Treatment strategies for high-risk locally advanced prostate cancer

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1 REVIEwS Treatment strategies for high-risk locally advanced prostate cancer Seth A. Rosenthal and Howard M. Sandler Abstract High-risk prostate cancer can be defined by the assessment of pretreatment prognostic factors such as clinical stage, Gleason score, and PSA level. High-risk features include PSA >20 ng/ml, Gleason score 8 10, and stage T3 tumors. Patients with adverse prognostic factors have historically fared poorly with monotherapeutic approaches. Multimodal treatment utilizing combined androgen suppression and radiotherapy has improved survival rates for patients with high-risk prostate cancer. In addition, multiple randomized trials in patients treated with primary radical prostatectomy have demonstrated improved outcomes with the addition of adjuvant radiotherapy. Improved radiotherapy techniques that allow for dose escalation, and new systemic therapy approaches such as adjuvant chemotherapy, present promising future therapeutic alternatives for patients with high-risk prostate cancer. Rosenthal, S. A. & Sandler, H. M. Nat. Rev. Urol. 7, (2010); doi: /nrurol Continuing Medical Education online This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of MedscapeCME and Nature Publishing Group. MedscapeCME is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. MedscapeCME designates this educational activity for a maximum of 0.75 AMA PrA Category 1 Credits TM. Physicians should only claim credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test and/or complete the evaluation at journal/nrurol; and (4) view/print certificate. learning objectives Upon completion of this activity, participants should be able to: 1 Define high-risk prostate cancer. 2 Identify the efficacy of androgen suppression therapy for high-risk prostate cancer. 3 Describe research of adjuvant chemotherapy for high-risk prostate cancer. 4 Compare emerging treatments for high-risk prostate cancer with standard therapy. Introduction Prostate cancer is a common malignancy, with 192,280 new cases and 27,360 deaths estimated in the us in although the mortality rate for prostate cancer declined significantly during the period between 1990 and 2005, it Competing interests: H. M. Sandler declares an association with the following company: Sanofi-Aventis. See the article online for full details of the relationship. S. A. Rosenthal, the Journal Editor S. Farley and the CME questions author C. P. Vega declare no competing interests. continues to be the most frequently diagnosed cancer in men, and the second most frequent cause of cancer death, after lung cancer, in the us. 1 although the benefit of active treatment versus surveillance for men with low-risk prostate cancer has been controversial, men with high-risk disease at presentation are acknowledged to be at higher risk of prostate cancer-related death. 2,3 therefore, attempts to further reduce prostate cancer mortality are directed at the high-risk population. High-risk prostate cancer has been variously defined, but the consensus is that a variety of pretreatment prognostic factors can identify patients for whom treatment is likely to fail. the primary risk factors for prostate cancer are clinical stage, Psa level, and Gleason score at presentation. the small proportion of patients who present with documented metastases are outside the scope of this review. 4 Before concluding that a patient has localized but high-risk prostate cancer, an assessment to exclude the presence of gross metastatic disease should be performed. Clinical stage is defined according to the american Joint Committee on Cancer staging system, which notes that patients with extensive palpable disease (stage t3) have a poorer prognosis than patients with incidentally noted (stage t1) or small volume palpable (stage t2) disease. 5 However, clinical staging of prostate cancer is subjective and potentially imprecise. it has long been recog nized that the histological grading of prostate tumors correlates with prognosis. Donald Gleason described a system for the assessment and communica tion of primary and secondary histological grades, which has become known as the Gleason score. in his initial paper, Gleason noted that the combination of histological grading and clinical staging improved prog nostic accuracy over that obtained with either parameter alone. 6 subsequently, Gleason score has been validated as an independent prognostic factor Radiation Oncology Centers, Radiological Associates of Sacramento, 1500 Expo Parkway, Sacramento, CA 95815, USA (S. A. rosenthal). Department of Radiation Oncology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA (H. M. Sandler). Correspondence to: S. A. Rosenthal rosenthals@ radiological.com nature reviews urology volume 7 JanuarY

