Prostate Cancer, Version 1.2014

The NCCN Guidelines for Prostate Cancer provide multidisciplinary recommendations on the clinical management of patients with prostate cancer. This report highlights notable recent updates. Radium-223 dichloride is a first-in-class radiopharmaceutical that recently received approval for the treatment of patients with symptomatic bone metastases and no known visceral disease. It received a category 1 recommendation as both a first-line and second-line option. The NCCN Prostate Cancer Panel also revised recommendations on the choice of intermittent or continuous androgen deprivation therapy based on recent phase III clinical data comparing the 2 strategies in the nonmetastatic and metastatic settings.

Abstract

The NCCN Guidelines for Prostate Cancer provide multidisciplinary recommendations on the clinical management of patients with prostate cancer. This report highlights notable recent updates. Radium-223 dichloride is a first-in-class radiopharmaceutical that recently received approval for the treatment of patients with symptomatic bone metastases and no known visceral disease. It received a category 1 recommendation as both a first-line and second-line option. The NCCN Prostate Cancer Panel also revised recommendations on the choice of intermittent or continuous androgen deprivation therapy based on recent phase III clinical data comparing the 2 strategies in the nonmetastatic and metastatic settings.

NCCN: Continuing Education

Accreditation Statement

This activity has been designated to meet the educational needs of physicians, nurses, and pharmacists involved in the management of patients with cancer. There is no fee for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians. NCCN designates this journal-based CE activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

NCCN is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center‘s Commission on Accreditation.

This activity is accredited for 1.0 contact hour. Accreditation as a provider refers to recognition of educational activities only; accredited status does not imply endorsement by NCCN or ANCC of any commercial products discussed/displayed in conjunction with the educational activity. Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity.

National Comprehensive Cancer Network is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. NCCN designates this continuing education activity for 1.0 contact hour(s) (0.1 CEUs) of continuing education credit in states that recognize ACPE accredited providers. This is a knowledge-based activity. UAN: 0836-0000-13-017-H01-P

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/36017; and 4) view/print certificate.

Release date: December 16, 2013; Expiration date: December 16, 2014

Learning Objectives:

Upon completion of this activity, participants will be able to:

  • Describe the current standard of care for the management of patients with prostate cancer

  • Discuss the role of adjuvant therapy in the management of prostate cancer

NCCN Categories of Evidence and Consensus

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

F1NCCN Guidelines Insights: Prostate Cancer, Version 1.2014

Version 1.2014 © National Comprehensive Cancer Network, Inc. 2013, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 12; 10.6004/jnccn.2013.0174

Overview

Other than skin cancer, prostate cancer is the most common cancer in men in the United States. In 2013, an estimated 238,590 new cases will be diagnosed, accounting for 28% of new cancer cases.1 Although most patients are diagnosed early and may be cured with surgery and/or radiation therapy, many eventually experience progression and require further treatment in the form of androgen deprivation therapy (ADT), chemotherapy, or other systemic treatments. Researchers estimate that prostate cancer will account for 29,720 deaths in 2013. ADT is the mainstay initial systemic treatment for advanced prostate cancer. The optimal timing, duration, and schedule of ADT remains an active area of research. Given the many potential side effects of ADT, intermittent administration is becoming an increasingly popular alternative to continuous administration. Recent data from 2 large phase III clinical trials compared the 2 approaches in the nonmetastatic and metastatic settings. Unfortunately, almost all patients on ADT eventually experience disease progression. Most patients with castration-recurrent or -resistant prostate cancer (CRPC) die of bone metastases and related complications. The recently approved radium-223 is the first bone-targeting agent to demonstrate a survival benefit in these patients.

F2NCCN Guidelines Insights: Prostate Cancer, Version 1.2014

Version 1.2014 © National Comprehensive Cancer Network, Inc. 2013, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 12; 10.6004/jnccn.2013.0174

NCCN convened a multidisciplinary panel of leading experts at NCCN Member Institutions to develop and continually update guidelines for the treatment of prostate cancer. The latest full guideline, which includes a complete list of updates, is available on the NCCN Web site (NCCN.org). These NCCN Guidelines Insights highlight 2 recent revisions.

