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The American Urological Association Prostate Cancer Clinical Guidelines Panel

ReportReport onon

TheThe ManagementManagement ofof ClinicallyClinically LocalizedLocalized Archived Document—ProstateProstate CancerCancer For Reference Only

CLINICAL PRACTICE GUIDELINES Prostate Cancer Clinical Guidelines Panel Members and Consultants

Members Consultants Richard G. Middleton, MD Robert P. Gibbons, MD Claus G. Roehrborn, MD (Panel Co-Chairman) Department of Urology (Facilitator Coordinator) Department of Urology The Virginia Mason Clinic Division of Urology The University of Utah Seattle, Washington The University of Texas Southwestern Salt Lake City, Utah Harry C. Miller, Jr., MD Medical Center Ian M. Thompson, MD Department of Urology Dallas, Texas (Panel Co-Chairman) The George Washington University Hanan S. Bell, PhD Urology Service Washington, D.C. (Consultant in Methodology) Brooke Army Medical Center Joseph E. Oesterling, MD Seattle, Washington San Antonio, Texas Division of Urology and the Michigan Brent Blumenstein, PhD Mark S. Austenfeld, MD Prostate Institute (Consultant in Biostatistics) (Panel Facilitator) The University of Michigan Fred Hutchinson Cancer Center Department of Urology Ann Arbor, Michigan Seattle, Washington The University of Kansas Medical Martin I. Resnick, MD Scott Optenberg, Dr. PH Center Department of Urology (Consultant for Health Care Kansas City, Kansas Case Western Reserve University Economics) William H. Cooner, MD Cleveland, Ohio Clinical Investigation Activity Department of Urology Stephen R. Smalley, MD U.S. Army Health Services Command Emory University Therapeutic Radiologists, Inc. San Antonio, Texas Atlanta, Georgia Kansas City, Missouri Patrick M. Florer Roy J. Correa, Jr., MD John H. Wasson, MD (Database Design and Coordination) Department of Urology Prostate Patient Outcomes Research Dallas, Texas The Virginia Mason Clinic Team Curtis Colby ArchivedSeattle, Washington Dartmouth MedicalDocument— School (Editor) Hanover, New Hampshire Washington, D.C. For Reference Only

The Prostate Cancer Clinical Guidelines Panel consists of board-certiﬁed urologists and other ex- perts in prostate cancer management. This Report on the Management of Clinically Localized Prostate Cancer was extensively reviewed by nearly 40 urologists throughout the country in early 1995. The panel ﬁnalized its recommendations for the AUA’s Practice Parameters, Guidelines and Standards Committee, chaired by Winston K. Mebust, MD, in June 1995. The AUA Board of Directors approved these practice guidelines in July 1995. The Summary Report also underwent independent scrutiny by the Editorial Board of the Journal of Urology, was accepted for publication in August 1995 and appeared in its December issue. A Patient’s Guide and a Technical Supplement have also been developed; both are available from the AUA. The American Urological Association expresses its gratitude for the dedication and leadership demonstrated by the members of the Prostate Cancer Clinical Guidelines Panel in producing this guideline.

Dedication

This report is dedicated to the memory of William H. Cooner, MD, who lent invaluable support, time and encouragement to the efforts of the panel.