2 Key points Risk stratification using prognostic factors such as clinical stage, Gleason score, and PSA level is essential for determining the appropriate treatment for patients with prostate cancer High-risk patients include those with Gleason score 8 10, PSA >20 ng/ml, and clinical stage T3 disease The combination of radiotherapy and long-term androgen suppression improves disease control and survival, compared with either treatment alone, for patients with high-risk disease Adjuvant radiotherapy following radical prostatectomy improves disease control and survival for patients with stage pt3 disease Improved local treatments, such as dose-escalated radiotherapy, adjuvant radiotherapy following prostatectomy, and novel systemic treatments such as adjuvant chemotherapy have the potential to improve disease control in the future Table 1 Definitions of high-risk prostate cancer Definition D Amico et al. 18 RTOG and NCCN 79 High-risk criteria Stage T2c or greater and either PSA level >20 ng/ml or Gleason score 8 10 PSA ng/ml, Gleason score 7 and any T stage or, stage T2 or greater, PSA <100 ng/ml and Gleason score 8 10 PSA level >20 mg/l or Gleason score 8 10 or stage T3 or greater Abbreviations: NCCN, National Comprehensive Cancer Network; RTOG, Radiation Therapy Oncology Group. in multiple settings. Patients with Gleason score 8 10 tumors are at high risk of recurrence, metastases, and death from prostate cancer. 7 9 Following the development of Psa testing in the late 1980s, pretreatment Psa level was also noted to be an independent prognostic factor for recurrence following primary treatment with radiotherapy or radical prostatectomy Historically, patients with poor prognostic factors had low survival rates after either surgery or external beam radiotherapy alone. 13,14 it was recognized that these patients were more likely to develop metastatic disease and to die from prostate cancer. as such, this group of men became the focus of efforts to improve thera peutic approaches. it is worth noting that in the early Psa era (late 1980s and early 1990s) patients presented with higher volume disease than in the current Psa screening epoch. in recent years, a number of clinical trials addressing potential therapeutic strategies for patients with high-risk prostate cancer have been reported and many more are either underway or awaiting maturation of data. Key randomized studies of radiotherapy in conjunction with androgen suppression therapy and trials of adjuvant radiotherapy following prostatectomy are discussed below. the potential advantages provided by dose-escalated radiotherapy and the addition of adjuvant chemotherapy to other primary treatment regimens are also discussed. the wealth of data produced by these trials can assist clinicians in selecting the optimal treatment for patients with high-risk prostate cancer. Risk stratification the idea that improved prognostic information could be gleaned from the combined use of clinical staging, Gleason score, and Psa levels led to the development of a variety of predictive tools in 1998 D amico et al. 18 suggested a stratification of patients into lowrisk, intermediate- risk, and high-risk groups that is still commonly used today. according to this classification scheme, high-risk patients are those with clinical stage t2c or higher, and either Psa >20 ng/ml, or Gleason score at present, cooperative research groups such as the radiation therapy oncology Group (rtog), and organizations such as the national Comprehensive Cancer network, use risk stratification schemes similar to those of D amico et al. to identify patients with highrisk prostate cancer. Commonly used criteria include patients with combinations of Gleason score 8 10, Psa levels >20 ng/ml, and clinical stage t2c t4 disease (table 1). overall, about 15 20% of patients with prostate cancer have high-risk disease at presentation. 19 a number of secondary risk factors have also been reported to be associated with a high risk of prostate cancer progression. For example, a prediagnosis Psa velocity of >2 ng/ml/year has been shown to increase the likelihood of death from prostate cancer after either radical prostatectomy or external beam radiation therapy. 20,21 Psa doubling time 22,23 and the volume of cancer at initial diagnosis (as assessed by percentage of positive biopsy cores) 24,25 have also been associated with recurrence following primary treatment with radio therapy or radical prostatectomy in addition, a tertiary Gleason pattern 5 is a significantly adverse prognostic factor in patients with Gleason score 7 cancers. 