This is the current release of the guideline.

This guideline updates a previous version: Lee WR, Papagikoa MA, Roach M III, Anscher MS, Beyer DC, Lawton CA, Merrick G, Michalski JM, Pollack A, Vijayakumar S, Carroll PR, Higano CS, Mauch PM, Expert Panel on Radiation Oncology-Prostate Work Group. Locally advanced (high-risk) prostate cancer. [online publication]. Reston (VA): American College of Radiology (ACR); 2006. 13 p. [49 references]

The appropriateness criteria are reviewed biennially and updated by the panels as needed, depending on introduction of new and highly significant scientific evidence.

Locally advanced (high-risk) prostate cancer

To evaluate the appropriateness of radiologic, endocrine, and surgical treatment procedures for patients with locally advanced (high risk) prostate cancer

Patients with locally advanced (high risk) prostate cancer

Literature Search Procedure

The Medline literature search is based on keywords provided by the topic author. The two general classes of keywords are those related to the condition (e.g., ankle pain, fever) and those that describe the diagnostic or therapeutic intervention of interest (e.g., mammography, MRI).

The search terms and parameters are manipulated to produce the most relevant, current evidence to address the American College of Radiology Appropriateness Criteria (ACR AC) topic being reviewed or developed. Combining the clinical conditions and diagnostic modalities or therapeutic procedures narrows the search to be relevant to the topic. Exploding the term "diagnostic imaging" captures relevant results for diagnostic topics.

The following criteria/limits are used in the searches.

1. Articles that have abstracts available and are concerned with humans.
2. Restrict the search to the year prior to the last topic update or in some cases the author of the topic may specify which year range to use in the search. For new topics, the year range is restricted to the last 5 years unless the topic author provides other instructions.
3. May restrict the search to Adults only or Pediatrics only.
4. Articles consisting of only summaries or case reports are often excluded from final results.

The search strategy may be revised to improve the output as needed.

The total number of source documents identified as the result of the literature search is not known.

Strength of Evidence Key

Category 1 - The conclusions of the study are valid and strongly supported by study design, analysis and results.

Category 2 - The conclusions of the study are likely valid, but study design does not permit certainty.

Category 3 - The conclusions of the study may be valid but the evidence supporting the conclusions is inconclusive or equivocal.

Category 4 - The conclusions of the study may not be valid because the evidence may not be reliable given the study design or analysis.

The topic author drafts or revises the narrative text summarizing the evidence found in the literature. American College of Radiology (ACR) staff draft an evidence table based on the analysis of the selected literature. These tables rate the strength of the evidence for all articles included in the narrative text.

The expert panel reviews the narrative text, evidence table, and the supporting literature for each of the topic-variant combinations and assigns an appropriateness rating for each procedure listed in the table. Each individual panel member forms his/her own opinion based on his/her interpretation of the available evidence.

More information about the evidence table development process can be found in the American College of Radiology (ACR) Appropriateness Criteria® Evidence Table Development document (see "Availability of Companion Documents" field).

Modified Delphi Technique

The appropriateness ratings for each of the procedures included in the Appropriateness Criteria topics are determined using a modified Delphi methodology. A series of surveys are conducted to elicit each panelist's expert interpretation of the evidence, based on the available data, regarding the appropriateness of an imaging or therapeutic procedure for a specific clinical scenario. American College of Radiology (ACR) staff distributes surveys to the panelists along with the evidence table and narrative. Each panelist interprets the available evidence and rates each procedure. The surveys are completed by panelists without consulting other panelists. The ratings are a scale between 1 and 9, which is further divided into three categories: 1, 2, or 3 is defined as "usually not appropriate"; 4, 5, or 6 is defined as "may be appropriate"; and 7, 8, or 9 is defined as "usually appropriate." Each panel member assigns one rating for each procedure per survey round. The surveys are collected and the results are tabulated, de-identified and redistributed after each round. A maximum of three rounds are conducted. The modified Delphi technique enables each panelist to express individual interpretations of the evidence and his or her expert opinion without excessive bias from fellow panelists in a simple, standardized and economical process.

Consensus among the panel members must be achieved to determine the final rating for each procedure. Consensus is defined as eighty percent (80%) agreement within a rating category. The final rating is determined by the median of all the ratings once consensus has been reached. Up to three rating rounds are conducted to achieve consensus.

