that Gy to the pelvic lymph nodes and Gy to the prostate produce 5-year biochemical control rates of only around 10% to 20%. More recent dose escalation studies with modern radiotherapy techniques allow for biochemical control rates on the order of 38% for high-risk patients for radiotherapy alone [42]. With the poor outcomes of single modality therapy, it appears that a multi-modal approach is indicated in the treatment of high-risk prostate cancer Radiotherapy and hormonal therapy Many trials have been performed combining radiotherapy and hormonal therapy. Hormonal therapy has been combined with radiotherapy as neoadjuvant, concurrent, or adjuvant therapy. A list of selected trials involving these therapies is included below with a detailed discussion to follow (See Table 3). In a recent meta-analysis, neoadjuvant hormonal therapy has been demonstrated to improve both clinical and biochemical disease-free survival [19]. Adjuvant hormonal therapy following radiotherapy resulted in a significant improvement in overall survival at 5 and 10 years. There was also a significant improvement in disease-specific survival and disease-free survival at 5 years [19]. A recent report outlining the results of a Canadian phase III randomized trial of 3 vs. 8 months of neoadjuvant androgen deprivation therapy before radiotherapy for localized prostate cancer has been published. The disease-free survival rate at 5 years was improved for the high-risk patients in the 8-month arm vs. the 3-month arm (71% vs. 42%, P 0.01). High-risk prostate cancer was defined as stage T3 or Gleason score 8 10 or PSA level 20 ng/ml [43]. The phase III RTOG trial evaluated the benefit of adding adjuvant luteinizing hormone-releasing hormone (LHRH)-agonist therapy following definitive radiotherapy for high-risk prostate cancer. Eligible patients included clinical T1and T2 patients with lymph node involvement or clinical T3 patients, regardless of lymph node status. Patients with bulky tumors 25 cm 2 on digital rectal exam were not eligible for this trial unless they had lymph node involvement outside the pelvis. All trial participants received Gy to the regional lymph nodes, if involved, with an additional boost to the prostate, bringing the total dose to the prostate up to Gy. A small number of patients ( 15%) in the study had undergone radical prostatectomy; those patients received a total dose of Gy to the prostatic fossa. Patients were randomized to radiation alone (with goserelin reserved for the time of relapse) or radiation followed by indefinite goserelin therapy. Improvements in multiple outcomes at a follow-up of 8-years were seen with the addition of immediate adjuvant goserelin therapy after radiotherapy including local failure (23% vs. 37%, P ), distant metastasis (27% vs. 37%, P ), disease-free survival (36% vs. 25%, P ), and biochemical relapse-free survival (32% vs. 8%, P ). Overall survival and cause-specific survival were not statistically different. A subset analysis of patients whom did not undergo prostatectomy with Gleason score 8 10

6 8 J.C. Picard et al. / Urologic Oncology: Seminars and Original Investigations 30 (2012) 3 15 showed a statistically significant improvement in overall (P 0.036) and cause-specific survival (P 0.019) [44]. The phase III RTOG trial evaluated short-term neoadjuvant and concurrent androgen deprivation combined with radiotherapy. In this study, 471 patients with locally advanced disease (T2b T4 with or without pelvic lymph node involvement) were randomized to receive radiation therapy alone or radiation therapy with short-term androgen deprivation using goserelin and flutamide. Goserelin and flutamide were started 2 months prior to and continued concurrently with radiotherapy in the combined therapy arm. After 8 years of follow-up, the addition of short-term androgen deprivation therapy was associated with improved local control (42% vs. 30%; P 0.016), a lower incidence of distant metastasis (34% vs. 45%, P 0.04), an improved disease-free survival (33% vs. 21%; P 0.004), and causespecific mortality (23% v,. 