American College of Radiology ACR Appropriateness Criteria LOCALLY ADVANCED (HIGH-RISK) PROSTATE CANCER

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1 American College of Radiology ACR Appropriateness Criteria Date of origin: 1996 Last review date: 2011 LOCALLY ADVANCED (HIGH-RISK) PROSTATE CANCER Expert Panel on Radiation Oncology Prostate: Jay P. Ciezki, MD 1 ; Gregory Merrick, MD 2 ; I-Chow Joe Hsu, MD 3 ; May Abdel-Wahab, MD, PhD 4 ; V. Elayne Arterbery, MD 5 ; Steven J. Frank, MD 6 ; James Lloyd Mohler, MD 7 ; Brian J. Moran, MD 8 ; Seth A. Rosenthal, MD 9 ; Carl J. Rossi Jr, MD 10 ; Yoshiya Yamada, MD. 11 Summary of Literature Review The high-risk cancer category has evolved as the clinical presentation of cancer has changed with the use of -specific antigen (PSA) screening. Prior to the advent of PSA screening in the general U.S. population, cancer was almost always diagnosed after local or systemic symptoms were noted by the patient. This shift from a preponderance of patients with metastatic disease to patients with a PSA-defined (and typically nonmetastatic) presentation has affected the definition and treatment of high-risk cancer. Definition of High-Risk Prostate Cancer Many stratification models for cancer have been proposed. The prognostic significance of pretreatment PSA, biopsy Gleason score, and (to a lesser extent) clinical stage has led to these factors being used as the determinants of cancer virulence when grouping patients based on risk of recurrence after definitive treatment. While various definitions have been proposed over the years, the National Comprehensive Cancer Network (NCCN) consensus of February 2010 provides the most recent definition for these risk groups [1]. It categorizes high-risk patients in two strata: high and very high. Patients defined as high have a clinical stage of T3a or biopsy Gleason score of 8-10 or pretreatment PSA >20 ng/ml, while those defined as very high are those with clinical T3b-T4 without the presence of metastatic disease (including bone and lymph nodes). For the purposes of this discussion, however, these two categories will be considered jointly as high-risk since they encompass the more contemporary (NCCN high risk) and the historical (NCCN very high risk) definitions of high-risk This difference is important because the outcome of treatment is different. The historical highrisk patients can be expected to have a 5 to 10-year overall survival (OS) rate of 47%-72% [2]. The contemporary high-risk patient will have a 5- to 10-year OS rate of ~60%-89% [3-5]. Because of these differences in survival between historical and contemporary patients, the era of treatment must be considered in order to determine the applicability of reported results from treatment to contemporary practice. Reports of Treatment Outcome As with all other risk categories of cancer, there are no studies comparing the efficacy of different treatment modalities to guide one s choice of therapy for high-risk cancer. A comparative toxicity study has recently been completed, but it does not confine itself to the high-risk population. However, with a review of the reports that exist one can propose reasonable treatment strategies for high-risk Efficacy is the most troubling area of the literature to interpret. The difficulty arises from the lack of comparative trials among modalities and the changing nature of cancer when screening with PSA has been implemented. When evaluating the literature the reader must focus on several factors: era of treatment, dose and target of radiation used (if applicable), type of endocrine therapy, and endpoints reported. Because biochemical failure/survival and clinical failure depend so heavily on the frequency of PSA testing, this evaluation will focus on disease-specific and OS endpoints [6]. A select group of publications encompassing the major modalities of therapy will be reviewed. 1 Principal Author, Cleveland Clinic Foundation, Cleveland, Ohio. 2 Panel Chair, Schiffler Cancer Center and Wheeling Jesuit University, Wheeling, West Virginia. 