If consensus is not reached, the panel is convened by conference call. The strengths and weaknesses of each imaging procedure that has not reached consensus are discussed and a final rating is proposed. If the panelists on the call agree, the rating is accepted as the panel's consensus. The document is circulated to all the panelists to make the final determination. If consensus cannot be reached on the call or when the document is circulated, "No consensus" appears in the rating column and the reasons for this decision are added to the comment sections.

Not applicable

A formal cost analysis was not performed and published cost analyses were not reviewed.

Criteria developed by the Expert Panels are reviewed by the American College of Radiology (ACR) Committee on Appropriateness Criteria.

ACR Appropriateness Criteria®

Clinical Condition: Locally Advanced (High-risk) Prostate Cancer

Variant 1: Stage T3/T4, PSA <20, Gleason <7.

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Variant 2: Stage T3/T4, PSA <20, Gleason ≥7.

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Variant 3: Stage T3/T4, PSA ≥20, Gleason <7.

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Variant 4: Stage T3/T4, PSA ≥20, Gleason ≥7.

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Variant 5: Stage T1/T2, PSA ≥20, Gleason <7, post-void residual = 350 cc.

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Variant 6: Stage T1/T2, PSA ≥20, Gleason ≥7, post-void residual = 20 cc.

Note: Abbreviations used in the tables are listed at the end of the "Major Recommendations" field.

Summary of Literature Review

The high-risk prostate cancer category has evolved as the clinical presentation of prostate cancer has changed with the use of prostate-specific antigen (PSA) screening. Prior to the advent of PSA screening in the general U.S. population, prostate 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 prostate cancer.

Definition of High-Risk Prostate Cancer

Many stratification models for prostate 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 prostate 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. 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 patients. This difference is important because the outcome of treatment is different. The historical high-risk patients can be expected to have a 5- to 10-year overall survival (OS) rate of 47% to 72%. The contemporary high-risk patient will have a 5- to 10-year OS rate of approximately 60% to 89%. 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 prostate cancer, there are no studies comparing the efficacy of different treatment modalities to guide one's choice of therapy for high-risk prostate 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 patients.

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 prostate 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. A select group of publications encompassing the major modalities of therapy will be reviewed.

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 one study, an OS advantage was seen with the combination-therapy arm. Prior to the reporting of this study, multiple randomized trials sought to determine the optimum dose/target of radiation in conjunction with neo/concurrent/adjuvant therapy (usually endocrine). Table 1 in the original guideline document details the salient features of the most pertinent studies. In reviewing the studies, several themes emerge. First, the addition of pelvic radiation to prostate/seminal vesicle radiation does not confer improved outcome when assessed in an overall analysis. This may be noted within a trial or among the other trials. Second, any duration of any of the cited combinations of endocrine therapy (androgen deprivation +/- anti-androgens) improves most outcome measures. Third, endocrine therapy of longer than 4 to 6 months does not improve OS. Lastly, more recent data show better outcome measures as expected given that the virulence of prostate cancer being detected has lessened with the implementation of PSA screening.

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. 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. 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 prostate-cancer-specific survival or OS.

Multiple other publications tell us that dose escalation of EBRT improves outcome. The dose escalation supported by two groups of researchers exceeds the doses used in the trials listed in Table 1 of the original guideline. 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. A preliminary report of the efficacy shows that this trial was negative.

Radical Prostatectomy

There are no randomized trials of prostatectomy for high-risk patients, and retrospective reviews are few in number. The results, however, are competitive with EBRT. One study reports a prostate-cancer-specific survival rate of 88% with an OS rate of 74% for patients treated between 1984 and 2003. For patients treated between 1977 and 1994, another study noted a 10-year prostate-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% to 20% of the study population comprised high-risk patients. 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. 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 prostatectomy has not been evaluated to any great degree. However, most retrospective reports on prostatectomy for high-risk disease likely contain patients treated in this manner. The prostatectomy literature is primarily focused on clinical T1-T3 and typically does not include clinical T4 patients.

Brachytherapy

The use of low dose-rate brachytherapy for high-risk prostate cancer has been discouraged by many for reasons that were based on theoretical disadvantages rather than observed outcomes. Some researchers, however, have provided outcome data for high-risk patients treated with brachytherapy. One study recently reported that for patients treated from 1995-2006, the prostate-cancer-specific survival rate was 95.2% and the OS rate was 69.2%. Another study also described an experience with brachytherapy in high-risk patients. That study noted that the prostate-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 prostatectomy.

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 prostate-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 prostatectomy 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. 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.