31%; P 0.05) compared with radiation therapy alone. There was no statistically significant benefit in overall survival for the entire group. A subgroup analysis suggested a significant benefit for all endpoints including overall survival (70% vs. 52%, P 0.015) for patients with a Gleason score less than 7 [45]. A recent update has confirmed these results for the overall group. There continued to be improvements in 10-year disease-free survival (11% vs. 3%, P ), distant metastasis rate (35% vs. 47%, P 0.006), and biochemical failure (65% vs. 80%, P ). There was no statistically significant improvement in overall survival, although a trend in favor of short-term androgen deprivation was observed (43% vs. 34%, P 0.12) [49]. A randomized trial by the EORTC published in 1997 examined the benefit of long-term hormonal therapy in combination with radiotherapy in 415 patients with locally advanced prostate cancer. The patients were stage T1-T2 and WHO grade 3 cancers, or T3-T4 without lymph node involvement. Both arms received radiotherapy to the pelvic lymph nodes to 50 Gy followed by a 20 Gy boost to the prostate and seminal vesicles. One arm received concurrent and adjuvant hormone therapy (goserelin) for 3 years. Fiveyear overall survival was 79% in the radiotherapy and hormonal therapy arm vs. 62% in the radiotherapy-alone arm (P 0.001). Similarly, the 5-year disease-free rate, local control rate, and time-to-treatment failure were all in favor of the combined therapy arm with P values 0.001, 0.001, and 0.001, respectively [46]. A 2002 update published with a median follow-up of 66 months had significant improvements in 5-year overall survival, disease-specific survival, and locoregional failure. Biochemical disease-free survival and the incidence of distant metastatic disease also trended in favor of the arm treated with radiation and hormonal therapy [9]. A 10-year update of this study was recently reported. Long-term androgen suppression increased the difference in 10-year survival between the two groups from 39.8% to 58.1% (P ) in favor of the combined modality arm. Once again, the clinical progression-free survival (P ), distant progression-free survival (P ), and clinical/biochemical progression-free survival (P ) were improved in the combined modality group. The 10-year incidence of prostate cancer mortality was 31.0% in the radiotherapy-alone arm and 11.1% with combined therapy (P 0.001) [50]. The RTOG has also evaluated neoadjuvant, concurrent, and long-term adjuvant androgen deprivation combined with radiotherapy. RTOG included patients with clinical T2-T4 without nodal involvement of the common iliac or higher chains. All patients received Gy to the pelvic lymphatics with a boost to a total of Gy to the prostate. Before radiotherapy began, all patients received total androgen blockade with flutamide and goserelin starting 2 months before radiotherapy. Total androgen blockade was continued in all patients until the completion of radiotherapy. Patients were randomized to receive no further treatment or adjuvant goserelin for an additional 2 years following radiotherapy. Five-year results showed significant improvements in all end points except overall survival. These improvements included gains in disease free survival (46.4% vs. 28.1%, P ), a lower distant metastasis rate (17.0% vs. 11.5%, P ), and increased local control (12.3% vs. 6.4%, P ). A subset analysis revealed a significant advantage for adjuvant hormonal therapy in patients with Gleason scores 8 10, including overall survival (81% vs. 70.7%, P 0.044) [47]. A 10-year update of RTOG was recently published and confirmed the outcomes described above for the 5-year analysis [51]. D Amico and associates reported the results of a randomized trial evaluating 6 months of hormonal therapy combined with approximately 70 Gy of radiotherapy for intermediate and some high-risk patients. Hormonal therapy consisted of 6 months (2 months neoadjuvant, 2 months concurrent and 2 months adjuvant) of total androgen blockade including a LHRH-agonist and flutamide. Patients were randomized between radiotherapy with hormonal therapy and radiotherapy alone. The 206 patients met one of the following criteria: clinical stage T1b-T2bNxM0 and PSA 10, Gleason score 7, or low-risk disease with an MRI consistent with seminal vesicle involvement or extracapsular extension. The radiation treatment consisted of 45 Gy to the prostate and seminal vesicles followed by an additional 22 Gy boost to the prostate. The prescription of the radiotherapy was such that the total dose to the center of the prostate was around 70 Gy. Salvage hormonal therapy was started in both groups following PSA failure (the PSA reached a level of 10 ng/ml). Overall survival was significantly increased for patients receiving hormonal therapy (P 0.04). Prostate cancer-specific mortality favored the combined therapy arm (P 0.02) and the rate of non-prostate cancer-specific mortality did not differ (P 0.31). However, the applicability of this trial to high-risk patients may be questioned since only 15% of patients had Gleason scores 7, 13% had PSA 20, and no patients with clinical stage greater than T2N0 were included in the study [48].