26,27 information about these secondary risk factors has not always been collected in routine clinical practice, however, and when noted they are not always reported consistently. Furthermore, the potential prognostic value of a number of biomarkers has been studied by rtog. though not yet ready for routine clinical use, if preliminary results are confirmed in further patient cohorts, these biomarkers might add strength to existing predictive models. 28 at present, primary risk stratifica tion schemes rely mainly on clinical stage, initial Psa level, and Gleason score. the use of secondary prog nostic factors to select and stratify patients for clinical trials of high-risk disease should be considered. Androgen suppression plus radiotherapy the sensitivity of prostate cancer to hormonal therapy has been appreciated for many decades, since it was first observed that prostate tumors respond to orchiectomy. estrogenic agents, such as diethylstilbesterol, were subsequently tried in adjuvant trials, but the toxicities of these agents, such as gynecomastia and cardiovascular adverse effects, prevented their widespread use. the development of novel agents such as luteinizing hormone-releasing hormone (lhrh) analogs (for example, goserelin, leuprolide), and nonsteroidal antiandrogens (for example, flutamide, bicalutamide) for androgen suppression in the 1980s prompted trials of combined radiotherapy and androgen suppression. the positive results of these trials modified clinical practice and improved outcomes for men with high-risk prostate cancer. 32 JANUARY 2010 volume 7

3 During the randomized rtog trial, patients received radiotherapy followed by either immediate indefinite adjuvant androgen suppression with an lhrh analog, or androgen suppression deferred until the time of relapse. Participants had an unfavorable prognosis defined as either positive lymph nodes, nonbulky tumor, or stage ct3, or stage pt3 disease. 977 patients were accrued from 1987 to the initial report of results highlighted improved local control, freedom from distant metastasis, and disease-free survival for patients treated with immediate androgen suppression compared with those that received deferred treatment. However, improved overall survival in the immediate group was noted only for those patients with Gleason score 8 10 tumors. subsequent analysis after longer follow-up revealed a survival benefit for the study population as a whole. subset analysis showed that this long-term benefit was limited to patients with Gleason score 7 10; patients with Gleason score 2 6 derived no marked advantage from immediate androgen suppression. 10-year survival rates for the study cohort as a whole were 49% and 39% (P = 0.002), and for patients with Gleason score 8 10 were 39% and 25% (P = ), in those treated with immediate and deferred androgen suppression therapy, respectively the rtog study was the first to demonstrate that survival could be significantly improved by androgen suppression therapy combined with radiotherapy. the magnitude of the effect was large and was primarily noted in patients with Gleason score 8 10 tumors, who experienced a greater than 50% improvement in overall survival with the use of adjuvant androgen suppression therapy. Despite this benefit, overall survival rates were disappointing. even in the study group with the best outcomes 61% of patients with Gleason score 8 10 tumors had died within 10 years. the rtog trial comprised 471 patients diagnosed with clinically bulky tumors between 1987 and Participants were randomized to receive external beam radiotherapy plus 2 months of neoadjuvant and 2 months of adjuvant androgen suppression, or to radiotherapy alone. androgen suppression was associated with better outcomes for many intermediate end points, including freedom from distant metastases, disease-free survival, and disease-specific mortality, but there was no statistically significant improvement in overall survival other trials of short-term androgen suppression in combination with radiotherapy produced conflicting results in terms of overall survival. in a population of intermediate-risk and high-risk patients, D amico and colleagues were able to discern a benefit in overall survival, in addition to improvements in other disease-control end points, following 6 months of androgen suppression therapy. 35 Conversely, a study of patients with locally advanced prostate cancer by the trans-tasman radiation oncology Group failed to show a positive effect of androgen suppression on overall survival, despite detecting highly significant improvements in all other end points, including prostate-cancer-specific survival. 