ISBN 0-9649702-0-1 Introduction

Prostate cancer is the most common nondermatologic malignancy and the second most common cause of cancer death among men in the United States. In 1995, an estimated 244,000 new cases were anticipated, and prostate cancer deaths were estimated at 40,400 (Wingo, Tong and Bolden, 1995). For a white male born in 1988-1990, the lifetime risk of developing clinically apparent prostate cancer is 13.34 percent. For an African-American male, the risk is 11.27 percent (Miller, Hayes, Potosky, et al., 1993). Lifetime risks of death from prostate cancer in these two groups are 3.18 percent and 3.96 percent, respectively. Because of an aging U.S. population, the number of men recognized to have prostate cancer will rise dramatically over the next 20 years. During the next 10 years, it is estimated that there will be a 90-percent increase in prostate cancer detection and a 37-percent increase in prostate cancer deaths (Carter and Coffey, 1990). Enhanced early detection techniques using digital rectal examination (DRE) and prostate specific antigen (PSA), as well as more public awareness of pros- Archivedtate cancer, have greatly increased Document— rates of diagnosis. One result has been a shift toward more tumors detected at lower stages. In 1982, an American Col- lege of Surgeons survey found the following percentages, by clinical stage, of newly diagnosed prostate tumors: stage T1 (A), 25.9 percent; stage T2 (B), For28.9 percent; Reference stages T3-T4 (C), 14.9 percent; stage M1 (D2), 24.9Only percent (Murphy, Natarajan, Pontes, et al., 1982). A 1990 survey found that more newly diagnosed tumors were organ confined: stage T1 (A), 29.3 percent; stage T2 (B), 37.7 percent; stages T3-T4 (C), 12.5 percent; and stage M1 (D2), 20.6 percent (Mettlin, Jones and Murphy, 1993). At a number of institutions where PSA is an integral part of early diagnosis, as many as 99 percent of prostate cancers diagnosed during serial PSA-based screening have been clinically organ confined, and 75 percent pathologically organ confined (Catalona, Smith, Ratliff, et al., 1993). With this growth in numbers of locally confined tumors found through early detection efforts has come greater scrutiny of the methods of treatment. A 1988 National Institutes of Health (NIH) consensus conference, employing an im- plicit approach to the development of conclusions, compared the efficacy of surgical therapy and radiotherapy. It was not possible, based upon available data, to determine the optimal treatment for localized disease (NIH Consensus Development Panel, National Cancer Institute’s Monograph No. 7, 1988). Since that time, the publication of a number of series on the management of clinically localized prostate cancer by surveillance (no treatment) has increased the uncertainty as to the optimal treatment for this stage of disease. For low- grade tumors, these series have generally reported cancer-specific survivals with management by surveillance that do not differ significantly from cancer-

Copyright © 1995 American Urological Association, Inc. Page i specific survivals following treatment by surgery or radiotherapy for periods up to 10 years (Johansson, Adami, Andersson, et al., 1992; Whitmore, Warner and Thompson, 1991). Pooled analyses and decision analyses employing data from surveillance series have further clouded the question of optimal treatment for localized disease (Chodak, Thisted, Gerber, et al., 1994; Fleming, Wasson, Albertsen, et al., 1993). Recognizing the need for a systematic analysis of the literature regarding the available methods of treatment for localized prostate cancer, and in the ab- sence of a randomized, prospective comparison of these methods, the American Urological Association (AUA) in 1989 convened the Prostate Cancer Clinical Guidelines Panel to conduct a comprehensive survey and analysis of published data. This document, Report on the Management of Clinically Local- ized Prostate Cancer, is the product of that effort. This report, as its title indicates, focuses on the treatment of tumors confined within the prostate, specifically clinical stage T2 (B) tumors. (“Stage” in this document means “clinical stage” unless “pathological stage” is specified.) Inevitably discussed in this report are stages other than T2, questions regarding staging methods and various issues related to the diagnosis as well as treatment of prostate cancer in general. However, the panel’s analysis and recommendations are intended to apply only to treatment of clinically localized prostate Archivedcancer. Document— The report summarizes the methodology employed by the panel, displays the outcomes evidence extracted from the prostate cancer treatment literature and recommends practice policies for the management of clinical stage T2 (B) Forprostate cancer Reference insofar as the evidence permits. The report also includesOnly analysis of the limitations in the treatment literature regarding outcomes evidence and makes recommendations for further research. A summary of this report has been published in the Journal of Urology December 1995: Vol. 154, pgs. 2144 – 2148. A 12-page Patient’s Guide including illustrations of the progressions of prostate cancer is available to assist the physician in discussing treatment options with the patient. Also available is a Technical Supplement providing more detailed displays of the data analysis.

