Neoadjuvant Hormonal Therapy in Men Being Treated With Radiotherapy for Localized Prostate Cancer

LHRH AGONISTS: CONTEMPORARY ISSUES Neoadjuvant Hormonal Therapy in Men Being Treated With Radiotherapy for Localized Prostate Cancer Mack Roach, III, MD, FACR Departments of Radiation Oncology and Urology, UCSF Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA Several prospective randomized trials have demonstrated that men with localized prostate cancer benefit from the use of short-term neoadjuvant hormonal therapy (NHT) in combination with external beam radiotherapy (EBRT). Seven randomized trials were summarized in 6 publications including patients treated with NHT in combination with EBRT on 1 or more arms. A total of 17 different arms were compared including radiotherapy alone (n = 3), and NHT and concurrent hormonal therapy (N&CHT) (n = 12) with or without short-term adjuvant hormonal therapy (SAHT) (n = 5) or long-term hormonal therapy (n = 1). Patients treated with EBRT alone had a worse outcome than those treated with NHT. Intermediate-risk patients treated with 2 to 3 months of NHT did as well as those treated with longer neoadjuvant therapy or SAHT. The preponderance of data supports the use of NHT in combination with EBRT in intermediate-risk patients. [Rev Urol. 2004;6(suppl 8):S24-S31] © 2004 MedReviews, LLC Key words: Prostate cancer • Radiotherapy • Randomized trials • Neoadjuvant hormonal therapy • External beam radiotherapy reatment recommendations for men with clinically localized prostate cancer should be based on data from prospective phase III randomized trials whenever possible. Based on several phase III trials, the most appropriate treatment for patients with bulky and high-grade disease has been well defined. All major prospective randomized trials completed to date, including the Radiation Therapy Oncology Group (RTOG) 85-31 trial reported by Pilepich and colleagues, the European Organization for Research and Treatment of Cancer trial reported by T S24 VOL. 6 SUPPL. 8 2004 REVIEWS IN UROLOGY Neoadjuvant Hormonal Therapy for Localized Prostate Cancer Bolla and associates, the RTOG study 92-02 reported by Hanks and colleagues, and a relatively small Swedish trial reported by Granfors and coworkers, suggest that longterm adjuvant hormone therapy (LAHT) improves survival in very high-risk patients managed with demonstrated a reduction in the incidence of extracapsular extension, and positive surgical margins following neoadjuvant androgen suppression but no improvement in freedom from biochemical failure or survival.8-10 The failure of neoadjuvant chemotherapy to benefit a patient prior to surgical The biologic rationale for using hormonal therapy with radiotherapy includes reductions in the tumor volume and enhanced biological effects. external beam radiotherapy (EBRT).1-4 These patients typically had highstage tumors (T) (T2c to T3), high Gleason scores (7 to 10), and high prostate-specific antigen (PSA) levels (> 20 ng/mL), with a significant number having lymph node involvement. The findings from these 4 studies are consistent with conclusions of a meta-analysis of RTOG trials and it should be noted that there are no completely negative trials in this setting.5 For patients with low- and intermediate-risk disease, the role of hormonal therapy (HT) is less well defined. Similarly, in the minds of many, the role of neoadjuvant hormonal therapy (NHT) remains controversial with no consensus on the matter. This review uses data from the prospective randomized trials completed to date in an effort to determine whether a strong case for a consensus can be made. Biologic Rationale for Hormonal and Radiotherapy The biologic rationale for using hormonal therapy with radiotherapy includes reductions in the tumor volume and enhanced biologic effects.6,7 This experimental evidence suggests that it may be best to administer androgen suppressive therapy until the tumor is maximally suppressed prior to the delivery of radiation. Surprisingly, a number of prospective randomized surgical trials have resection is not unique to prostate cancer. Several