3 Panel Vice-chair, University of California San Francisco, San Francisco, California. 4 University of Miami, Miami, Florida. 5 Karmanos-Crittenton Cancer Center, Rochester Hills, Michigan. 6 MD Anderson Cancer Center, Houston, Texas. 7 Roswell Park Cancer Institute, Buffalo, New York, American Urological Association. 8 Chicago Prostate Cancer Center, Westmont, Illinois. 9 Radiological Associates of Sacramento, Sacramento, California. 10 Loma Linda University Medical Center, Loma Linda, California. 11 Memorial Sloan Kettering Cancer Center, New York, New York. The American College of Radiology seeks and encourages collaboration with other organizations on the development of the ACR Appropriateness Criteria through society representation on expert panels. Participation by representatives from collaborating societies on the expert panel does not necessarily imply individual or society endorsement of the final document. Reprint requests to: Department of Quality & Safety, American College of Radiology, 1891 Preston White Drive, Reston, VA ACR Appropriateness Criteria 1 Locally Advanced Prostate Cancer

2 External Beam Radiotherapy External beam radiotherapy (EBRT) has the greatest volume of literature available. A recent trial has confirmed the value of adding EBRT to endocrine therapy. In Widmark et al [7] an OS advantage was seen with the combination-therapy arm. Prior to the reporting of Widmark et al multiple randomized trials sought to determine the optimum dose/target of radiation in conjunction with neo/concurrent/adjuvant therapy (usually endocrine). Table 1 details the salient features of the most pertinent studies. In reviewing the studies, several themes emerge. First, the addition of pelvic radiation to /seminal vesicle radiation does not confer improved outcome when assessed in an overall analysis. This may be noted within a trial [8] or among the other trials [9-15]. Second, any duration of any of the cited combinations of endocrine therapy (androgen deprivation +/- anti-androgens) improves most outcome measures [10-14]. Third, endocrine therapy of longer than 4-6 months does not improve OS [9,15]. Lastly, more recent data show better outcome measures as expected given that the virulence of cancer being detected has lessened with the implementation of PSA screening [8-15]. Two caveats must be considered when interpreting this body of literature. The examination of the addition of pelvic radiotherapy (RT) to the treatment algorithm conducted by Radiation Therapy Oncology Group (RTOG ) contained what may be an excessively heterogeneous study population [8]. Subgroup analysis has suggested that there may be a group of patients who would benefit from whole-pelvis radiation provided that the endocrine therapy is given in the neoadjuvant setting. This group appears to be those with Gleason scores 7 and clinical T- stages T2c. In addition another analysis of this trial supported the link between better outcome and larger size of the radiation portal [16]. These considerations are so persuasive that RTOG is planning a follow-on trial to assess the value of whole-pelvis RT in this more select group. The second caveat is that few of these trials were powered to detect a difference in a hard endpoint such as -cancer-specific survival or OS. Multiple other publications tell us that dose escalation of EBRT improves outcome [17,18]. The dose escalation supported by Kupelian et al and Kuban et al exceeds the doses used in the trials listed in Table 1. One cannot know how such modern doses of RT will affect the outcome, but the assumption is that, since dose escalation >72 Gy and 78 Gy is feasible with few additional side effects, there would be an improvement with no major additional toxicity. This assumption should be tempered with the fact that some patients may present with comorbidities that preclude safely delivering these higher doses. The effect of taxane-based chemotherapy on high-risk patients is being evaluated by the RTOG 0521 trial. This trial