Introduction ...... i Executive Summary ...... 1 Methodology ...... 1 Background ...... 1 Treatment alternatives and treatment outcomes ...... 2 Treatment recommendations ...... 3 Literature limitations and recommendations for research ...... 6 Chapter 1: Methodology ...... 8 Methods and deﬁnitions ...... 8 Literature search ...... 9 Data extraction ...... 9 Data inadequacy ...... 9 Data display for survival and disease progression ...... 10 Treatment complications data ...... 10 Literature citations and panel opinions in discussion sections ...... 10 Chapter 2: Prostate cancer and its management ...... 12 Background ...... 12 Natural history and grade classiﬁcation ...... 12 ArchivedStaging ...... Document— ...... 13 Treatment alternatives ...... 15 Chapter 3: Outcomes of treatments for localized prostate cancer ...... 21 Types of outcomes ...... 21 ForVariability Referenceof outcomes data ...... Only...... 22 Summary outcomes tables and graphs ...... 22 Analysis of summary outcomes tables ...... 32 Treatment complications summary outcomes table and graphs ...... 35 Analysis of treatment complications summary outcomes table ...... 36 Chapter 4: Treatment recommendations ...... 37 The standard patient ...... 37 Recommendations: Standards ...... 37 Recommendations: Treatment options ...... 38 Advantages and disadvantages of treatment options ...... 38 Chapter 5: Literature limitations and recommendations for research ...... 42 Limitations in the prostate cancer treatment literature ...... 42 Recommendations for future research ...... 43 References ...... 46 Appendix A: Data presentation ...... A-1 Appendix B: Data abstraction form ...... B-1 Appendix C: U.S. life expectancy table ...... C-1 Index ...... I-1

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course over many years. Others advance rapidly by Methodology local extension and/or metastasis. Evaluation of the effect of active intervention must take into account In developing recommendations for the manage- the course the disease would follow if allowed to ment of clinically localized prostate cancer, the proceed without interference. Active treatment of a AUA Prostate Cancer Clinical Guidelines Panel ex- prostatic cancer destined never to present a clinical tensively reviewed the prostate cancer treatment lit- problem would not be expected to improve patient erature from 1966 to December 1993 and extracted outcomes over treatment by surveillance alone. all relevant data to estimate as accurately as possi- Prostate cancer aggressiveness, however, does tend ble desirable and undesirable outcomes of the alter- to increase with time (Adolfsson and Tribukait, native treatment modalities. The panel followed an 1990). Given sufficient time, small localized tumors explicit approach to guideline development (Eddy, can be expected to become large, multifocal, nonlo- 1992). This approach emphasizes use of scientific calized tumors (Whitmore, Warner and Thompson, evidence in estimating outcomes of interventions. 1991), with decreasing likelihood of cure. “Cure” is When panel opinion is necessary, the explicit ap- defined in this report as lifetime freedom from dis- proach calls for explaining why and discussing the ease. factors considered. For a full description of the Thus, patient longevity becomes a major consid- methodology, see Chapter 1. eration, especially since techniques to distinguish Archived Document—rapidly growing from slow-growing tumors are still evolving. Treatment of prostate cancer depends to a Background significant degree upon the patient’s age, functional level and medical status. Factors such as tumor vol- For Referenceume (stage) and grade, Only along with evaluation of nu- Of the malignant conditions that arise primarily clear chromatin content and nuclear roundness, al- within the prostate gland, by far the most frequently low some prediction of a tumor’s biologic potential. occurring type is adenocarcinoma. Because of the However, at present, such factors are not all fully rarity of other primary neoplasms within the gland, applicable to individual patients because of the the terms “prostate cancer” and “carcinoma of the many exceptions to these predictive indices. prostate” are generally understood to be synony- mous with “adenocarcinoma.” Staging Adenocarcinoma of the prostate is the most commonly diagnosed visceral neoplasm in men. The es- Accurate determination of tumor stage is impor- timated 244,000 new cases diagnosed in 1995 rep- tant, in that therapy is highly dependent upon the resent 36 percent of cancers in men, compared with knowledge of whether the tumor is localized to the 14 percent for lung cancer and 10.4 percent for col- gland. Several staging systems for prostate cancer orectal cancer, the next two most frequently diag- have been described. The two most often used are nosed cancers (Wingo, Tong and Bolden, 1995). the Jewett-Whitmore (ABCD) system and the The 40,400 deaths from prostate cancer anticipated American Joint Committee (TNM) system. They in 1995 represent 14 percent of all cancer deaths in are shown in Table 1 on page 13. A new clinical men, placing prostate cancer second only to lung stage has been designated primarily for PSA-detect- cancer mortality (33 percent) and ahead of colorec- ed prostate cancers. In the TNM staging system, tal cancer mortality (9.4 percent). these tumors are categorized as stage T1c and in the Jewett-Whitmore staging system as stage B0. Clinical staging has improved in recent years, Natural history but considerable inaccuracy remains. The result can Prostate cancer has a wide spectrum of growth be understaging or, to a lesser extent, overstaging as rates. Many tumors pursue a relatively indolent compared with surgical or pathologic staging. This