7 J.C. Picard et al. / Urologic Oncology: Seminars and Original Investigations 30 (2012) A meta-analysis of 5 RTOG clinical trials involving 2,743 patients identified 4 prognostic groups, and defined subsets of patients who either do not benefit from the use of adjuvant hormone treatment at all or who benefit from short-term or long-term hormone therapy. Patients with tumors of a high Gleason grade (8 10) and T3 disease had a significantly greater survival chance when treated with adjuvant hormonal therapy. However, the optimum duration of treatment has not been established. High-risk patients should be offered neoadjuvant and concurrent androgen deprivation therapy followed by long-term adjuvant therapy for at least 2 years [52]. The studies described above evaluate the benefit of hormonal therapy combined with external beam radiotherapy. Some institutions have evaluated the role of hormonal therapy combined with brachytherapy for high-risk prostate cancer. Since these patients are at a higher risk of extracapsular extension, brachytherapy is most often combined with a short course of external beam radiotherapy. While there are no randomized trials reported that have evaluated this trimodality approach, investigators at Mount Sinai School of Medicine in New York have reported their experience in treating high-risk patients with neoadjuvant hormonal therapy followed by Pd-103 permanent brachytherapy, with concurrent hormonal therapy followed by 2 months of external beam radiotherapy, including 45 Gy to the prostate and seminal vesicles. Patients receive 2 to 3 months of adjuvant hormonal therapy for an average of 9 total months of hormonal therapy. With a median follow-up of 50 months on 132 patients with high-risk disease, 5-year freedom from biochemical relapse for patients was 76% for patients with Gleason scores 8 10, 79% for patients with a serum PSA 20 ng/dl, and 85% for patients with clinical stage greater than T2b [53]. From the studies discussed above, one may conclude that the addition of hormonal therapy to radiotherapy improves outcomes for high-risk prostate cancer patients. While most men in the United States with high-risk prostate cancer are treated aggressively with multimodal therapy, many noncurative approaches, such as hormonal monotherapy, may be considered in other parts of the world. A recently published study evaluated the addition of radiotherapy to hormonal therapy for high-risk prostate cancer. Widmark et al. reported the results of the Scandinavian Prostate Cancer Group Study 7, a randomized controlled trial that included 880 men with locally advanced prostate cancer. Patients were required to have T1b-T2 disease with WHO grade 2 3 tumors or T3 disease regardless of grade. Patients with lymph node involvement were excluded. Patients were randomized to receive either 3 months of total androgen blockade with flutamide and leuprorelin followed by continuous anti-androgen therapy with flutamide until progression, or the same hormonal treatment regimen plus radiotherapy. Radiotherapy included a dose of 50 Gy to the prostate and seminal vesicles followed by a radiation boost for a total dose of 70 Gy to the prostate. At 4 years, the quality of life was similar between the 2 study groups. However, 18% of patients who underwent hormone therapy alone died of prostate cancer as compared with 9% of those who had combined therapy. The combined therapy provided a 50% reduction in the risk of death due to prostate cancer [54]. This study supports the conclusion that high-risk prostate cancer patients benefit from a combined modality approach Radiotherapy and salvage surgery Salvage radical prostatectomy may cure patients who have local prostate cancer recurrence after radiotherapy. Bianco et al. reported the long-term outcome of 100 consecutive patients (58 after external beam radiation, 42 after brachytherapy), between 1984 and 2003, treated with salvage prostatectomy for biopsy-confirmed locally recurrent prostate cancer. He reported an overall 5-year progressionfree probability of 55% and a mean progression-free interval of 6.4 years. The preoperative serum PSA was significantly associated with the progression-free probability. The 5-year progression-free probabilities with serum PSA levels 4, 4 10, and 10 ng/dl were 86%, 55%, and 37%, respectively. The 10- and 15-year cancer-specific mortality after salvage prostatectomy was 27% and 40%, respectively. An important note is that 16 patients received ADT with radiotherapy [55]. Lerner et al. reported comparable results on 132 patients undergoing salvage prostatectomy