prospective randomized trials have demonstrated that the use of chemotherapy prior to surgical excision does not improve survival for other solid tumors. In contrast to the surgical experience, patients treated for unresectable, non-small cell lung cancer, small cell lung cancer, esophageal cancer, anal cancer, nasopharyngeal cancer, and rectal cancer have demonstrated a survival advantage when the chemotherapy was combined with radiation. The unifying features for all of these sites include: (1) the presence of locally advanced disease, (2) the availability of chemotherapeutic agents with date were critically reviewed in an attempt to answer the following questions: • Is there consistent evidence that NHT is beneficial? • Is there evidence of a sequencedependent biologic interaction between hormonal therapy and radiotherapy? • Is there a sub-population of patients treated with radiotherapy in which NHT is not justified? • If justified, how long should NHT be used? • What volume should be irradiated? • Should high-risk patients receive short-term NHT? Materials and Methods This review is based on an analysis of the data provided in 7 prospective randomized trials summarized in 6 publications that included patients treated with NHT in combination with EBRT on 1 or more arms. All trials were published between 2001 and 2004. A total of 17 different arms were compared including radiotherapy alone (n = 3), and concurrent hormonal radiotherapy (n = 12) with or without short-term adjuvant HT (n = 5) or long-term HT (n = 1). The trials The first major phase III trial testing the hypothesis that N&CHT combined with EBRT would improve the outcome compared to EBRT alone was RTOG 8610. modest independent activity, (3) a primary site and nodal drainage that can be easily incorporated into a radiotherapy portal, and (4) evidence of favorable interactions between the drug in question and radiation. Prostate cancer seems to meet all of these criteria, making it a good candidate for hormonal therapy combined with radiotherapy. In this report, all major prospective randomized trials published to ranged in size from 161 to 1514 patients. All patients received combined hormonal blockade for at least a portion of their treatment. The studies included are summarized below. RTOG 8610 RTOG 8610 was the first major phase III randomized trial testing the hypothesis that neoadjuvant and concurrent hormonal therapy (N&CHT) combined with EBRT would improve the out- VOL. 6 SUPPL. 8 2004 REVIEWS IN UROLOGY S25 Neoadjuvant Hormonal Therapy for Localized Prostate Cancer continued come compared to EBRT alone.11 This trial included 456 patients and was conducted from 1987 to 1991. Eligible patients were those with “bulky tumors” (5 x 5 cm), stages T2 to T4, using the 1988 American Joint Committee on Cancer staging system. Patients with or without pelvic lymph node involvement were randomized to receive combined androgen blockade (CAB) consisting of goserelin (3.6 mg every 4 weeks) and flutamide (250 mg tid for 2 months) before radiation therapy (neoadjuvant) and concurrent with EBRT (Arm I) or EBRT alone (Arm II). At 8 years, CAB was associated with an improvement in local control (42% vs 30%, P = .016), reduction in distant metastases (34% vs 45%, P = .04), disease-free survival (DFS) (33% vs 21%, P = .004), biochemical DFS with PSA level < 1.5 ng/dL (24% vs 10%, P < .0001), and cause-specific mortality (23% vs 31%, P = .05). In a subset analysis, an overall survival benefit associated with 4 months of N&CHT appeared to be limited to patients with “bulky disease” and a Gleason score ≤ 6 (70% vs 52% for EBRT alone, P = .015). Randomized Trials from Quebec Laverdiere and colleagues12 first published the preliminary findings of a 3-arm trial in 1997. They initially reported biopsy findings in 120 patients treated with EBRT alone or in combination with CAB. Patients with clinical stage B1-T2a, B2T2b/T2c, and C-T3/T4 disease were randomly allocated to EBRT alone (group 1), 3 months of neoadjuvant CAB prior to EBRT (group 2), or 3 months before, concurrent with EBRT and 6 months after EBRT (adjuvant) (group 3). Transrectal ultrasounddirected needle biopsies were obtained from the initial cancer sites at 12 and 24 months after the completion of EBRT. At 12 months, 62% of the S26 VOL. 6 SUPPL. 