Intermittent Versus Continuous ADT

ADT has long been the gold standard for androgen-stimulated metastatic prostate cancer and is used frequently in men who have experienced biochemical failure after local therapy. However, ADT is associated with substantial side effects, including hot flashes, hot flushes, vasomotor instability, osteoporosis, greater incidence of clinical fractures, weight gain, sarcopenia, insulin resistance, alterations in lipids, and greater risk for diabetes and cardiovascular disease.2,3 In general, the side effects of continuous ADT increase with the duration of treatment. One proposed approach to alleviate toxicity was an intermittent schedule. Supported by preclinical data and early clinical studies, intermittent ADT is based on the premise that cycles of androgen deprivation followed by re-exposure may delay “androgen independence,” reduce treatment morbidity, and improve quality of life.4,5

The risk-to-benefit ratio of therapy is very different between asymptomatic patients experiencing an increase in prostate-specific antigen (PSA) and patients with symptomatic metastases. However, past phase III studies were underpowered and did not differentiate between these groups of patients.6,7 Recently, long-awaited results from 2 phase III noninferiority trials provided valuable insights into each of these settings, although uncertainty remains in the field.

F3NCCN Guidelines Insights: Prostate Cancer, Version 1.2014

Version 1.2014 © National Comprehensive Cancer Network, Inc. 2013, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 12; 10.6004/jnccn.2013.0174

Biochemical Relapse

The Canadian-led PR.7 trial provided the best phase III data to date comparing intermittent and continuous ADT in patients without metastasis. Crook et al8 randomly assigned 1386 patients with PSA levels greater than 3 ng/mL after radiation therapy to either intermittent ADT or continuous ADT. In the intermittent ADT arm, ADT was given in 8-month cycles followed by off-treatment periods until PSA reached 10 ng/mL. At a median follow-up of 6.9 years, the intermittent approach was noninferior to continuous ADT with respect to overall survival (8.8 vs 9.1 years, respectively; hazard ratio [HR], 1.02; 95% CI, 0.86-1.21). Although more patients died of prostate cancer in the intermittent arm (120 of 690 patients) than the continuous arm (94 of 696 patients), this was balanced by more non-prostate cancer deaths in the continuous ADT arm. The increased mortality from other causes in the continuous group cannot be attributed to any specific type of ADT toxicity. Several quality-of-life factors showed modest improvement in the intermittent ADT group, including physical function, fatigue, urinary problems, hot flashes, libido, and erectile dysfunction.

An unplanned Cox regression analysis of the trial showed that men with Gleason sum greater than 7 in the continuous ADT arm lived 14 months longer than those with the same Gleason sum in the intermittent ADT arm.8 The caveats to this analysis are that pathology was not centrally reviewed and the study was not powered to detect a small difference based on Gleason sum.

The authors cautioned that these results should not be extrapolated to other treatment schedules. The test population was heterogenous, and therefore which of these asymptomatic patients benefitted from treatment remains unclear. It is possible that many of these patients could have delayed ADT without harm. The optimal PSA threshold to initiate therapy remains elusive, because the eligibility threshold of PSA level greater than 3 ng/mL was chosen mainly to aid accrual. Furthermore, 59% of deaths in the PR.7 trial were not related to prostate cancer. Because the test population had a low disease burden, a follow-up longer than 6.9 years may be required for disease-specific deaths to out-balance deaths from other causes.

F4NCCN Guidelines Insights: Prostate Cancer, Version 1.2014

Version 1.2014 © National Comprehensive Cancer Network, Inc. 2013, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 11, 12; 10.6004/jnccn.2013.0174

Metastatic Disease

Hussain et al9 conducted the SWOG 9346 trial to evaluate intermittent and continuous ADT in metastatic patients. Eligibility criteria included a new diagnosis of metastatic, androgen-stimulated prostate cancer; performance status of 0 to 2; and PSA level of 5 ng/mL or higher. After 7 months of induction ADT, 1535 patients whose PSA decreased to 4 ng/mL or below (thereby showing androgen sensitivity) were randomized to intermittent or continuous ADT. In the intermittent group, ADT was reinitiated when the PSA level reached 20 ng/mL, and stopped after 7 months if PSA decreased to 4 ng/mL or below. At a median follow-up of 9.8 years, median survival was 5.1 years for the intermittent ADT arm and 5.8 years for the continuous ADT arm. The HR for death with intermittent ADT was 1.10 with a 90% confidence interval between 0.99 and 1.23, which exceeded the prespecified upper boundary of 1.20 for noninferiority. The authors stated that the survival results were inconclusive, and that a 20% greater mortality risk with the intermittent approach cannot be ruled out. The study showed better erectile function and mental health in patients receiving intermittent ADT at 3 months, but the difference became insignificant thereafter.