36 long-term androgen suppression the european organization for research and treatment of Cancer (eortc) conducted two important studies that helped to define the role of long-term androgen suppression plus radiotherapy in prostate cancer management. the first trial, eortc 22863, was performed between 1987 and patients with locally advanced prostate cancer were randomized to either 3 years of androgen suppression combined with external beam radiotherapy or external beam radiotherapy alone. outcomes for all end points, including overall survival, were superior in the combination-therapy cohort. 5-year overall survival was 78% in the androgen suppression plus radiotherapy group and 62% for patients who received radiotherapy alone (P = ) the rtog followed the and studies with rtog 92-02, which involved the randomization of 1,554 intermediate-risk or high-risk patients to radiotherapy plus 4 months of androgen suppression (2 months before and 2 months concurrent with radiotherapy) with or without 2 additional years of androgen suppression following completion of radiotherapy. significant improvements in all end points of disease progression were observed in the prolonged hormone therapy group; overall survival was the exception. Prolongation of androgen suppression extended 10-year disease-specific survival, but not overall survival. in the subset of 337 patients with Gleason score 8 10 tumors, the difference between the two treatment arms was more pronounced; there was a significant improvement in 10-year overall survival in patients who received prolonged androgen suppression (45%) compared with patients who did not (32%; P = 0.006). 40,41 eortc was a comparison of short-term and long-term androgen suppression plus radiotherapy in 970 men with locally advanced prostate cancer randomized to radiotherapy with either 6 months or 3 years of androgen suppression. marked improvement in diseasecontrol outcomes was noted, including significant enhancement of overall survival, in favor of the cohort who received prolonged hormone therapy. 42 taken together, these studies established prolonged androgen suppression (of at least 2 years duration) combined with radiotherapy as a standard of care for patients with high-risk, Gleason score 8 10, prostate cancer. one criticism of the data supporting the use of long-term hormone therapy plus radiotherapy in these patients is that the trials did not include an androgen suppressiononly cohort. this shortcoming was addressed in a recent scandinavian trial. widmark et al. 42,43 studied a group of 875 men with locally advanced prostate cancer randomized to long-term indefinite androgen suppression alone or long-term androgen suppression plus radiotherapy. they noted that combination therapy reduced the number of prostate-cancer-specific deaths by a factor of two at 10 years (from 24% to 12%; P <0.001) and markedly improved overall survival. 43,44 unresolved issues although combined radiotherapy and androgen suppression is now a well-accepted treatment for localized nature reviews urology volume 7 JanuarY

4 high-risk prostate cancer, there remains room for further improvement. randomized trials to date have utilized differing regimens. the clinical significance of these variations has not been determined. 45 the definition of prolonged androgen suppression is also a subject of debate. it is generally accepted that 2 3 years of androgen suppression results in better outcomes than 4 6 months, but comparisons between 2 years and 3 years or 2 years and 1 year have not been made. Crook et al. 45 conducted a trial of 3 months versus 8 months of neoadjuvant androgen suppression, and noted a slight improvement in survival in high-risk patients that received 8 months of therapy but no significant improvement in outcomes overall. 46 recruitment of patients for an rtog trial with a similar protocol, rtog 99-10, is complete but results have not yet been reported. nevertheless, it is clear that the benefits of prolonged androgen suppression are most evident in patients with high-risk disease. the question of whether elective treatment of the pelvic lymph nodes provides any benefit in patients undergoing radiotherapy for high-risk prostate cancer has not been definitively addressed in clinical trials. men with high-risk prostate cancer are most likely to develop lymph node metastasis. 