between 1967 and At 5 and 10 years, the cancer-specific mortality was 11% and 28%, respectively [56]. Many physicians are hesitant to offer salvage prostatectomy to their patients due to the concern that salvage prostatectomy is associated with increased complication rates. Lerner et al. reported an overall complication rate of 44% after salvage prostatectomy with a 6% incidence of rectal injury. His incontinence rate (requiring at least 2 pads per day) was 23% [56]. A recent report by Bianco et al. noted an overall complication rate of 33% between 1984 and 1993, including a 15% risk of rectal injury. He compared those older rates with his complication rates between 1993 and 2003, where his overall complication rate was only 13%, including a 2% risk of rectal injury. He attributed his high complication rates between 1984 and 1993 to the performance of staging lymph node dissections with or without retropubic brachytherapy. These procedures are now rarely performed. Overall, 23% of patients required an artificial urethral sphincter for moderate to severe incontinence, while 68% of patients were either continent or minimally incontinent (requiring only 1 pad per day) [55] Radiotherapy and chemotherapy Radiotherapy and adjuvant chemotherapy The RTOG conducted a randomized trial evaluating the role of adjuvant chemotherapy in men with high-risk prostate cancer treated with external beam radiotherapy (RTOG 99-02). They planned to enroll 1,440 men who would be

8 10 J.C. Picard et al. / Urologic Oncology: Seminars and Original Investigations 30 (2012) 3 15 treated with adjuvant hormonal therapy for 2 years with or without combination chemotherapy with estramustine, paclitaxel, and etoposide. The primary endpoint was overall survival. This trial was closed after only 397 patients had been enrolled due to grade 4 or 5 adverse events and a high incidence of thromboembolic disease in 34 patients [57,58]. An additional phase III trial has been initiated by the RTOG based on the positive results using docetaxel in hormone-refractory disease. RTOG 0521 plans to recruit 600 men with high-risk disease to receive radiation therapy and 2 years of androgen deprivation with or without adjuvant docetaxel (6 cycles at 75 mg/m 2 every 3 weeks) after completion of radiotherapy. No estramustine or etoposide is included in this trial. The primary endpoint is overall survival. It is designed to detect a 7% absolute improvement in overall survival at 4 years, which is equivalent to 90% power to detect a 51% reduction in yearly death rate Radiotherapy and concurrent chemotherapy A few small phase I/II studies have been performed or initiated looking at combining chemotherapy and radiotherapy concurrently. With the success of the docetaxel trials in hormone refractory disease, interest has turned to combining docetaxel with radiotherapy for earlier stages of highrisk prostate cancer. For example, Kumar and colleagues at the Cancer Institute of New Jersey reported their results of a phase I docetaxel dose-escalation trial. This trial treated patients with high-risk localized prostate cancer with external beam radiotherapy and weekly docetaxel in doses 5 25 mg/m 2. Radiotherapy included 45 Gy to the pelvic lymph nodes using a 4-field approach followed by a boost to the prostate for a total dose of 70.2 Gy using a 3D-conformal technique. The dose limiting toxicity was grade 3 diarrhea that was encountered in the first 2 patients at the 25 mg/m 2 dose level. The maximally tolerated dose was determined to be 20 mg/m 2 for weekly docetaxel given with radiotherapy that included treatment of the pelvic lymph nodes [59]. The same group completed another phase I/II trial using a fixed dose of 20 mg/m 2 of docetaxel with intensity modulated radiotherapy (IMRT) to 72 Gy. Seventeen of the 20 patients enrolled in this trial also received hormonal therapy. Radiotherapy details of this trial are not thoroughly described, but the majority of patients tolerated the treatment with mild to moderate toxicity. Three patients did require treatment breaks, 2 for dehydration from diarrhea and 1 from a gastrointestinal bleed, while an additional patient required I.VS. hydration without hospitalization [60]. Investigators at the Hollings Cancer Center at the Medical University of South Carolina are nearing completion of a phase I/II trial investigating total androgen blockade, weekly docetaxel, and intensity modulated radiotherapy to 77.4 Gy. In this trial, patients start radiotherapy 8 to 12 weeks after starting total androgen blockade. The seminal vesicles and prostate receive 45 Gy followed