In a post hoc stratification analysis of the trial, patients with minimal disease had a median survival of 5.4 years when receiving intermittent ADT versus 6.9 years when receiving continuous ADT (HR, 1.19; 95% CI, 0.98-1.43).9 The median survival was 4.9 years in the intermittent ADT arm compared with 4.4 years in the continuous ADT arm for patients with extensive disease (HR, 1.02; 95% CI, 0.85-1.22). Subgroup analyses are hypothesis-generating and raise the interesting question of whether men with different disease burdens may respond differently to intermittent versus continuous ADT.

The interpretation of the SWOG 9346 data is further complicated by issues regarding the design and underlying statistics of noninferiority trials.10 The NCCN Prostate Cancer Panel struggled additionally with differences in the prespecified noninferiority margin between the PR.7 and SWOG trials.9 The upper limit of HR for death was set at 1.20 in SWOG 9346 and 1.25 in PR.7, translating to an absolute survival difference of 1.0 and 1.8 years, respectively.

NCCN Recommendations

The panel outlined its recommendations based on recent data in the “Principles of Androgen Deprivation Therapy” section of the algorithm (see PROS-F, 1 and 2 of 4; pages 1475 and 1476). In the setting of biochemical relapse after local therapy, one must first determine whether the patient is a candidate for a salvage approach, such as radiation rescue for biochemical failure after surgery, or, less commonly, radical prostatectomy or cryosurgery rescue for biochemical failure after radiation. Men with prolonged PSA doubling times who are older are excellent candidates for observation. Intermittent ADT has been shown to be noninferior to continuous ADT in terms of overall survival, and may improve quality of life for men who choose to initiate ADT.

Patients should be queried about adverse effects related to ADT. Intermittent ADT should be used for patients with metastatic disease who experience significant side effects from ADT. Some men who have no ADT-related morbidity may find the uncertainty of intermittent ADT not worthwhile. Men who have significant pain at the onset may have longer survival with continuous versus intermittent ADT, but this finding is derived from a post hoc analysis. Intermittent ADT requires close monitoring of PSA and testosterone levels, especially during off-treatment periods, and patients may need to switch to continuous therapy on signs of disease progression. Furthermore, the panel continues to believe that not enough emphasis is placed on delaying the initiation of ADT in patients with biochemical relapse after primary and salvage therapy.11 Even in metastatic disease, intermittent ADT seems appropriate, in that survival is similar to that seen with ADT administered continuously in all studies comparing the 2 strategies thus far, and quality of life is better with intermittent ADT in most studies.9,12-17

Radium-223 Dichloride

Bone metastases are a major cause of mortality, morbidity, and poor quality of life in men with CRPC.18 Although systemic radiopharmaceutical therapy (strontium-89 and samarium-153) has been used to treat these patients, its role has been limited traditionally to palliation of multifocal bone pain.19,20

In May 2013, the FDA approved radium-223 dichloride for the treatment of metastatic CRPC in patients with symptomatic bone metastases and no known visceral metastatic disease. This intravenous radioactive agent selectively binds to newly formed bone stroma at the site of bone metastases and induces double-strand DNA breaks in tumor cells.21,22 Unlike the β-emitting palliative radiopharmaceuticals, radium-223 emits high-energy α particles that have a shorter path, which reduce toxic effects on adjacent tissue.22

