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The AUA Prostate Cancer Guideline: What's New?

Introduction

The American Urological Association (AUA) recently published its anxiously anticipated update of the Guideline for the Management of Clinically Localized Prostate Cancer.[1] The original guideline was published in 1995 and for more than a decade served as a valuable physician and patient resource in clinical decision-making for newly diagnosed, clinically localized prostate cancer.[2] However, time marches on, and since that sentinel publication, much has changed in terms of clinical presentation and refinements in treatment options.[3] Furthermore, there is a greater understanding of the impact of treatments on oncologic outcomes and quality of life in men with localized disease.[4] In this article, the key features of this important new guideline are highlighted in the context of a clinician's standpoint. It is highly recommended, however, that the reader review the complete document (available on the AUA Web site: www.auanet.org/Guidelines/) to gain an understanding of the full breadth of material contained within it.

Methodology

The importance of sound scientific methodology in the preparation of a clinical guideline cannot be overstated. An increasing number of guidelines have become available, but clinicians should be aware that a guideline is only as reliable as the methods and data used to prepare it; no guideline should be accepted without first examining how it was formulated. In an era of increasing awareness of the importance of evidence-based medicine in the clinical decision-making process, the question of methodology is especially important. Differences in recommendations in guidelines issued by different organizations are the result mainly of different methodologic approaches. Only clinicians who understand the methods used will be able to evaluate them critically.

The AUA Guideline Panel (Table 1), led by Dr. Ian Thompson (chair) and Dr. James Brantley Thrasher (co-chair), approached their task by performing extensive reviews of the published literature with outcomes for patients with clinical stage T1 to T2N0M0 prostate cancer. Four PubMed searches were performed using the MeSH Major Topics of prostate cancer or prostate neoplasm covering January 1991 through April 2004.[1] From an initial pool of 13,888 articles, 436 met the inclusion criteria, and data from them were then extracted for analysis. An attempt to do a separate extraction of published materials on quality of life was not completed due to methodologic challenges and lack of funding.

Table 1. Prostate Cancer Clinical Guidelines Update Panel (2007)

Members (Specialty) Consultants
Ian Thompson, MD, Chair (Urology)
James Brantley Thrasher, MD, Co-Chair (Urology)

Gunnar Aus, MD (Urology)
Arthur L. Burnett, MD (Sexual Medicine)
Edith D. Canby-Hagino, MD (Urology)
Michael S. Cookson, MD (Urology)
Anthony V. D'Amico, MD, PhD (Radiation Oncology)
Roger R. Dmochowski, MD (Urology)
David T. Eton, PhD (Health Services Research)
Jeffrey D. Forman, MD (Radiation Oncology)
S. Larry Goldenberg, OBC, MD (Urology)
Javier Hernandez, MD (Urology)
Celestia S. Higano, MD (Medical Oncology)
Stephen R. Kraus, MD (Neurourology)
Judd W. Moul, MD (Urology)
Catherine M. Tangen, DrPH (Biostatistics and Clinical Trials)		 Hanan S. Bell, PhD
Patrick M. Florer
Diann Glickman, PharmD
Scott Lucia, MD
Timothy J. Wilt, MD, MPH,

AUA Staff:

Monica Liebert, PhD
Edith Budd
Michael Folmer
Katherine Moore

The Panel developed the Guideline statements according to the level of evidence, and statements were essentially graded with varying degrees of flexibility. A "standard" has the least flexibility as treatment policy, a "recommendation" has significantly more flexibility, and an "option" is even more flexible. The actual definitions of the Guideline grading system are listed in Table 2.

Table 2. AUA Guideline Grading System

Standard A guideline statement is a standard if: (1) the health outcomes of the alternative interventions are sufficiently well known to permit meaningful decisions, and (2) there is virtual unanimity about which intervention is preferred.
Recommendation A guideline statement is a recommendation if: (1) the health outcomes of the alternative intervention are sufficiently well known to permit meaningful decisions, and (2) an appreciable, but not unanimous, majority agrees on which intervention is preferred.
Option A guideline statement is an option if: (1) the health outcomes of the interventions are not sufficiently well known to permit meaningful decisions, or (2) preferences are unknown or equivocal.