is closed to accrual at the time of writing this review. The closure was due to the trial meeting its accrual goal, not excessive toxicity. This is encouraging since a previous trial, RTOG 9902, did halt accrual due to excessive toxicity, presumably due to the taxane-based chemotherapy included in the treatment algorithm [19]. A preliminary report of the efficacy show that this trial was negative [20]. Radical Prostatectomy There are no randomized trials of ctomy for high-risk patients, and retrospective reviews are few in number. The results, however, are competitive with EBRT. Loeb et al [3] reports a -cancer-specific survival rate of 88% with an OS rate of 74% for patients treated between 1984 and For patients treated between 1977 and 1994, van den Ouden et al [21] noted a 10-year -cancer-specific survival rate of 72% and a 10-year OS rate of 60%. The role of neoadjuvant endocrine therapy in the setting of high-risk patients has not been specifically examined. The effect of neoadjuvant endocrine therapy has been studied in a case mix in which approximately 10%-20% of the study population comprised high-risk patients [22]. The results mirror the results seen in the low-risk population: an improvement of the pathologic specimen without translation into an improved disease-specific outcome. As in EBRT, taxane-derived chemotherapy has been used in the neoadjuvant setting [23]. With a median follow-up of 42.7 months, 30% of patients had a relapse of their disease, and toxicity seemed acceptable. The planned use of adjuvant EBRT for high-risk disease after radical ctomy has not been evaluated to any great degree. However, most retrospective reports on ctomy for high-risk disease likely contain patients treated in this manner. The ctomy literature is primarily focused on clinical T1-T3 and typically does not include clinical T4 The use of low dose-rate brachytherapy for high-risk cancer has been discouraged by many for reasons that were based on theoretical disadvantages rather than observed outcomes. Some researchers, however, have provided us with outcome data for high-risk patients treated with brachytherapy. Taira et al [5] recently reported that for patients treated from , the -cancer-specific survival rate was 95.2% and the OS rate was Radiation Oncology-Prostate 2 Locally Advanced Prostate Cancer

3 69.2%. Hoffman et al [24] also described an experience with brachytherapy in high-risk They noted that the -cancer-specific survival at 5 years was 93% for brachytherapy alone and 97% for brachytherapy combined with EBRT and endocrine therapy (P=0.01). No difference was noted in OS (76.4% for brachytherapy alone and 79.6% for brachytherapy combined with EBRT and endocrine therapy, P=0.631). The data seem to show that brachytherapy is competitive with EBRT and radical ctomy. The need for EBRT in combination with brachytherapy is questionable given its lack of effect on OS and its modest effect (and potentially clinically insignificant effect since only 25 total events in their study were noted for this endpoint) on -cancer-specific survival. The use of neoadjuvant endocrine therapy and chemotherapy combined with brachytherapy in the high-risk patient has not been rigorously studied. The brachytherapy literature, as in the ctomy literature, does not include data on clinical T4 disease in any great quantity. A recent report on the outcome of high-dose-rate brachytherapy in combination with EBRT for intermediate-risk and high-risk patients shows significant progression-free survival benefits to patients with intermediate-risk disease but not for those with high-risk disease [25]. It must be noted that this trial had few high-risk patients receiving high-dose-rate brachytherapy plus EBRT (24) relative to those with EBRT alone (183) so firm conclusions are not possible for this risk group. (See Variant 1, Variant 2, Variant 3, and Variant 4.) Other Therapies Cryotherapy has re-emerged recently as an option for definitive therapy. The long-term results for high-risk patients are difficult