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. One study reports a series of patients treated from 1994 to 1999 who were predominately high-risk. The 10-year prostate-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 prostate cancer as well. Another study described a series of patients treated from 1999 to 2007. That study reported a biochemical disease-free rate at 5 years of 45%. Two randomized trials of cryotherapy versus EBRT have been reported. Neither trial was powered to detect a difference in prostate-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 and suggest equivalence between the arms in the other. 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 prostatectomy. 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 patients.

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 prostatectomy 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 patients. 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 prostatectomy significantly improves urinary obstruction.

Recent data highlight the systemic effects of androgen deprivation. 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. 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 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 prostate cancer has the potential for misleading the practitioner into believing that EBRT with endocrine therapy is the standard of care. Because there are no comparative trials between modalities, one cannot truly state that there is a standard of care for high-risk prostate cancer patients. Based on available information on efficacy and toxicity, it can be concluded that it is reasonable to employ EBRT plus endocrine therapy, radical prostatectomy, or brachytherapy for treating high-risk prostate cancer. It is known that, based on available data, an evidence-based way to deliver EBRT is with doses of 72-78Gy to the prostate region coupled with approximately 6 months of endocrine therapy. The optimum method for performing radical prostatectomy-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.

Abbreviations

• CAB, combined androgen blockade
• EBRT, external beam radiation therapy
• HDR, high-dose rate
• LDR, low-dose-rate
• LHRH, luteinizing hormone-releasing hormone
• PSA, prostate-specific antigen

Algorithms were not developed from criteria guidelines.

The recommendations are based on analysis of the current literature and expert panel consensus.

Selection of appropriate radiation therapy, endocrine therapy, surgical procedures (radical prostatectomy), and chemotherapy for management of patients with locally advanced (high-risk) prostate cancer

The American College of Radiology (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 U.S. Food and Drug Administration (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.

An implementation strategy was not provided.

Not applicable: The guideline was not adapted from another source.

The American College of Radiology (ACR) provided the funding and the resources for these ACR Appropriateness Criteria®.

Committee on Appropriateness Criteria, Expert Panel on Radiation Oncology–Prostate

Panel Members: Jay P. Ciezki, MD; Gregory Merrick, MD; I-Chow Joe Hsu, MD; May Abdel-Wahab, MD, PhD; V. Elayne Arterbery, MD; Steven J. Frank, MD; James Lloyd Mohler, MD; Brian J. Moran, MD; Seth A. Rosenthal, MD; Carl J. Rossi Jr, MD; Yoshiya Yamada, MD

Not stated

This is the current release of the guideline.

This guideline updates a previous version: Lee WR, Papagikoa MA, Roach M III, Anscher MS, Beyer DC, Lawton CA, Merrick G, Michalski JM, Pollack A, Vijayakumar S, Carroll PR, Higano CS, Mauch PM, Expert Panel on Radiation Oncology-Prostate Work Group. Locally advanced (high-risk) prostate cancer. [online publication]. Reston (VA): American College of Radiology (ACR); 2006. 13 p. [49 references]

The appropriateness criteria are reviewed biennially and updated by the panels as needed, depending on introduction of new and highly significant scientific evidence.

Electronic copies: Available in Portable Document Format (PDF) from the American College of Radiology (ACR) Web site.

Print copies: Available from the American College of Radiology, 1891 Preston White Drive, Reston, VA 20191. Telephone: (703) 648-8900.

The following are available:

• ACR Appropriateness Criteria®. Overview. Reston (VA): American College of Radiology; 2 p. Electronic copies: Available in Portable Document Format (PDF) from the American College of Radiology (ACR) Web site.
• ACR Appropriateness Criteria®. Literature search process. Reston (VA): American College of Radiology; 1 p. Electronic copies: Available in Portable Document Format (PDF) from the ACR Web site.
• ACR Appropriateness Criteria®. Evidence table development. Reston (VA): American College of Radiology; 4 p. Electronic copies: Available in Portable Document Format (PDF) from the ACR Web site.

None available

This NGC summary was completed by ECRI on September 5, 2006. This summary was updated by ECRI Institute on January 11, 2011 following the U.S. Food and Drug Administration (FDA) advisory on gonadotropin-releasing hormone agonists. This summary was updated by ECRI Institute on June 27, 2011.

Instructions for downloading, use, and reproduction of the American College of Radiology (ACR) Appropriateness Criteria® may be found on the ACR Web site .