47 although it has been customary to treat the lymph nodes in rtog trials of highrisk prostate cancer, the benefit of pelvic lymph node treatment has not been unequivocally established as such, the role of elective nodal irradiation in these patients remains controversial. elective irradiation might become more clinically significant in the current era of escalating radiotherapy doses; better control of intra prostatic disease could result in a clinical situation where the treatment of occult nodal disease might provide further improvement to outcomes. 51 elucidation of the exact role of nodal irradiation awaits further study. this knowledge will help to optimize the role of androgen suppression therapy, as well as to define the risks and benefits of androgen suppression in prostate cancer more precisely. no treatment is completely free of potential adverse effects, and there has been concern regarding the morbid ity associated with androgen suppression therapy, even of short duration. in addition to hot flashes, night sweats, fatigue, and deterioration of sexual function, some investigators have noted potential long-term toxicities including loss of bone density, 52 gastrointestinal and genitourinary morbidity, 53 and cardiac morbidity and mortality other investigators, however, have failed to detect increased cardiac, gastrointestinal or genitourinary morbidity in patients treated with longterm androgen suppression. 42,57 reports of morbidity should serve as an impetus for the prospective study of potential adverse effects in randomized trials, as well as for consideration of mitigation strategies (for example, targeted therapy for patients with decreased bone density). 58,59 evidence supporting morbidity associated with long-term androgen suppression indicates that the risk:benefit ratio will be most favorable for patients with high-risk disease, for whom the magnitude of treatment effect is greatest. Adjuvant chemotherapy now that combined long-term androgen suppression and radiotherapy are commonly used to treat highrisk prostate cancer, interest has turned to thera peutic enhancement. as the vast majority of patients who die from prostate cancer have widespread metastases, one possible means of augmenting treatment results is systemic therapy directed against micrometastatic disease presumed to be present at the time of diag nosis of clinically localized high-risk disease. improvements in chemo therapy led to the hypothesis that cytotoxic agents administered during initial treatment of men with high-risk nonmetastatic prostate cancer would target androgen- insensitive clones earlier in the course of disease, thereby improving therapeutic outcomes. the rtog initiated a trial, rtog 99-02, to test this hypothesis. eligible participants were at higher risk of disease progression than those enrolled in rtog 92-02, and included those with any t-stage tumor, Gleason score 7 and Psa ng/ml, or palpable tumors, Gleason score 8 and any Psa value. the trial comprised a standard therapy arm of radiotherapy with 2 years of androgen suppression, including combined androgen blockade during the first 4 months and radiotherapy initiated after 2 months, similar to the experimental arm of rtog Patients were randomized to either standard therapy alone, or with the addition of four cycles of chemotherapy with a three-drug regimen of paclitaxel, etoposide, and estramustine. Chemotherapy was administered after the initial period of combined androgen blockade and radiotherapy had been completed. 397 patients were accrued before the trial was terminated prematurely; increased thrombo embolic toxicity (attributed to estramustine) had been noted in the adjuvant chemotherapy arm. analysis of initial efficacy has yet to be performed. 60 a successor trial, rtog 05-21, was subsequently initiated. it used the same basic protocol as rtog 99-02, but with updated radiotherapy techniques and doses, and a chemotherapy regimen of docetaxel and prednisone. 60 this regimen had previously been shown to increase survival in patients with metastatic hormone-refractory prostate cancer. 61 the trial completed accrual of 612 patients in august results are yet to be published. the ability to recruit patients to randomized trials that include chemotherapy for nonmetastatic disease suggests that patients with prostate cancer will accept and tolerate chemotherapy as a component of primary therapy. in Britain, the stampede clinical trial (medical research Council Pr08) was initiated in this study includes men with localized high-risk disease as well as patients with known metastatic prostate cancer. Participants are randomized to either long-term androgen suppression therapy alone or long-term androgen suppression therapy with either docetaxel, zoledronic acid, or celecoxib. a total of 3,000 patients is anticipated, with 500 patients reported to have been accrued in trials examining the role of chemotherapy in conjunction with radical prostatectomy are also underway. 63 the Cancer and leukemia Group B has initiated a randomized 34 JANUARY 2010 volume 7