to dissect out of the literature. Cheetham et al [26] reports a series of patients treated from who were predominately high-risk. The 10-year -cancer-specific survival rate was 86.8% and the OS rate was 56.6%. High-intensity focused ultrasound (HIFU) has recently been used for high-risk cancer as well. Uchida et al [27] described a series of patients treated from They reported a biochemical disease-free rate at 5 years of 45%. Two randomized trials of cryotherapy versus EBRT have been reported [28,29]. Neither trial was powered to detect a difference in -cancer-specific survival or OS. The RT techniques and dosage would currently be considered suboptimal (70 Gy in one trial and 66 Gy in the other). The less-robust endpoints measured such as biochemical disease progression favor EBRT in one [28] and suggest equivalence between the arms in the other [29]. Further analyses of these trials may clarify the picture. Toxicity The PROST-QA trial is the only multi-institutional, multimodality trial reporting toxicity for EBRT, brachytherapy, and ctomy [30]. It is an inception cohort study with intermediate-term follow-up. The trial includes few high-risk patients, but does provide valuable information about the treatment strategies commonly used for high-risk The most common therapy given for high-risk patients is the combination of EBRT and androgen deprivation. When compared to EBRT alone, this combination yields inferior sexual function and vitality scores that do not recover to baseline after 2 years of follow-up. The combination of brachytherapy with EBRT fares just as poorly relative to EBRT or brachytherapy alone. Radical ctomy has the greatest negative effect on the sexual function and urinary incontinence relative to either EBRT with or without hormonal manipulation or brachytherapy. This effect does not return to the baseline in the surgical Both brachytherapy and EBRT affect the bowel function score, but it returns to near baseline. The surgical patients do not experience a decline of their rectal function score. EBRT and brachytherapy significantly worsen urinary obstruction, while ctomy significantly improves urinary obstruction. (See Variant 5 and Variant 6.) Recent data highlight the systemic effects of androgen deprivation [31,32]. The results are difficult to sort through. On re-review of early RTOG trials, androgen deprivation was not associated with a greater risk of cardiovascular events [33,34]. It must be noted however, that the dataset from which those conclusions were made did not include a full assessment of pretreatment parameters known to influence cardiovascular health. A more comprehensive review reported by Levine et al [32] leaves one with the impression that long-term (>6 months) androgen deprivation is associated with excessive cardiovascular risk in men with pre-existing cardiovascular morbidity, while androgen deprivation for 6 months seems to be well-tolerated from the cardiovascular standpoint. Summary The large volume of randomized trials of EBRT and endocrine therapy for high-risk cancer has the potential for misleading the practitioner into believing that EBRT with endocrine therapy is the standard of care. Radiation Oncology-Prostate 3 Locally Advanced Prostate Cancer

4 Because we have no comparative trials between modalities, one cannot truly state that there is a standard of care for high-risk cancer Based on available information on efficacy and toxicity, we can conclude that it is reasonable to employ EBRT plus endocrine therapy, radical ctomy, or brachytherapy for treating high-risk cancer. We know that, based on available data, an evidence-based way to deliver EBRT is with doses of 72-78Gy to the region coupled with approximately 6 months of endocrine therapy. The optimum method for performing radical ctomy-based or brachytherapy-based strategies has not been defined, and their usefulness in patients with clinical T4 disease is unknown. Cryotherapy and HIFU are currently experimental therapies. Acknowledgement The authors would like to thank Mack Roach III MD (University of California San Francisco) for his thoughtful review of this manuscript. Supporting Documents ACR Appropriateness Criteria Overview Evidence Table References 1. The NCCN Clinical Practice Guidelines in Oncology Prostate Cancer V National Comprehensive Cancer Network, Inc. 2010; Available at: physician_gls/pdf/.pdf. 2. Zagars GK, von Eschenbach AC, Johnson DE, Oswald MJ. Stage C adenocarcinoma of the. An analysis of 551 patients treated with external beam radiation. Cancer. 