by a boost to the prostate for a total dose of 77.4 Gy. IMRT is delivered using image-guidance with implanted fiducials and an endorectal balloon to minimize target motion and set-up error. To date, 15 patients have been enrolled. With 3 patients enrolled in the final dose level of 25 mg/m 2, only 1 dose-limiting toxicity has been seen, an elevation in total bilirubin in a patient with a history of hyperbilirubinemia in the months prior to starting therapy. There have been no other grade 3 toxicity events to date in the study (unpublished data, DTM). The trial continues to accrue ( NCT ). Other similar trials are underway as well at the University of North Carolina Chapel Hill ( clinicaltrials.gov/ct2/show/nct ), and the National Cancer Institute of Canada ( NCT ) Radiotherapy and neoadjuvant chemotherapy There is little data regarding the use of neoadjuvant chemotherapy with radiotherapy in prostate cancer. Zelefsky and colleagues treated 27 men who had prostate cancer with estramustine and vinblastine before and during conformal radiotherapy. After a median follow-up of 26 months, 7 of the 23 patients who completed therapy had PSA relapses, and the treatment demonstrated modest toxicity [42]. Ben- Josef et al. treated 18 patients who had T3 or T4 disease, a Gleason score of 8 10 and/or a PSA level greater than 15 ng/ml, with estramustine and etoposide. Overall 3-year disease-free survival was 73%. Repeat prostate needle biopsies performed 18 months after the completion of radiotherapy showed persistent local control in 71% of patients [61]. A current multi-center, randomized phase III trial from the Dana-Farber Cancer Institute is aiming to recruit 350 patients with high-risk disease in order to assess 6 months of androgen deprivation plus radiotherapy with or without neoadjuvant and concurrent docetaxel. Patients in the chemotherapy group will receive 3 cycles of neoadjuvant docetaxel (60 mg/m 2 every 3 weeks) plus a luteinizing hormone-releasing agonist followed by 7 doses of weekly docetaxel (20 mg/m 2 ) beginning with the first week of radiotherapy. The primary endpoint of this study is 5-year patient overall survival ( clinicaltrials.gov/show/nct ). 4. The role of hormonal therapy Androgen deprivation therapy (ADT) with either medical or surgical castration remains the initial treatment for metastatic prostate cancer, localized disease in patients with poor prognostic factors, or in combination with other treatments. The ideal treatment would rapidly lower serum testosterone levels to castrate levels (20 50 ng/dl). Surgical castration has been found to lower serum testosterone levels to castrate levels within 3 to 12 hours after orchiectomy, with a subsequent decrease in serum PSA levels [62]. Medical castration is commonly performed with a LHRH or gonadotropin-releasing hormone (GnRH) agonist. The LHRH agonist binds to the LHRH receptor in the pituitary triggering a transient rise in serum LH and subsequent

9 J.C. Picard et al. / Urologic Oncology: Seminars and Original Investigations 30 (2012) increase in serum testosterone. This flare is followed by an inhibition in LH secretion and subsequent reduction in serum testosterone. As an example, Sasagawa et al. administered a 3.75 mg depot injection of leuprolide and measured the serum LH and testosterone levels on days 0, 2, 5, 7, 14, 21, and 28 following the injection. He observed an increase in LH levels above pre-injection levels for approximately 7 days after the injection. Castrate levels of testosterone were not achieved until approximately 21 days after injection [63]. The benefits of early administration of ADT are primarily improvements in a patient s quality of life. These benefits include reduction in pathologic fractures, spinal cord compression, and urinary obstruction [64]. Despite these benefits of immediate ADT, immediate vs. symptom-onset institution of ADT has demonstrated no overall survival advantage over delayed or symptom-onset institution of ADT at this time [65]. Adverse effects of ADT include hot flashes, skeletal complications, including loss of bone mineral density and fracture, increased sexual dysfunction, metabolic syndrome (increasing fat mass, increasing cholesterol, and glucose intolerance), anemia, gynecomastia, dry eyes, body hair loss, and vertigo [66]. Anti-androgen therapy also plays a significant role in the management of prostate cancer. Anti-androgen therapy has been utilized to minimize the impact of the testosterone flare by treating patients with a short 2 to 3 week course at the initiation of LHRH agonist administration or to provide