5 Table 2 Phase III randomized trials of adjuvant chemotherapy for high-risk nonmetastatic prostate cancer Study n year closed Protocol RTOG Long-term androgen suppression plus radiotherapy vs long-term androgen suppression plus radiotherapy followed by four cycles of adjuvant chemotherapy with paclitaxel, estramustine, and oral etoposide CALGB Recruitment ongoing Ongoing Neoadjuvant chemotherapy consisting of six cycles of estramustine and docetaxel followed by radical prostatectomy versus radical prostatectomy alone SwOG Radical prostatectomy followed by 2 years of androgen suppression with or without six cycles of mitoxantrone RTOG Long-term androgen suppression plus radiotherapy vs long-term androgen suppression plus radiotherapy followed by six cycles of adjuvant chemotherapy with docetaxel and prednisone Abbreviations: CALGB, Cancer and Leukemia Group B; RTOG, Radiation Therapy Oncology Group; SwOG, Southwest Oncology Group. Table 3 Postprostatectomy radiotherapy for high-risk prostate cancer Trial (year) n Median follow-up (years) Adjuvant rt (%) Progression-free survival Surgery alone (%) P value Adjuvant rt (%) overall survival Surgery alone (%) P value German Cancer P = NS NS NS Society (2009) 82 SwOG (2006) P < NR NR NR SwOG (2009) NR NR NR P = EORTC (2005) P < NS NS NS Adjuvant radiotherapy was Gy for stage pt3a or pt3b disease or evidence of positive margins. Abbreviations: EORTC, European Organization for Research and Treatment of Cancer; NR, not reported; NS, not significant; RT, radiotherapy; SwOG, Southwest Oncology Group. phase iii trial (90203) to compare therapy with estramustine and docetaxel before radical prostat ectomy with radical prostatectomy alone for patients with high-risk disease. 64 this trial is ongoing. the southwest oncology Group conducted a study of chemotherapy with mitoxantrone and prednisone following radical prostat ectomy. 983 patients were enrolled but the trial was halted owing to three cases of acute myelogenous leukemia developing in the adjuvant chemotherapy arm. 65 randomized phase iii cooperative group trials of adjuvant chemotherapy for high-risk, but clinically and radiographically localized, prostate cancer are summarized in table 2. the toxicity of adjuvant chemotherapy noted in trials of high-risk prostate cancer to date reinforces the need for well-controlled multi-institutional randomized studies that are large enough to detect important but infrequent adverse effects as well as discern potential improvements in tumor control associated with novel therapies. Dose-escalated radiotherapy local therapy for prostate cancer has been evolving concurrently with systemic treatment. Clinical trials initiated during the 1980s and 1990s typically utilized radiation doses of 70 Gy or less. in the past 10 years, development of new radiotherapy techniques, such as three- dimensional conformal radiation therapy, intensity-modulated radiation therapy, image-guided radiation therapy and proton therapy, has made delivery of higher doses of external beam radiation feasible with acceptable morbidity. randomized trials have demonstrated improved local control and freedom from recurrence with higher radiation doses in the md anderson trial, doses of 78 Gy were found to be superior to doses of 70 Gy, 66,71 and in a Dutch multicenter trial, doses of 78 Gy were noted to be superior to doses of 68 Gy. 70 these trials were conducted primarily in low-risk and intermediate-risk populations, but interest has developed in extending dose escalation to high-risk cohorts. Brachytherapy has long allowed the delivery of high doses of radiotherapy to the prostate. in the absence of data from a high number of large multicenter random ized trials of brachytherapy for high-risk prostate cancer, the experience of some institutions is noteworthy. researchers have obtained favorable disease control and long-term survival rates using high-dose rate brachy therapy in combina tion with external beam radiotherapy the use of low-dose rate permanent prostate seed brachytherapy has also produced promising results according to selected reports. it is generally accepted that androgen suppression does not improve control and survival rates in patients with low-risk prostate cancer, 75 but stock et al. 76,77 have reported favorable outcomes using a combined trimodal approach of external beam radiotherapy, prostate seed brachytherapy, and 9 months of androgen suppression. 76,77 Comparable results have also been reported by a consortium of six north american centers using a similar approach. 78 approaches such as these utilizing brachytherapy for high-risk prostate cancer merit further study in clinical trials, and must be validated in a randomized, multi-institutional, and controlled setting. Prostatectomy plus radiotherapy treating patients with radical prostatectomy is advocated by some urologists, and is considered by the national nature reviews urology volume 7 JanuarY

