Multimodal treatment utilizing combined androgen suppression and radiotherapy has improved survival rates for patients with high-risk prostate cancer.
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, 31–38 (2010); doi:10.1038/nrurol.2009.237
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 CreditsTM. 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 http://www.medscapecme.com/ 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 2009. 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 recognized that the histological grading of prostate tumors correlates with prognosis. Donald Gleason described a system for the assessment and communication 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 prognostic accuracy over that obtained with either parameter alone.6 subsequently, Gleason score has been validated as an independent prognostic factor
nature reviews | urology
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
volume 7 | JanuarY 2010 | 31 © 2010 Macmillan Publishers Limited. All rights reserved
reviewS 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
High-risk criteria
D’Amico et al.18
Stage T2c or greater and either PSA level >20 ng/ml or Gleason score 8–10
RTOG 99-02 and 05-2160
PSA 20–100 ng/ml, Gleason score ≥7 and any T stage or, stage T2 or greater, PSA 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.10–12 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 therapeutic 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.15–17 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 8–10.18 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 time22,23 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 radiotherapy or radical prostatectomy.22–25 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 stratification 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.
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reviewS During the randomized rtoG 85-31 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 1992. 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 = 0.0046), in those treated with immediate and deferred androgen suppression therapy, respectively.29–31 the rtoG 85-31 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 86-10 trial comprised 471 patients diagnosed with clinically bulky tumors between 1987 and 1991. 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.32–34 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 1995. 415 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 = 0.0002).37–39 the rtoG followed the 85-31 and 86-10 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 22961 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