8 2004 patients treated with EBRT alone had positive biopsies compared to only 30% and 4% for groups 2 and 3, respectively (P = .00005). A similar difference between arms was seen at 24 months. These investigators recently expanded and updated the results of this 3arm trial as well as those of a second confirmatory trial.13 Altogether between 1990 and 1999, 486 patients were entered into their consecutive trials (first trial N = 161, second trial N = 325). In the updated analysis of study 1, the 7-year biochemical-free survival rates were 42%, 66%, and 69% in groups 1, 2, and 3, respectively. There was no difference in the outcome between groups 2 and 3 (P = .6) but both CAB arms were better than EBRT alone (groups 1 vs 2 and 1 vs 3 (P = .009 and .003, respectively). In the second trial, patients were randomized between N&CHT (total 5 months) and neoadjuvant, concomitant, and shortcourse adjuvant HT (N&C&SAHT) (total 10 months) with EBRT. PSA failure was defined as 2 consecutive rises with at least 1 of 1.5 ng/mL or greater (“Vancouver rules”). In study 2, there was no difference in the outcomes between 5 month N&CHT and N&C&SAHT (P = .55). The authors concluded there was no advantage in adding a short course of adjuvant HT after neoadjuvant HT was provided, but NHT improved the outcomes compared to EBRT alone. RTOG 9202 This trial followed the findings of RTOG 8610 (described above) and RTOG 8531 that initially reported a survival advantage limited to patients with a Gleason score of 8 to 10.1,3 A subsequent update of 8531 patients demonstrated an overall survival advantage (although subset analysis suggests it may be limited to patients with T stage 3 tumors and Gleason score 7 or patients with Gleason REVIEWS IN UROLOGY scores of 8 to 10).5,14 Patients with clinical stage T2c-T4 disease (N = 1554) were randomized to receive a total of 4 months of CAB, 2 months before and 2 months during EBRT. They were then randomly assigned to receive no additional therapy or 24 months of long-term adjuvant goserelin (LAHT). At 5 years, overall survival was not statistically different between the 2 arms (80.0% vs 78.5%, P = .73). However, patients with Gleason scores of 8 to 10 had significantly better cancer-specific and overall survival if treated with 2 years of adjuvant HT (81 % vs 71%, P = .04). The American Society for Therapeutic Radiology and Oncology (ASTRO) definition of PSA was used to assess biochemical failure, but it cannot be considered a valid endpoint given the dramatic differences in the duration of HT between the 2 arms. RTOG 9413 This trial tested the hypothesis that CAB and whole-pelvic (WP) radiotherapy (RT) followed by a boost to the prostate improves progression-free survival (PFS) by 10% compared with CAB and prostate-only (PO) RT.15 This trial also tested the hypothesis that N&CHT improves PFS compared with short-term adjuvant hormonal therapy (SAHT) by 10%. Eligibility included localized prostate cancer with an estimated risk of lymph node (LN) involvement of 15% using the equation: risk + node = 2/3 (PSA) + [(GS-6)
10]. More than 1300 patients were enrolled between April 1995 and June 1999, and randomly assigned to WP + N&CHT, PO + N&CHT, WP + SAHT, or PO + SAHT. Failure for PFS was defined as the first occurrence of local, regional, or distant disease, or death from any cause. PSA failure was defined as 2 consecutive and significant rises separated by at least 1 month. For PSA level < 1.5 ng/mL an increase of ≥ 0.3 Neoadjuvant Hormonal Therapy for Localized Prostate Cancer ng/mL was considered a significant rise. For PSA values > 1.5 ng/mL an increase of 20% or more was considered significant. A PSA level ≥ 4 ng/mL was also considered a failure. With a median follow-up of 59.5 months, when comparing all 4 arms, there was a progression-free difference in favor of WP RT + N&CHT, compared to PO RT + N&CHT, WP RT + SAHT, and PO RT + SAHT (60% vs 44% vs 49% vs 