6 Comprehensive Cancer network to be an acceptable primary treatment option for selected patients with lowvolume high-risk prostate cancer and a limited number of adverse prognostic factors. 79 the results of three randomized trials of adjuvant radiotherapy in high-risk patients, typically categorized as pathologic stage t3n0 by virtue of extracapsular extension, positive surgical margins, or seminal vesicle invasion, have been reported. all detected improvements in biochemical progression-free survival with acceptable rates of toxicity (table 3) Furthermore, reports of swog trial noted a marked improvement in overall survival following adjuvant radiation therapy. 83 the magnitude of the improvement was striking, with a 10-year survival rate of 74% in patients who received adjuvant radiotherapy, compared with 66% in patients who did not. Furthermore, a 50% reduction in the number of biochemical failures was noted with the use of adjuvant radiotherapy. more than 15 years of follow-up were needed for the difference in biochemical freedom from relapse to translate into a survival benefit in this study, indicating the need for long-term follow-up in clinical trials seeking to detect an absolute survival benefit. these studies have established a new standard of prostate cancer treatment that must include the concept of combining surgery and radiotherapy. However, there have not yet been any randomized trials comparing radiotherapy plus prolonged androgen suppression with radical prostatectomy followed by radiotherapy. Conclusions substantial progress has been made in reducing prostate cancer mortality over the past 20 years. improved prognostic tools have made it possible to identify highrisk patients, and thus to focus efforts on testing novel therapeutic approaches in these men. randomized trials have identified groups of patients treated with primary external beam radiotherapy who have better outcomes when also treated with long-term androgen suppression, and patients treated with radical prostatectomy whose life is prolonged by adjuvant radiotherapy. Clinical trials addressing the role of adjuvant chemotherapy have been completed, and are awaiting maturation of data. improved outcomes for low-risk and intermediate-risk patients have been achieved with the incorporation of higher radiotherapy doses into multimodal treatment approaches. the use of dose-escalated radiotherapy in high-risk patients has yet to be studied. other treatments for high-risk patients, includin g biologic agents, 84,85 novel therapies targeting the hormonal axis, 86,87 and bone-targeted therapies 88,89 are also being investigated. many therapies are being studied in patients with metastatic disease. agents shown to be effective in this setting could be utilized in future trials of primary therapy for men with high-risk prostate cancer. Review criteria we searched for original articles focusing on high-risk prostate cancer in MEDLINE and PubMed published between 1985 and The search terms we used were prostate cancer, high-risk prostate cancer, Gleason score 8 10 and clinical trials. All papers identified were English-language full-text papers. we also searched the reference lists of identified articles, and used our personal knowledge of the literature, to find further papers. 1. Jemal, A. et al. Cancer Statistics, CA Cancer J. Clin. 59, (2009). 2. Albertsen, P. C., Fryback, D. G., Storer, B. E., Kolon, T. F. & Fine, J. Long-term survival among men with conservatively treated prostate cancer. JAMA 274, (1995). 3. Albertsen, P. C. A challenge to contemporary management of prostate cancer. Nat. Clin. Pract. Urol. 6, (2009). 4. Ryan, C. J., Elkin, E. P., Cowan, J. & Carroll, P. R. Initial treatment patterns and outcome of contemporary prostate cancer patients with bone metastases at initial presentation: data from CaPSURE. Cancer 110, (2007). 5. American Joint Committee on Cancer. AJCC Staging Manual, 6th edn (Springer, New York, 2002). 6. Gleason, D. F. & Mellinger, G. T. Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. J. Urol. 111, (1974). 