Initial Evaluation

In the initial evaluation and discussion of treatment options with the patient, the Guideline recommends as a standard that an assessment of the patient's life expectancy, overall health status, and tumor characteristics be undertaken before any treatment decisions are made.[1] The Guideline clearly states that it is the patient's life expectancy rather than chronologic age which is factored into the decision process. Not surprisingly, no specific age cutoff was listed in the document. The Panel acknowledged that men with competing risks for mortality, such as advanced age, are at significantly lower risk for disease progression or disease-related death. Another key consideration in the decision process during the initial evaluation is the overall health status of the patient, which will likely have an impact on life expectancy, response, and/or side effects of the various treatments.

One of the most substantial changes in the new Guideline is the recommendation for risk stratification at the time of diagnosis.[1] The importance of categorizing patients into risk groups has been shown in published reports that have demonstrated a benefit in terms of both biochemical relapse and cancer-specific mortality when patients were divided into groups based on serum prostate-specific antigen (PSA), Gleason score on biopsy, and clinical stage as assessed by digital rectal examination (DRE).[5,6] Recognizing that there are several different risk-stratification schemes available and that no one system is clearly superior to another, the Panel chose to divide patients into 1 of 3 risk categories: low, intermediate, and high. The AUA Panel's risk-stratification scheme is displayed in Table 3.

Table 3. AUA Risk Strata

Risk Level Definition
Low PSA ≤10 ng/mL and Gleason score 6 or less, and clinical stage T1c or T2a
Intermediate PSA > 10-20 ng/mL or Gleason score 7 or clinical stage T2b, but not qualifying for high risk
High PSA > 20 ng/mL or Gleason score 8 to 10 or clinical stage T2c

Treatment Options and Alternatives

The Guideline document describes in detail the alternatives for the most commonly accepted treatment options for localized prostate cancer.[1] These options include watchful waiting (WW), active surveillance (AS), interstitial prostate brachytherapy (IR), external beam radiotherapy (EBRT), and radical prostatectomy (RP). The Panel stated that primary hormonal therapy or androgen deprivation therapy (ADT) may be used with a goal of providing symptomatic control of prostate cancer for patients in whom definitive treatment is not possible or acceptable. The Panel reported that the published data describing the use of primary ADT in localized prostate cancer was either retrospective or did not clearly address its use in clinical T1 or T2 disease. Accordingly, the Panel did not consider primary ADT as a treatment option for localized disease. The Panel further stated that there is a distinction between primary ADT and the use of neoadjuvant (before therapy) or adjuvant (after therapy) hormonal therapy. The Panel did not include other treatment options -- including cryotherapy, high-intensity focused ultrasound, and high-dose IR -- for a number of reasons, including limited published experience, short-term follow-up, and failure to meet the inclusion criteria as listed in the methodology of the Guideline. However, cryotherapy for the treatment of localized prostate cancer is currently under review with an AUA best-practice policy anticipated in the near future.

The Panel listed as a standard that a patient with clinically localized prostate cancer should be informed about the commonly accepted initial interventions including, at a minimum, active surveillance, radiotherapy (EBRT and brachytherapy), and RP.[1] The Guideline further states, on the basis of Panel consensus, that a discussion of the estimates for benefits and harms of each intervention should be offered to the patient. Cancer treatment recommendations in the document are presented by risk group as stratified in Table 3. Of note, the Panel emphasized that it included information about relevant randomized clinical trials where available for each risk group.

Treatment Recommendations

Low-Risk Patients

The Panel based its treatment recommendations for patients with low-risk disease on a review of the data and on Panel consensus.[1] Appropriate treatment options for this group of patients include AS, IR, EBRT, and RP, and all are appropriate monotherapy treatments. Furthermore, study outcomes data did not provide clear-cut evidence for superiority of any one treatment over the others.

As a standard, the Panel felt that patient preferences and health conditions related to urinary, sexual, and bowel function should be considered in decision-making. The various treatment options have varying effects on specific health conditions in these areas, making no single treatment modality preferable for all patients. The Panel went on to state that when counseling patients regarding treatment options, as a standard, "physicians should consider" the available randomized clinical trials (RCTs). There are 2 RCTs demonstrating that higher-dose radiation may decrease the risk for PSA recurrence,[7,8] and 1 RCT indicating that when WW and RP are compared, RP may be associated with a lower risk for cancer recurrence, cancer-related death, and improved survival.[9]

Consequently, as a standard, the Panel recommended that "patients who are considering specific treatment options should be informed" of the findings of recent high-quality clinical trials. For example, those considering EBRT should be informed of data indicating that higher-dose radiation may decrease the risk for PSA recurrence,[7,8] and patients considering WW should be told that RP may lower the risk for cancer recurrence and improve survival.[9]

The Panel also distinguished between AS and WW. Patients choosing AS opt for initial close monitoring with frequent PSA, DRE, symptom checks, and periodic repeat biopsies followed by treatment for evidence of tumor progression. In contrast, patients on WW may have a greater focus on quality of life and may have "little interest in intervention" other than palliation. On the basis of Panel consensus, the Panel recommends, as a standard for patients choosing AS, that the aim of the second-line therapy (curative or palliative) should be determined and follow-up tailored accordingly.