50%, respectively; P = .008). As expected with short follow-up, there was not yet a survival advantage. The Harvard N&C&SAHT Trial This study was designed to determine The Princess Margaret Multicenter Study This study evaluated the impact of NHT prior to EBRT on disease-free survival using PSA levels and biopsies as endpoints.17 From February 1995 to June 2001, 400 men were randomized to either 3 or 8 months of flutamide and goserelin prior to (NHT) EBRT. With a median followup of 44 months, the 8-month arm achieved a lower PSA nadir prior to starting RT (0.37 vs 0.74 ng/mL, P ≤ .001) as well as a more dramatic reduction in prostate volumes (mean volume 26.6 cc vs 30.5 cc, P ≤ .001). Despite these findings, the freedom from PSA failure rates (ASTRO defi- Patients randomized to receive 3D-CRT plus N&C&SAHT had a significantly higher overall survival and lower rate of death from prostate cancer. whether there was a survival benefit when 3-dimensional conformal radiation therapy (3D-CRT) was administered alone or in combination with 6 months of N&C&SAHT in patients with clinically localized intermediate-risk prostate cancer.16 In total, 206 patients were entered from December 1, 1995, to April 15, 2001, in this prospective, randomized, controlled trial to receive 70 Gy 3D-CRT alone (n = 104) or in combination with 6 months of N&C&SAHT (n = 102). Eligible patients included those with a PSA level of at least 10 ng/mL, a Gleason score of at least 7, or radiographic evidence of extra-prostatic disease. The major endpoints were overall survival and the time to PSA >1.0 ng/mL and an increase in the PSA by >0.2 ng/mL on 2 consecutive occasions. Patients randomized to receive 3D-CRT plus N&C&SAHT had a significantly higher overall survival (P = .04), and lower rate of death from prostate cancer (P = .02) despite a surprisingly short median follow-up of 4.52 years. nition) were similar at 5 years (61% vs 62%). The researchers noted a trend for an improvement in the 8-month arm for disease-free survival at 5 years for high-risk patients (39% vs 52%), but this did not reach statistical significance. Results Table 1 summarizes the major pretreatment features of the patients included in the 7 randomized trials reviewed. More than 4300 patients were treated on all 17 arms. The doses of radiation used were remarkably similar with all using 65 to 70 Gy. Three trials omitted prophylactic pelvic radiotherapy in all patients (the Quebec series and the Harvard trial) and all 3 showed an advantage of NHT over EBRT alone. One study irradiated the pelvic lymph nodes only in the patients with an estimated risk of > 10% to 15% (Princess Margaret series), 2 studies radiated the lymph nodes in all patients (RTOG 8610 and 9202), and in the remaining study, half of the patients received pelvic radiotherapy (RTOG 9413). The median PSA levels available for the trials reviewed ranged from 10 to 26 ng/mL. The RTOG trials were larger than the other trials (n = 456 to 1514 compared to 161 to 378) and tended to include patients with more advanced disease. For example, the median pretreatment PSA levels for the patients treated on RTOG trials ranged from 20 ng/mL to 26 ng/mL compared to the other trials with values of approximately 10 ng/mL to 12 ng/mL. Patients treated on RTOG trials also tended to have higherstage disease with fewer patients having T1-T2b tumors (0 to 30%) compared with 52% to 100% in the 2 other trials providing such data. Similarly, the patients treated on RTOG trials tended to have more high-grade tumors with 60% to 73% having Gleason scores of 7 to 10, compared with 28% to 74% of patients treated on the other trials. The 3 studies that compared EBRT alone versus EBRT + NHT demonstrated a worse outcome for patients treated with EBRT alone. Three trials included arms using pure NHT. One of these trials showed no advantage to using longer NHT (3 vs 8 months), whereas the 2 others showed there was no benefit to adding concurrent and short-term adjuvant hormonal therapy (3 months NHT vs N&C&SAHT [total time, 10 months]). In considering only the arms using prostate-only EBRT, N&CHT appeared to be equivalent to SAHT. Patients with very high-risk disease did better if treated with long-term adjuvant HT (n = 1) and a trend was noted for them to do better with longer NHT (8 months) (n = 1), although the latter trend did not reach statistical significance. Despite a wide variety of study designs and definitions of PSA failures, there appears to be consistent evidence for the benefit of the use VOL. 6 SUPPL. 