long-term co-administration with LHRH agonists to achieve maximum androgen blockade. The benefits of maximum androgen blockade are controversial. Many studies have been undertaken to determine the efficacy of maximum androgen blockade; however, the results of these studies have been inconsistent as a result of flawed study design including small study numbers, recruitment bias, and varying endpoints. Additionally, these studies were performed at a time when we did not fully understand the mechanism of the androgen receptor or appreciate the phenomenon of androgen withdrawal syndrome. A large number of meta-analyses were subsequently performed with the hopes of clarifying the benefits of maximum androgen blockade. One of the most useful meta-analyses was the Prostate Cancer Trialists Collaborative Group meta-analysis. This group performed a meta-analysis of 27 randomized trials comparing maximum androgen blockade (surgical castration or LHRH agonist plus anti-androgen) vs. surgical castration or LHRH agonist alone in 8,275 men (88% metastatic and 12% locally advanced). The results demonstrated a 5-year survival benefit of 2% to 3% [67]. Recently, as our understanding of the androgen receptor improved, a new wave of interest has developed in recommending maximum androgen blockade over LHRH-agonist monotherapy. Currently, a phase III randomized, doubleblind multicenter trial is underway in a cohort of 205 Japanese patients randomized to receive a LHRH agonist in combination with either placebo or bicalutamide 80 mg daily (the approved dose of bicalutamide in Japan). Currently, the maximum androgen blockade cohort has demonstrated a significant improvement in the median time to PSA reduction to less than 4 ng/ml (8.1 vs weeks, P 0.001), as well as the time-to-treatment failure (117.7 vs weeks, P 0.001) and the time-to-disease progression (not yet reached vs weeks, P 0.001) compared with LHRH agonist monotherapy. An interim comparison of overall survival was not significant due to relatively low mortality rates of both arms; however, with continued monitoring of these cohorts, it was expected that there would be a significant improvement in overall survival with maximum androgen blockade compared with LHRH agonist monotherapy [68]. A follow-up analysis was presented at the 2008 American Society of Clinical Oncology Annual Meeting. At a median follow-up of 270 weeks, 5-year overall survival for combination therapy with LHRH agonist plus bicalutamide vs. LHRH agonist monotherapy was 75.3% vs. 63.4%, respectively. This difference was significant with P Cause-specific survival was higher with maximum androgen blockade vs. LHRH monotherapy; however, the difference did not reach significance. Interestingly, overall survival was significantly better for patients with a PSA nadir 1 ng/ml compared with 1 ng/ml (P ) [69]. This trial is ongoing and will likely revolutionize the way we perform hormonal manipulations in the treatment of prostate cancer. This corroborates an indirect analysis by Klotz et al. published in 2004, in which he estimated that a combination of LHRH agonist plus bicalutamide 50 mg may provide a reduction in mortality risk of approximately 20% (range 2% 34%) compared with LHRH agonist monotherapy [70]. Recently, a new LHRH receptor antagonist, degarelix, has been FDA-approved for the treatment of advanced prostate cancer. This medication reversibly binds to pituitary LHRH receptors. Klotz et al. reported on the safety and efficacy of degarelix in a 610-patient, 1-year trial compared with leuprolide, in achieving and maintaining testosterone suppression in prostate cancer patients. Three dosing regimens were utilized 240 mg degarelix initially plus 80 mg degarelix monthly, 240 mg degarelix initially plus 160 mg degarelix monthly, or leuprolide 7.5 mg monthly. Testosterone levels were 50 ng/dl as measured monthly between days 28 and 364 in 97.2%, 98.3%, and 96.4% in the degarelix 240/80 mg, degarelix 240/160 mg. and leuprolide groups respectively. Testosterone levels, as measured on day 3 were 50 ng/dl in 96.1%, 95.5%, and 0% of patients in the degarelix 240/80 mg, degarelix 240/160 mg, and leuprolide groups, respectively. Side effects of degarelix included injection site reactions, hot flashes, elevation in hepatic transaminases, back pain, hypertension, arthralgia, fatigue, urinary tract infections, hypercholesterolemia, chills, and constipation [71]. Gittelman et al. reported their results of a phase II dosefinding trial of degarelix for the treatment of prostate cancer in North America. A total of 127 patients received an initial