1987;60(7): Loeb S, Smith ND, Roehl KA, Catalona WJ. Intermediate-term potency, continence, and survival outcomes of radical ctomy for clinically high-risk or locally advanced cancer. Urology. 2007;69(6): Nguyen PL, Chen MH, Beard CJ, et al. Radiation with or without 6 months of androgen suppression therapy in intermediate- and high-risk clinically localized cancer: a postrandomization analysis by risk group. Int J Radiat Oncol Biol Phys. 2010;77(4): Taira AV, Merrick GS, Butler WM, et al. Long-term outcome for clinically localized cancer treated with permanent interstitial brachytherapy. Int J Radiat Oncol Biol Phys. 2011;79(5): Ciezki JP, Reddy CA, Stephenson AJ, et al. The importance of serum -specific antigen testing frequency in assessing biochemical and clinical failure after cancer treatment. Urology. 2010;75(2): Widmark A, Klepp O, Solberg A, et al. Endocrine treatment, with or without radiotherapy, in locally advanced cancer (SPCG-7/SFUO-3): an open randomised phase III trial. Lancet. 2009;373(9660): Lawton CA, DeSilvio M, Roach M, 3rd, et al. An update of the phase III trial comparing whole pelvic to only radiotherapy and neoadjuvant to adjuvant total androgen suppression: updated analysis of RTOG 94-13, with emphasis on unexpected hormone/radiation interactions. Int J Radiat Oncol Biol Phys. 2007;69(3): Bolla M, de Reijke TM, Van Tienhoven G, et al. Duration of androgen suppression in the treatment of cancer. N Engl J Med. 2009;360(24): D'Amico AV, Chen MH, Renshaw AA, Loffredo M, Kantoff PW. Androgen suppression and radiation vs radiation alone for cancer: a randomized trial. JAMA. 2008;299(3): Denham JW, Steigler A, Lamb DS, et al. Short-term androgen deprivation and radiotherapy for locally advanced cancer: results from the Trans-Tasman Radiation Oncology Group randomised controlled trial. Lancet Oncol. 2005;6(11): Pilepich MV, Winter K, Lawton CA, et al. Androgen suppression adjuvant to definitive radiotherapy in carcinoma--long-term results of phase III RTOG Int J Radiat Oncol Biol Phys. 2005;61(5): Roach M, 3rd, Bae K, Speight J, et al. Short-term neoadjuvant androgen deprivation therapy and externalbeam radiotherapy for locally advanced cancer: long-term results of RTOG J Clin Oncol. 2008;26(4): Radiation Oncology-Prostate 4 Locally Advanced Prostate Cancer

5 14. Bolla M, Van Tienhoven G, Warde P, et al. External irradiation with or without long-term androgen suppression for cancer with high metastatic risk: 10-year results of an EORTC randomised study. Lancet Oncol. 2010;11(11): Horwitz EM, Bae K, Hanks GE, et al. Ten-Year Follow-Up of Radiation Therapy Oncology Group Protocol 92-02: A Phase III Trial of the Duration of Elective Androgen Deprivation in Locally Advanced Prostate Cancer. Journal of Clinical Oncology. 2008;26(15): Roach M, 3rd, DeSilvio M, Valicenti R, et al. Whole-pelvis, "mini-pelvis," or -only external beam radiotherapy after neoadjuvant and concurrent hormonal therapy in patients treated in the Radiation Therapy Oncology Group 9413 trial. Int J Radiat Oncol Biol Phys. 2006;66(3): Kuban DA, Tucker SL, Dong L, et al. Long-term results of the M. D. Anderson randomized dose-escalation trial for cancer. Int J Radiat Oncol Biol Phys. 2008;70(1): Kupelian PA, Potters L, Khuntia D, et al. Radical ctomy, external beam radiotherapy <72 Gy, external beam radiotherapy > or =72 Gy, permanent seed implantation, or combined seeds/external beam radiotherapy for stage T1-T2 cancer. Int J Radiat Oncol Biol Phys. 2004;58(1): Rosenthal SA, Bae K, Pienta KJ, et al. Phase III Multi-Institutional Trial of Adjuvant Chemotherapy With Paclitaxel, Estramustine, and Oral Etoposide Combined With Long-Term Androgen Suppression Therapy and Radiotherapy Versus Long-Term Androgen Suppression Plus Radiotherapy Alone for High-Risk Prostate Cancer: Preliminary Toxicity Analysis of RTOG International Journal of Radiation Oncology*Biology*Physics. 