8 2004 REVIEWS IN UROLOGY S27 Neoadjuvant Hormonal Therapy for Localized Prostate Cancer continued Table 1 Pretreatment Features of Patients on Phase III Trials Using Neoadjuvant ± Concurrent ± Adjuvant HT Total/No. Pts with Neoadjuvant +/- Concurrent HT No. HT No. Short/ Long-term Adjuvant HT Pilepich (2001) 456/226 230 Roach15 (2003) 1291/645 Hanks3 (2003) Laverdiere13 (2004)† Pretreatment PSA Levels (Median) Comments Clinical Tumor Stage, % Gleason Score (GS), % 0/0 T1-T2b:0 T2c:30 T3-T4:70 GS 2-6: GS 7: GS 8-10: 28 26 ng/mL Survival advantage for GS < 7, included N+ pts 0 646/0 T1-T2b:33 T2c:NR T3-T4:NR GS 2-6: 28 GS 7: NR GS 8-10: NR 23 ng/mL Progression-free survival advantage with short follow-up 1514/[761 vs 753 (+ adjuvant)] 0 0/753 T1-T2b:0 T2c:45 T3-T4:55 GS 2-6: 40 GS 7: 35 GS 8-10: 26 20 ng/mL Disease-specific survival and overall for GS = 8-10 161/63 43 55/0 T1-T2b:NA T2c:NA T3-T4:30 (7-10): 26* 10 ng/mL* PSA failure rates higher with EBRT alone, otherwise no differences 296/148 (3 mo) 0 148/0 T1-T2b:NA T2c:NA T3T4:13.5 (7-10): 28 12 ng/mL D’Amico16 (2004) 206/104 102 0/0 T1-T2b:100 T2c:0 T3-T4:NA GS 2-6: 35 GS 7: 59 GS 8-10:15 11 ng/mL Overall and diseasespecific survival advantage Crook17 (2004)‡ 378/378 (3 mo vs 8 mo) 0 0 T1-T2b: ~52 T2c: ~35 T3-T4:13 GS 2-6: 50 GS 7: 38 GS 8-10: 11 ~10 ng/mL Overall no difference in PSA failure rates First Author (Year) 11 HT, hormonal therapy; PSA, prostate-specific antigen; NR, not recorded; NA, not available; EBRT, external beam radiotherapy; N, node. *Average based on pooled data. † Estimated value from paper. ‡ Abstract only. of NHT in patients with intermediate-risk disease. Discussion In this analysis of all major prospective randomized trials published to date, we attempted to answer the several questions mentioned above. Based on the data provided in these studies the following conclusions have been made. First, there appears to be consistent evidence that neoadjuvant hormonal therapy is beneficial when combined with 70 Gy of EBRT in patients with intermediate- to S28 VOL. 6 SUPPL. 8 2004 high-risk clinically localized prostate cancer (RTOG 8610, Quebec study #1, Harvard study). Second, when only the prostate is irradiated, the biologic appear to be sequence dependent when the lymph nodes are irradiated (Arm 1 vs Arm 3 of RTOG 9413). Third, NHT and EBRT have not yet There appears to be consistent evidence for the benefit of NHT when combined with 70 Gy of EBRT in patients with intermediate- to high-risk disease. interactions between radiation and HT may not be sequence dependent (Arm 2 vs 4 of RTOG 9413). However, the biologic interactions between hormonal therapy and radiotherapy REVIEWS IN UROLOGY been shown to be beneficial in patients with low-risk disease. NHT (without long-term adjuvant HT) combined with EBRT appears to be inadequate treatment for patients Neoadjuvant Hormonal Therapy for Localized Prostate Cancer A How Could HT Impact EBRT? Low Risk • Local Control Intermediate Risk • Regional Control High Risk • Distant Control B How Could HT Impact EBRT? • Local Control Low Risk • Regional Control Intermediate Risk • Distant Control C High Risk How Could HT Impact EBRT? • Local Control Low Risk • Regional Control Intermediate Risk • Distant Control High Risk Figure 1. The density of the arrows is meant to be proportionate to the potential benefit when stratified by risk group. (A) Given the “noise” of competing causes of death, patients at low risk for regional and distant disease are only likely to experience benefits from NHT due to improvements in local control. (B) Intermediate-risk patients are at significant risk for local and regional disease and may benefit from radiation interactions