Approval of radium-223 was based on clinical data from a multicenter, phase III, randomized trial that enrolled 921 men with symptomatic CRPC, 2 or more bone metastases, and no known visceral disease.23 A total of 57% of the patients received prior docetaxel, and all patients received best supportive care. Patients were randomized in a 2:1 ratio to a total of 6 monthly intravenous injections of radium-223 or placebo. Compared with placebo, radium-223 significantly improved overall survival (median, 14.9 vs 11.3 months; HR, 0.70; 95% CI, 0.058-0.83; P<.001) and prolonged time to first skeletal-related event (SRE; median, 15.6 vs 9.8 months). This result rendered radium-223 the first bone-targeting agent to provide a survival advantage; benefits from other agents, such as zoledronic acid and denosumab, are limited to delay of SREs in the setting of bone metastases.24,25 The effect on control of existing pain was not reported. In addition, the safety of using chemotherapy after radium-223 has also not been established. Preliminary data suggest that combination with standard doses of docetaxel should not be undertaken.26

Radium-223 was well tolerated. Grade 3/4 hematologic toxicity was low (3% neutropenia, 6% thrombocytopenia, and 13% anemia), possibly because of the short range of radioactivity.23 Fecal elimination of the agent led to generally mild nonhematologic side effects, which included nausea, diarrhea, and vomiting. This favorable toxicity profile and extension of survival renders radium-223 an attractive first-line alternative for patients with symptomatic bone metastases who are too frail to receive docetaxel.

NCCN Recommendations

The panel included recommendations for radium-223 in the treatment of metastatic CRPC, assigning it a category 1 recommendation as a first-line or second-line option for patients with symptomatic bone metastases and no known visceral disease (see PROS-11, page 1473, and PROS-D 2 of 2, page 1474). Hematologic evaluation should be performed according to the FDA label before treatment initiation and before each subsequent dose.26 Radium-223 given in combination with chemotherapy (such as docetaxel) outside of a clinical trial is not recommended because of the potential for additive myelosuppression.26 There are no restrictions on combining radium-223 with denosumab or a bisphosphonate.

Given the wide variety of second-line options available to patients with symptomatic metastatic CRPC who have been exposed to chemotherapy, the choice of therapy should be based on clinical considerations, which include patient preferences, prior treatment, presence or absence of visceral disease, and symptoms. Studies on the direct comparison or sequential efficacy of radium-223 with other available agents are warranted.

Conclusions

Important updates to the management of prostate cancer in the NCCN Guidelines for Prostate Cancer are highlighted in these NCCN Guidelines Insights. The NCCN Guidelines are updated at least annually, and more often when new high-quality clinical data become available in the interim. The most up-to-date version of these continuously evolving guidelines is available online at NCCN.org. The recommendations in the NCCN Guidelines are based on evidence from clinical data when available and expert consensus of the panel. Independent medical judgment is required to apply these guidelines to individual patients to optimize care. The physician and patient have the responsibility to jointly explore and select the most appropriate option from among the available alternatives. When possible, and consistent with NCCN philosophy, the panel strongly encourages patient/physician participation in prospective clinical trials.

EDITOR: Kerrin M. Green, MA, Assistant Managing Editor, JNCCN— Journal of the National Comprehensive Cancer Network, has disclosed that she has no relevant financial relationships.

CE AUTHORS: Deborah J. Moonan, RN, BSN, Manager, CE Supporter-Outreach, has disclosed the following relationships with commercial interests: AstraZeneca: Stockholder/Former Employee. Ann Gianola, MA, Manager, Medical Education Accreditation and Grant Development, has disclosed the following relationship with commercial interests: Actelion: Grant/Research Support. Dorothy A. Shead, MS, Director, Patient & Clinical Information Operations, has disclosed that she has no relevant financial relationships. Maria Ho, PhD, Oncology Scientist/Senior Medical Writer, has disclosed that she has no relevant financial relationships.

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    NCCN Guidelines Insights: Prostate Cancer, Version 1.2014

    Version 1.2014 © National Comprehensive Cancer Network, Inc. 2013, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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    NCCN Guidelines Insights: Prostate Cancer, Version 1.2014

    Version 1.2014 © National Comprehensive Cancer Network, Inc. 2013, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

  • View in gallery
    NCCN Guidelines Insights: Prostate Cancer, Version 1.2014

    Version 1.2014 © National Comprehensive Cancer Network, Inc. 2013, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

  • View in gallery
    NCCN Guidelines Insights: Prostate Cancer, Version 1.2014

    Version 1.2014 © National Comprehensive Cancer Network, Inc. 2013, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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