2009;73(3): Sandler HM, Hunt D, Sartor AO, et al. A phase III protocol of androgen suppression (AS) and radiation therapy (RT) versus AS and RT followed by chemotherapy with paclitaxel, estramustine, and etoposide (TEE) for localized, high-risk, cancer, RTOG J Clin Oncol. 2010;28(15s):abstr van den Ouden D, Hop WC, Schroder FH. Progression in and survival of patients with locally advanced cancer (T3) treated with radical ctomy as monotherapy. J Urol. 1998;160(4): Gleave ME, Goldenberg SL, Chin JL, et al. Randomized comparative study of 3 versus 8-month neoadjuvant hormonal therapy before radical ctomy: biochemical and pathological effects. J Urol. 2001;166(2): ; discussion Chi KN, Chin JL, Winquist E, Klotz L, Saad F, Gleave ME. Multicenter phase II study of combined neoadjuvant docetaxel and hormone therapy before radical ctomy for patients with high risk localized cancer. J Urol. 2008;180(2): ; discussion Hoffman KE, Chen MH, Moran BJ, et al. Prostate cancer-specific mortality and the extent of therapy in healthy elderly men with high-risk cancer. Cancer. 2010;116(11): Deutsch I, Zelefsky MJ, Zhang Z, et al. Comparison of PSA relapse-free survival in patients treated with ultra-high-dose IMRT versus combination HDR brachytherapy and IMRT ;9(4): Cheetham P, Truesdale M, Chaudhury S, Wenske S, Hruby GW, Katz A. Long-term cancer-specific and overall survival for men followed more than 10 years after primary and salvage cryoablation of the. J Endourol. 2010;24(7): Uchida T, Shoji S, Nakano M, et al. Transrectal high-intensity focused ultrasound for the treatment of localized cancer: eight-year experience. Int J Urol. 2009;16(11): Chin JL, Ng CK, Touma NJ, et al. Randomized trial comparing cryoablation and external beam radiotherapy for T2C-T3B cancer. Prostate Cancer Prostatic Dis. 2008;11(1): Donnelly BJ, Saliken JC, Brasher PM, et al. A randomized trial of external beam radiotherapy versus cryoablation in patients with localized cancer. Cancer. 2010;116(2): Sanda MG, Dunn RL, Michalski J, et al. Quality of life and satisfaction with outcome among -cancer survivors. N Engl J Med. 2008;358(12): Keating NL, O'Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for cancer. J Clin Oncol. 2006;24(27): Levine GN, D'Amico AV, Berger P, et al. Androgen-deprivation therapy in cancer and cardiovascular risk: a science advisory from the American Heart Association, American Cancer Society, and American Urological Association: endorsed by the American Society for Radiation Oncology. Circulation. 2010;121(6): Efstathiou JA, Bae K, Shipley WU, et al. Cardiovascular mortality and duration of androgen deprivation for locally advanced cancer: analysis of RTOG Eur Urol. 2008;54(4): Radiation Oncology-Prostate 5 Locally Advanced Prostate Cancer

6 34. Efstathiou JA, Bae K, Shipley WU, et al. Cardiovascular mortality after androgen deprivation therapy for locally advanced cancer: RTOG J Clin Oncol. 2009;27(1): The ACR Committee on Appropriateness Criteria and its expert panels have developed criteria for determining appropriate imaging examinations for diagnosis and treatment of specified medical condition(s). These criteria are intended to guide radiologists, radiation oncologists and referring physicians in making decisions regarding radiologic imaging and treatment. Generally, the complexity and severity of a patient s clinical condition should dictate the selection of appropriate imaging procedures or treatments. Only those examinations generally used for evaluation of the patient s condition are ranked. Other imaging studies necessary to evaluate other co-existent diseases or other medical consequences of this condition are not