in both areas. They may be less likely to experience benefits from NHT-based improvements in local control if higher radiation doses are used but still benefit from pelvic RT. (C) High-risk patients are likely to benefit from treatment of systemic therapy in addition to local and regional disease when given HT. NHT, neoadjuvant hormonal therapy; RT, radiotherapy, EBRT, external beam radiotherapy. with very high-risk disease (RTOG 9202, and subset analysis from RTOG 9413, patients with Gleason scores 7 to 10 and PSA levels > 30 ng/mL). It has also been discovered that 2 to 3 months of NHT combined with EBRT appears to be adequate for intermediate-risk patients with no additional benefit with concurrent and/or SAHT (Quebec studies, Princess Margaret study). Also, patients with a risk of positive nodes ≥ 15% should undergo prophylactic pelvic nodal therapy in conjunction with NHT (RTOG 9413, RTOG 8610 and RTOG 9202). Last, based on the sequence-dependent nature of favorable biologic interactions between radiation and hormonal therapy, high-risk patients should probably receive short-term NHT in addition to long-term adjuvant HT (RTOG 9413, RTOG 9202, RTOG 8610). How Do We Explain These Findings? The decision to divide the studies into groups on the basis of whether they used neoadjuvant, concurrent, or adjuvant HT was somewhat arbitrary and, in some ways, illogical. For example, a patient who receives 3 months of NHT immediately prior to EBRT is still likely to be at castrate levels when EBRT is started, so he in fact receives concurrent HT as well. However, by dividing the trials into these categories, an argument can be made that there is a lack of duration-of-HT effect for 3 months versus 5 months, versus 8 months, and versus 10 months, whether given before, during, or after, respectively. This raises practical considerations such as an opportunity for cost containment as well as providing insights into the biology of radiation hormonal therapy interactions. A model for how EBRT might interact with HT is shown in Figure 1. It should be noted that for patients at low risk for progression (A), if local EBRT is made more effective (eg, higher radiation doses > 70 Gy) without HT, the benefits of NHT might be reduced or lost. The failure of NHT to be of benefit in the setting of radical prostatectomy may, in part, be due to the fact that local recurrences may occur more frequently in patients with bulky disease treated to doses of < 72 Gy than when radical prostatectomy is used.18 Another way of explaining why the net benefits of NHT may be greatest in patients with intermediate-risk disease is summarized in Figure 2. As shown in this figure, the blue line represents the impact of prostate cancer on survival by risk group, assuming no treatment. The yellow line represents the relative reduction in mortality due to the use of NHT. The red line represents the net effect of the disease and NHT. As is shown, prostate cancer has, relatively speaking, a much lower impact on survival effect in patients with low-risk disease. Thus, there is less opportunity for improvement. In contrast, patients with intermediate- to high-risk disease experience the greatest risk of death. There is room for improvement and, thus, it is easier to see the benefits of NHT. In VOL. 6 SUPPL. 8 2004 REVIEWS IN UROLOGY S29 Neoadjuvant Hormonal Therapy for Localized Prostate Cancer continued Model and Trials on the Impact of Short-term Neoadjuvant Hormonal Therapy and EBRT on Outcome in Treatment of Clinically Localized Prostate Cancer 40 30 20 10 0 -10 -20 -30 Net Impact of Disease & HT -40 Impact of Disease on Survival Impact of Short-term NHT on Survival -50 Relative Extent of Disease Low Risk Disease Intermediate Risk Disease High Risk Disease Very High Risk Disease Harvard Study Quebec Studies Princess Margaret Multicenter Study RTOG 8610 RTOG 9202 RTOG 9413 Figure 2. Prostate cancer has a much lower impact on survival effect in patients with low-risk disease (blue line). Patients with intermediate- to high-risk disease experience the greatest benefit from NHT, particularly when the nodes are