Intermediate-Risk Patients

The Panel based its treatment recommendations for patients with intermediate-risk disease on review of the data and Panel consensus.[1] Appropriate treatment options for this group of patients include AS, IR, EBRT, and RP. Of note, study outcomes data did not provide clear-cut evidence for superiority of any one treatment over the others. As a standard, therefore, the Panel indicates that patient preferences and functional status, with a specific focus on functional outcomes including urinary, sexual, and bowel function, should be considered in decision-making.

As a standard, the Panel recommends that when counseling patients regarding treatment options, "physicians should consider" that, on the basis of outcomes of 1 RCT, the use of neoadjuvant and concurrent hormonal therapy for a total of 6 months may prolong survival in the patient who has opted for conventional-dose EBRT;[10] that on the basis of the outcomes of 1 RCT, when WW and RP are compared, RP may be associated with a lower risk for cancer recurrence, cancer-related death, and improved survival;[9] and that on the basis of the outcomes of 2 RCTs, higher-dose radiation therapy may decrease the risk for PSA recurrence.[7,8]

Taking this information into account, the Panel recommended as a standard that "patients who are considering specific treatment options should be informed" of the findings of these high-quality clinical trials. Patients considering EBRT should be informed that combining hormonal therapy with conventional-dose radiotherapy may prolong survival,[10] and that higher-dose radiation therapy may decrease the risk for PSA recurrence.[7,8] Patients considering WW should be informed that RP may lower the risk for cancer recurrence and improve survival.[9]

On the basis of Panel consensus, the following additional recommendation was made as a standard for patients with intermediate-risk disease: For patients choosing AS, the aim of the second-line therapy (curative or palliative) should be determined and follow-up tailored accordingly. It should be noted that this same recommendation was made for patients with low-risk disease.

High-Risk Patients

On the basis of review of the data, the Panel stated that although AS, IR, EBRT, and RP are options for the management of patients with high-risk localized prostate cancer, recurrence rates are high.

Additional Panel recommendations for the high-risk patient include the following: As a standard, when counseling patients regarding treatment options, physicians should consider that on the basis of the outcomes of 1 RCT, when WW and RP are compared, RP may be associated with a lower risk for death and improved survival.[9] In addition, on the basis of the outcomes of 2 RCTs, the use of adjuvant and concurrent hormonal therapy may prolong survival in the patient who has opted for radiotherapy.[11] In addition, as a standard, "high-risk patients who are considering specific treatment options" should be informed of findings of recent high-quality clinical trials including the finding that, when compared with WW, RP may lower the risk for recurrence and improve survival.[9] Additionally, for those considering EBRT, use of hormonal therapy combined with conventional-dose radiotherapy may prolong survival.[10,11]

Additional Treatment Recommendations

Two additional treatment recommendations included in the Guideline[1] are also based on Panel consensus. As a recommendation, the Panel notes that patients with localized prostate cancer should be offered the opportunity to enroll in available clinical trials examining new forms of therapy, including combination therapies, with the goal of improved outcomes. The Panel went on to elaborate that all physicians treating patients with prostate cancer have the responsibility to inform patients of the availability of clinical trials. Second, as a recommendation, the Panel indicates that first-line hormonal therapy is seldom indicated in patients with localized prostate cancer. An exception may be made for the palliation of symptomatic patients with more extensive or poorly differentiated tumors whose life expectancy is too short to benefit from treatment with curative intent. The morbidities of ADT should be considered in the context of the existing comorbidities of the patient when choosing palliative ADT.