considered in this document. The availability of equipment or personnel may influence the selection of appropriate imaging procedures or treatments. Imaging techniques classified as investigational by the FDA have not been considered in developing these criteria; however, study of new equipment and applications should be encouraged. The ultimate decision regarding the appropriateness of any specific radiologic examination or treatment must be made by the referring physician and radiologist in light of all the circumstances presented in an individual examination. Radiation Oncology-Prostate 6 Locally Advanced Prostate Cancer

7 Table 1. Comparison of Major Studies of External Beam Radiotherapy for High-Risk Prostate Cancer Study RTOG 8610; Roach et al [13] RTOG 8531; Pilepich et al [12] EORTC; Bolla et al [14] RTOG 9202; Horwitz et al [15] RTOG 9413; Lawton et al [8] D Amico et al [10] Trans- Tasman Radiation Oncology Group 96.01; Denham et al [11] EORTC; Bolla et al [9] Treatment Era Radiation Dose and Target Gy to pelvis Gy to Gy to pelvis Gy to 50 Gy to pelvis + 20 Gy to Gy to pelvis Gy to 70.2 Gy to only 50.4 Gy to pelvis Gy to 70 Gy to 66 Gy to 50 Gy to pelvis + 20 Gy to Endocrine Therapy None vs AD 1 + AA 2 for 4 months None vs AD 1 indefinitely None vs AD 1 for 3 years AD 1 for 4 months vs AD 1 for 28 months AD 1 + AA 2 for 4 months neoadjuvantl y vs adjuvantly AD 1 + AA 2 for 4 months neoadjuvantl y vs adjuvantly Biochemical Failure 3 65% vs 80% at P< % vs 91% at P< N/A 51.9% vs 68.1% at P % vs 41% at 5 years; P= % vs 33% at 5 years; P-value not significant Clinical Failure 3 35% vs 47% at 10 years; P=0.006 ~25% vs ~40% at P< % vs 51% at P< Prostate Cancer- Specific Survival % vs 76.6% at 10 years; P= % vs 84% at P= % vs 89.7% at P< N/A 83.9% vs 88.7% at P=0.042 N/A 93% vs 95% at 5 years; P= N/A 95% vs 93% at 5 years; P= None vs AD 1 N/A N/A 88% vs 97% + AA 2 at 8 years; P=0.007 None vs AD 1 + AA 2 for 3 months vs AD 1 + AA 2 for 6 months AD 1 + AA 2 for 6 months vs 3 years 62% vs 48% vs 56% at 5 years; P=0.002 for none vs 3 months, P< for none vs 6 months N/A 91% vs 92% vs 94% at 5 years; P=0.91 for none vs 3 months, P<0.56 for none vs 6 months N/A N/A 95.3% vs 96.8% at 5 years; P=0.002 Overall Survival 3 34% vs 43% at P= % vs 49% at P= % vs 58.1% at P=0.0004, however a Log-rank test was not performed and this p-value is assumed to be a univariate comparison at 10 years 51.6% vs 53.9% at P= % vs81% at 5 years; P= % vs 75% at 5 years; P= % vs 74% at 8 years; P= % vs78% vs 82% at 5 years; P-value not shown 81% vs 84.8% at 5 years; P= Androgen deprivation (or LHRH); 2 Anti-androgen (when combined with LHRH it is referred to as CAB); 3 reported as control group vs treatment group; 4 P-value calculated from all 4 arms of the trial rather than pairwise. Radiation Oncology-Prostate 7 Locally Advanced Prostate Cancer

8 Clinical Condition: Locally Advanced (High Risk) Prostate Cancer Variant 1: Stage T3/T4, PSA <20, Gleason <7. Treatment Rating Comments Endocrine Therapy Mixed with EBRT CAB followed by LHRH ( 4 and 6 months) 7 CAB followed by LHRH (>6 months) 7 LHRH ( 4 and 6 months) 5 CAB (<4 months) 3 External Beam Pelvic Dose (assumes hormone therapy given) Gy 6 None 5 External Beam Prostate Dose (including pelvic dose) (assumes hormone therapy given) <72 Gy 3 72 Gy to 78 Gy 7 >78 Gy 8 Prostatectomy 4 LDR with EBRT and LHRH 6 LDR and LHRH 3 LDR alone 3 EBRT with HDR boost 5 Addition of Taxane-based Chemotherapy to any Modality Rating Scale: 1,2,3 Usually not appropriate; 4,5,6 May be appropriate; 7,8,9 Usually appropriate 2 Newer technology may permit the safe delivery of these higher doses. Newer technology may permit the safe delivery of these higher doses. Radiation Oncology-Prostate 8 Locally Advanced Prostate Cancer