irradiated (yellow line). The impact of very high-risk disease (blue line) overwhelms the benefits of NHT such that the net effect on this disease is smaller (red line) and long-term HT is required to dramatically reduce mortality (not shown). A qualitative summary of relative extent of disease for the various trials is shown below. Because of the distribution of disease only a subset of patients from RTOG 8610 (GS < 7) benefited, whereas subsets from RTOG 9202 and 9413 did not benefit. NHT, neoadjuvant hormonal therapy; HT, hormonal therapy; RTOG, Radiation Therapy Oncology Group; GS, Gleason score. patients with very high-risk disease, the impact of the disease (blue line) overwhelms the benefits of NHT so the effect of the disease dominates outcome. For this population of patients, long-term HT is required to dramatically reduce mortality. Defining Risk Groups: Who Should Receive Hormonal Therapy? After reviewing these data, it appears S30 VOL. 6 SUPPL. 8 2004 that intermediate-risk patients benefit from the use of NHT combined with EBRT. Although it is now relatively routine to hear clinicians talk about the treatment of patients of “intermediate risk,” how is such a group best defined? The findings of the Harvard trial are consistent with the conclusions of the meta-analysis of RTOG trials that demonstrated that patients with clinical stage T1-T2 REVIEWS IN UROLOGY tumors and Gleason score of 7 benefited from short-term hormone therapy.16 Patients with a Gleason score of 6 and bulky disease or a PSA level > 10 ng/mL also appear to benefit from NHT (Harvard study, RTOG 8610, and 9413). Of note, a subset analysis based on pretreatment stratification variables suggests that the patients who appeared to benefit most from the addition of whole pelvic radiotherapy were those patients with Gleason scores ≥ 7 and PSA levels < 30 ng/mL and those with Gleason scores 2–6 but PSA levels > 30 ng/mL.15 This observation is consistent with the retrospective data from the University of California San Francisco.19 The low-risk to intermediate-risk patients might be effectively treated with NHT and prostate only EBRT, but as the risk goes up, consideration should also be given to adding whole pelvic RT. What Is the Optimal Duration of Hormonal Therapy? Given the results of several randomized trials, it is clear that long-term hormone therapy is indicated for patients with high-risk disease (T3, Gleason score 7 and Gleason scores 8 to 10).2,3,14 Patients who would otherwise appear to be at intermediate risk, based on tumor stage and Gleason score, might also be considered candidates for long-term HT if they have PSA values > 20 ng/mL or a large number of positive biopsies, but the data are less clear here. Thus far, it appears that for most intermediate-risk patients (risk of positive nodes >15% to approximately 35%), long-term HT is not indicated.3 Conclusion The preponderance of data supports the use of NHT in combination with EBRT in intermediate-risk patients, whereas high-risk patients require the addition of longer-term HT. The Neoadjuvant Hormonal Therapy for Localized Prostate Cancer optimal timing and duration of HT remains to be elucidated. References 1. 2. 3. 4. 5. 6. Pilepich MV, Caplan R, Byhardt RW, et al. Phase III trial of androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate treated with definitive radiotherapy: report of Radiation Therapy Oncology Group Protocol 85-31. J Clin Oncol. Mar 1997; 15:1013-1021. 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; 360:103-106. Hanks GE, Pajak TF, Porter A, et al. Phase III trial of long-term 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. Nov 2003; 21:3972-3978. Granfors T, Modig H, Damber JE, Tomic R. Combined orchiectomy and external radiotherapy versus radiotherapy alone for nonmetastatic prostate cancer with or without pelvic lymph node involvement: a prospective randomized study. J Urol. 1998;159:2030-2034. Roach M, Lu J, Pilepich MV, et al. Predicting long term survival, and the need for hormonal therapy: a meta-analysis of RTOG prostate cancer trials. Int J Radiat Oncol Biol Phys. 2000;47:617-627. Zelefsky MJ, Harrison A. Neoadjuvant androgen ablation prior to radiotherapy for prostate can- 7. 