7. Zagars, G. K., Ayala, A. G., von Eschenbach, A. C. & Pollack, A. The prognostic importance of Gleason grade in prostatic adenocarcinoma: a long term-follow-up study of 648 patients treated with radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 31, (1995). 8. Rioux-Leclercq, N. C., Chan, D. Y. & Epstein, J. I. Prediction of outcome after radical prostatectomy in men with organ-confined Gleason score 8 10 adenocarcinoma. Urology 60, (2002). 9. Bastian, P. J. et al. Clinical and pathologic outcome after radical prostatectomy for prostate cancer patients with a preoperative Gleason Sum of 8 to 10. Cancer 107, (2006). 10. Zagars, G. K., Pollock, A. & Eschenbach, A. C. Prognostic factors for clinically localized prostate carcinoma: analysis of 938 patients irradiated in the prostate specific antigen era. Cancer 79, (1997). 11. Mitchell, R. E. et al. Preoperative serum prostate specific antigen remains a significant prognostic variable in predicting biochemical failure after radical prostatectomy. J. Urol. 175, (2006). 12. Inman, B. A. et al. Long-term outcomes of radical prostatectomy with multimodal adjuvant therapy in men with a preoperative serum prostatespecific antigen level of > or = 50 ng/ml. Cancer 113, (2008). 13. Pisansky, T. M., Kahn, M. J. & Bostwick, D. G. An enhanced prognostic system for clinically localized carcinoma of the prostate. Cancer 79, (1997). 14. Soloway, M. & Roach, M. Prostate cancer progression after therapy of primary curative intent: a review of data from prostate-specific antigen era. Cancer 104, (2005). 15. Partin, A. w. et al. Combination of prostatespecific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. JAMA 277, (1997). 16. Kattan, M. w., Eastham, J. A., Stapleton, A. M., wheeler, T. M. & Scardino, P. T. A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. J. Natl Cancer Inst. 90, (1998). 17. Kattan, M. w. et al. Pretreatment nomogram for predicting the outcome of three-dimensional conformal radiotherapy in prostate cancer. J. Clin. Oncol. 18, (2000). 18. D Amico, A. V. et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 280, (1998). 19. Greene, K. L. et al. who is the average patient presenting with prostate cancer? Urology 66, (2005). 20. D Amico, A. V., Chen, M. H., Roehl, K. A. & Catalona, w. J. Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N. Engl. J. Med. 351, (2004). 21. D Amico, A. V., Renshaw, A. A., Sussman, B. & Chen, M. H. Preoperative PSA velocity and risk of death from prostate cancer following external beam radiation therapy. JAMA 294, (2005). 22. Hanks, G. E., Hanlon, A. L., Lee, w. R., Slivjak, A. & Schultheiss, T. E. Pretreatment prostatespecific antigen doubling times: clinical utility of this predictor of prostate cancer behavior. Int. J. Radiat. Oncol. Biol. Phys. 34, (1996). 36 JANUARY 2010 volume 7

7 23. Roberts, S. G., Blute, M. L., Bergstralh, E. J., Slezak, J. M. & Zincke, H. PSA doubling time as a predictor of clinical progression after biochemical failure following radical prostatectomy for prostate cancer. Mayo Clin. Proc. 76, (2001). 24. Grossfeld, G. D. et al. Predicting disease recurrence in intermediate and high-risk patients undergoing radical prostatectomy using percent positive biopsies: results from CaPSURE. Urology 59, (2002). 25. Dong, F. et al. Prostate cancer volume at biopsy predicts clinically significant upgrading. J. Urol. 179, (2008). 26. whittemore, D. E. et al. Significance of tertiary Gleason pattern 5 in Gleason Score 7 radical prostatectomy specimens. J. Urol. 179, (2008). 27. Nanda, A., Chen, M. H., Renshaw, A. A. & D Amico, A. V. Gleason pattern 5 prostate cancer: further stratification of patients with high-risk disease and implications for future randomized trials. Int. J. Radiat. Oncol. Biol. Phys. 74, (2009). 28. Roach, M., waldman, F. & Pollack, A. Predictive models in external beam radiotherapy for clinically localized prostate cancer. Cancer 115, (2009). 29. Pilepich, M. V. et al. Phase III trial of androgen suppression using goserelin in unfavorableprognosis carcinoma of the prostate treated with definitive radiotherapy: report of Radiation Therapy Oncology Group Protocol J. Clin. Oncol. 15, (1997). 30. Lawton, C. A. et al. Updated results of the phase III Radiation Therapy Oncology Group (RTOG) trial evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate. Int. J. Radiat. Oncol. Biol. Phys. 49, (2001). 31. Pilepich, M. V. et al. Androgen suppression adjuvant to definitive radiotherapy in prostate adenocarcinoma long-term results of phase III RTOG Int. J. Radiat. Oncol. Biol. Phys. 61, (2005). 32. Pilepich, M. V. et al. 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