9 Clinical Condition: Locally Advanced (High Risk) Prostate Cancer Variant 2: Stage T3/T4, PSA <20, Gleason 7. Treatment Rating Comments Endocrine Therapy Mixed with EBRT CAB followed by LHRH ( 4 and 6 months) 7 CAB followed by LHRH (>6 months) 8 LHRH ( 4 and 6 months) 5 CAB (<4 months) 3 External Beam Pelvic Dose (assumes hormone therapy given) Gy 7 None 5 External Beam Prostate Dose (including pelvic dose) (assumes hormone therapy given) <72 Gy 3 72 Gy to 78 Gy 7 >78 Gy 8 Prostatectomy 4 LDR with EBRT and LHRH 6 LDR and LHRH 3 LDR alone 3 EBRT with HDR boost 5 Addition of Taxane-based Chemotherapy to any Modality Rating Scale: 1,2,3 Usually not appropriate; 4,5,6 May be appropriate; 7,8,9 Usually appropriate 2 Higher Gleason scores may warrant longer duration of endocrine therapy. Radiation Oncology-Prostate 9 Locally Advanced Prostate Cancer

10 Clinical Condition: Locally Advanced (High Risk) Prostate Cancer Variant 3: Stage T3/T4, PSA 20, Gleason <7. Treatment Rating Comments Endocrine Therapy Mixed with EBRT CAB followed by LHRH ( 4 and 6 months) 6 CAB followed by LHRH (>6 months) 7 LHRH ( 4 and 6 months) 4 CAB (<4 months) 3 External Beam Pelvic Dose (assumes hormone therapy given) Gy 7 None 5 External Beam Prostate Dose (including pelvic dose) (assumes hormone therapy given) <72 Gy 3 72 Gy to 78 Gy 7 >78 Gy 8 Prostatectomy 3 LDR with EBRT and LHRH 6 LDR and LHRH 3 LDR alone 3 EBRT with HDR boost 5 Addition of Taxane-based Chemotherapy to any Modality 2 Rating Scale: 1,2,3 Usually not appropriate; 4,5,6 May be appropriate; 7,8,9 Usually appropriate Radiation Oncology-Prostate 10 Locally Advanced Prostate Cancer

11 Clinical Condition: Locally Advanced (High Risk) Prostate Cancer Variant 4: Stage T3/T4, PSA 20, Gleason 7. Treatment Rating Comments Endocrine Therapy Mixed with EBRT CAB followed by LHRH ( 4 and 6 months) 5 CAB followed by LHRH (>6 months) 8 LHRH ( 4 and 6 months) 4 CAB (<4 months) 3 External Beam Pelvic Dose (assumes hormone therapy given) Gy 7 None 5 External Beam Prostate Dose (including pelvic dose) (assumes hormone therapy given) <72 Gy 3 72 Gy to 78 Gy 7 >78 Gy 8 Prostatectomy 3 LDR with EBRT and LHRH 5 LDR and LHRH 2 LDR alone 2 EBRT with HDR boost 4 Addition of Taxane-based Chemotherapy to any Modality 2 Rating Scale: 1,2,3 Usually not appropriate; 4,5,6 May be appropriate; 7,8,9 Usually appropriate Radiation Oncology-Prostate 11 Locally Advanced Prostate Cancer

12 Clinical Condition: Variant 5: Locally Advanced (High Risk) Prostate Cancer Stage T1/T2, PSA 20, Gleason <7, post-void residual = 350 cc. Treatment Rating Comments Endocrine Therapy Mixed with EBRT CAB followed by LHRH ( 4 and 6 months) 6 CAB followed by LHRH (>6 months) 6 LHRH ( 4 and 6 months) 5 CAB (<4 months) 3 External Beam Pelvic Dose (assumes hormone therapy given) Gy 6 None 5 External Beam Prostate Dose (including pelvic dose) (assumes hormone therapy given) <72 Gy 3 72 Gy to 78 Gy 8 >78 Gy 8 Prostatectomy 5 LDR with EBRT and LHRH 3 LDR and LHRH 2 LDR alone 2 EBRT with HDR boost 3 Addition of Taxane-based Chemotherapy to any Modality Rating Scale: 1,2,3 Usually not appropriate; 4,5,6 May be appropriate; 7,8,9 Usually appropriate 2 A patient s comorbidities may preclude higher radiation doses. A patient s comorbidities may preclude higher radiation doses. Radiation Oncology-Prostate 12 Locally Advanced Prostate Cancer

13 Clinical Condition: Variant 6: Locally Advanced (High Risk) Prostate Cancer Stage T1/T2, PSA 20, Gleason 7, post-void residual = 20 cc. Treatment Rating Comments Endocrine Therapy Mixed with EBRT CAB followed by LHRH ( 4 and 6 months) 6 CAB followed by LHRH (>6 months) 7 LHRH ( 4 and 6 months) 5 CAB (<4 months) 3 External Beam Pelvic Dose (assumes hormone therapy given) Gy 7 None 5 External Beam Prostate Dose (including pelvic dose) (assumes hormone therapy given) <72 Gy 3 72 Gy to 78 Gy 8 >78 Gy 8 Prostatectomy 4 LDR with EBRT and LHRH 6 LDR and LHRH 3 LDR alone 3 EBRT with HDR boost 5 Addition of Taxane-based Chemotherapy to any Modality Rating Scale: 1,2,3 Usually not appropriate; 4,5,6 May be appropriate; 7,8,9 Usually appropriate 2 A patient s comorbidities may preclude higher radiation doses. A patient s comorbidities may preclude higher radiation doses. Radiation Oncology-Prostate 13 Locally Advanced Prostate Cancer