8. 9. 10. 11. 12. 13. cer: reducing the potential morbidity of therapy. Urology. Mar 1997;49(Suppl 3A):38-45. Zietman AL. The case for neoadjuvant androgen suppression before radiation therapy. Mol Urol. 2000;4:203-208; discussion 215. VanPoppel H, Ridder DD, Elgamal AA, et al. Neoadjuvant hormonal therapy before radical prostatectomy decreases the number of positive surgical margins in stage T2 prostate cancer: interim results of a prospective randomized trial. J Urol. 1995;154:429-434. Meng MV, Grossfeld GD, Carroll PR, Small EJ. Neoadjuvant strategies for prostate cancer prior to radical prostatectomy. Semin Urol Oncol. Aug 2002;20(Suppl 1):10-18. Gleave ME, Goldenberg SL, Chin JL, et al. Randomized comparative study of 3 versus 8month neoadjuvant hormonal therapy before radical prostatectomy: biochemical and pathological effects. J Urol. 2001;166:500-506; discussion 506-507. 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;50:1243-1252. Laverdiere J, Gomez JL, Cusan L, et al. Beneficial effect of combination hormonal therapy administered prior and following external beam radiation therapy in localized prostate cancer. Int J Radiat Oncol Biol Phys. 1997;37:247-252. Laverdiere J, Nabid A, De Bedoya LD, et al. The efficacy and sequencing of a short course of androgen suppression on freedom from biochemical failure when administered with radiation therapy for T2-T3 prostate cancer. J Urol. 2004;171:1137-1140. Pilepich MV, Winter K, Lawton C, et al. Androgen suppression adjuvant to radiotherapy in carcinoma of the prostate. Long-term results of phase III RTOG study 85-31. Paper presented at: 45th Annual Meeting of American Society for Therapeutic Radiology and Oncology (ASTRO), October 21, 2003, Salt Lake City, UT. 15. Roach M 3rd, DeSilvio M, Lawton C, et al. Phase III trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413. J Clin Oncol. 2003;21:1904-1911. 16. D'Amico AV, Manola J, Loffredo M, et al. 6month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial. JAMA. 2004;292: 821-827. 17. Crook J, Ludgate C, Lim J, et al. Multicenter Canadian phase III trial of 3 months vs 8 months neoadjuvant androgen deprivations before standard dose radiotherapy for clinically localized prostate cancer. Int J Radiat Oncol Biol Phys. 2004; 60:15-23. 18. Kupelian PA, Potters L, Khuntia D, et al. Radical prostatectomy, external beam radiotherapy < 72 Gy, external beam radiotherapy > or = 72 Gy, permanent seed implantation, or combined seeds/external beam radiotherapy for stage T1T2 prostate cancer. Int J Radiat Oncol Biol Phys. Jan 2004;58:25-33. 19. Seaward SA, Weinberg V, Lewis P, et al. Identification of a high-risk clinically localized prostate cancer subgroup receiving maximum benefit from whole-pelvic irradiation. Cancer J Sci Am. 1998;4:370-377. 14. Main Points • The evidence for the use of hormonal therapy in combination with radiation is based on 7 randomized trials published between 2001 and 2004. The trials ranged in size from 161 to 1514 patients. • Prostate cancer is a good candidate for hormonal therapy combined with radiotherapy because it (1) is a locally advanced disease, (2) has the availability of chemotherapeutic agents with modest independent activity, (3) has a primary site and nodal drainage that can be easily incorporated into a radiotherapy portal, and (4) shows evidence of favorable interactions between specific drugs and radiation. • Every study comparing external beam radiotherapy (EBRT) alone versus EBRT plus neoadjuvant hormonal therapy (NHT) demonstrated a worse outcome for patients treated with EBRT alone. • Based on the sequence dependent nature of favorable biologic interactions between radiation and hormonal therapy, high-risk patients should probably receive short-term NHT in addition to long-term adjuvant HT. • The data to date support the use of NHT in combination with EBRT in intermediate-risk patients, whereas high-risk patients require the addition of longer-term hormonal therapy. 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