Data Limitations

It is disappointing to find that despite more than a decade of additional experience and progress in the management of localized prostate cancer, the Panel ultimately faced many of the same limitations as their predecessors in the original document. Specifically, the Panel found that due to significant limitations in the published literature, "the data are still insufficient to provide adequate summary outcomes estimates for the target patient(s)."[1] The limitations include a lack of data supporting the most important outcomes, including patient survival, disease-free survival, and progression to metastatic disease. Most of the articles reporting outcomes used PSA recurrence as a measure of long-term cancer control, but the huge amount of variability in definition (166 various definitions were counted) made comparisons within similar treatments and between different treatments particularly problematic.[12]

Another severe limitation of the literature was the lack of RCTs to allow for direct comparison of treatment-related outcomes among the various forms of treatment. Further limiting the data collection was the overlap and duplication of patient populations created between many of the studies when data from the entire or part of the patient population were later reported with similar or slightly updated results. Additionally, there were significant inconsistencies in the way data were reported and the number of patients at risk during the time frame, as well as a high variability in the time at which the outcomes data were reported. Thus, disappointing but not surprising, the conclusion of the Guideline Panel was that "study outcomes do not provide clear-cut superiority of one treatment over another."[1]

Future Prostate Cancer Guideline Activities

Due in part to the insufficient number of high-quality clinical trials and significant limitations in the current literature, the Panel was unable to develop standards or firm recommendations for most of the important clinical decisions that patients face in the management of localized prostate cancer. Consequently, the majority of the treatment statements are listed as "options" rather than as "standards" or "recommendations." The Panel has recommended that changes be made in the development of future prostate cancer guidelines. From here forward, the Panel has recommended that this Guideline be updated regularly, and that these updates be based solely on evidence from RCTs.

Conclusions

The new AUA Guideline for the Management of Clinically Localized Prostate Cancer emphasizes several important points and enhances the clinician's ability to counsel patients prior to making important treatment-related decisions. There is now an emphasis on tailoring treatment for the individual patient's risk for prostate cancer recurrence. In addition, where available, treatment recommendations are based not only on patient risk but also on anticipated outcomes based on data from RCTs. Patients are encouraged to enroll in such trials when available in an attempt to improve outcomes for future generations of patients. This is particularly important for high-risk patients, among whom cancer recurrence rates remain high. Unfortunately, due to limitations in the available published data, there is still no single best treatment to recommend for patients with clinically localized prostate cancer. Treatment options will continue to be based on honest communication with patients regarding individual risk, potential outcomes, and the impact on health-related quality of life.

Portions of this summary have been published previously in The Journal of Urology (Thompson I, Thrasher JB, Aus G, et al. Guideline for the management of clinically localized prostate cancer: 2007 update. J Urol. 2007;177:2106). For the complete document, visit http://www.auanet.org/guidelines/.

References
  1. Thompson I, Thrasher JB, Aus G, et al. Guideline for the management of clinically localized prostate cancer: 2007 update. J Urol. 2007;177:2106-2131. Abstract
  2. Middleton RG, Thompson IM, Austenfeld MS, et al. Prostate Cancer Clinical Guidelines Panel Summary report on the management of clinically localized prostate cancer. The American Urological Association. J Urol. 1995;154:2144-2148. Abstract
  3. Cooperberg MR, Lubeck DP, Meng MV, Mehta SS, Carroll PR. The changing face of low-risk prostate cancer: trends in clinical presentation and primary management. J Clin Oncol. 2004;22:2141-2149. Abstract
  4. Wright JL, Lin DW, Cowan JE, Carroll PR, Litwin MS. Quality of life in young men after radical prostatectomy. Prostate Cancer Prostatic Dis. 2007.
  5. D'Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy or external beam radiation therapy for patients with clinically localized prostate carcinoma in the prostate specific antigen era. Cancer. 2002;95:281-286. Abstract
  6. D'Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998;280:969-974. Abstract
  7. Pollack A, Zagars GK, Starkschall G, et al. Prostate cancer radiation dose response: results of the M. D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys. 2002;53:1097-1105. Abstract
  8. Zietman AL, DeSilvio ML, Slater JD, et al. Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial. JAMA. 2005;294:1233-1239. Abstract
  9. Bill-Axelson A, Holmberg L, Ruutu M, et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med. 2005;352:1977-1984. Abstract
  10. D'Amico AV, Manola J, Loffredo M, Renshaw AA, DellaCroce A, Kantoff PW. 6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial. JAMA. 2004;292:821-827. Abstract
  11. Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet. 2002;360:103-106. Abstract
  12. Cookson MS, Aus G, Burnett AL, et al. Variation in the definition of biochemical recurrence in patients treated for localized prostate cancer: the American Urological Association Prostate Guidelines for Localized Prostate Cancer Update Panel report and recommendations for a standard in the reporting of surgical outcomes. J Urol. 2007;177:540-545. Abstract

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