Copyright © 1995, American Urological Association, Inc. Page 1 Executive Summary has confounded accurate evaluation of treatment radical prostatectomy, external beam radiotherapy, modalities based solely upon clinical staging. brachytherapy (interstitial radiotherapy) and sur- Methods available for the staging of clinically veillance (also known as expectant management, localized prostate cancer include digital rectal ex- watchful waiting or observation). Treatment meth- amination (DRE), serum prostate specific antigen ods considered investigational are thermotherapy, (PSA), serum acid phosphatase, transrectal ultra- cryotherapy, androgen deprivation and chemothera- sonography (TRUS), computerized tomography py. The panel categorized a treatment method as in- (CT) scan and magnetic resonance imaging (MRI). vestigational if the number of patients treated has For determination of distant metastases, staging been inadequate for evaluation and/or if follow-up methods include CT scan, MRI and radioisotopic has been inadequate to provide sufficiently precise bone scan. In the panel’s opinion and based on outcome estimates. growing evidence from recent studies, many of the methods available do not necessarily provide useful information and may not be required for patients Treatment outcomes with clinically localized prostate cancer. For assessing the benefits and harms of treatment Regarding clinical staging, several conclusions interventions for stage T2 (B) prostate malignancy, can be drawn from the medical literature that affect the panel considered the following outcomes as clinical practice: most important to the patient: (1) CT scan and MRI may not be required in the (1) Survival at 5, 10 and 15 years (overall sur- staging evaluation of patients with clinically local- vival, disease-specific survival, progression-free ized prostate cancer. These tests can often detect survival and metastasis-free survival); gross extraprostatic disease, but that degree of spread can usually be predicted by the serum PSA (2) Progression rates at 5, 10 and 15 years concentration, DRE or TRUS at time of biopsy. (metastatic, local and biochemical); and Capsular perforation, seminal vesicle invasion and (3) Complications of treatment. Although all pelvicArchived lymph node involvement most often are mi-Document—complications were evaluated, the most important croscopic phenomena and cannot be diagnosed by are: death from treatment, incontinence, impotence either CT scan or MRI. (erectile dysfunction), cystitis, proctitis, major (2) Evidence is mounting that the majority of bleeding, pulmonary embolism, rectal injury and patients who are candidates for a radical prostatec- bladder neck contracture/urethral stricture. tomy orFor radiotherapy have Referencea very low risk of having Only positive pelvic lymph nodes. When the serum PSA Survival at 5, 10 and 15 years concentration, tumor grade and local clinical stage used together are below certain levels, a pelvic Clinically localized prostate cancer (stages T1 lymph node dissection may not be necessary be- and T2) is rarely lethal within the first 5 years after cause, as noted on page 15, the probability of posi- diagnosis. The overall death rate during this period tive lymph nodes is extremely low. is low and usually secondary to comorbid process- (3) From the results of two large clinical studies es. Almost any treatment for localized prostate can- (Chybowski, Larson-Keller, Bergstralh, et al., 1991; cer would appear to have an excellent survival re- Oesterling, Martin, Bergstralh, et al., 1993), it ap- sult at 5 years. Survival at 10 years and 15 years al- pears that a staging radionuclide bone scan may not lows a more accurate assessment of the influence of be necessary for patients with newly diagnosed, un- prostate cancer treatment on patient survival. treated prostate cancer who have no skeletal symp- It is not enough to assess survival independently toms and a serum PSA of 10 ng/ml or less. of tumor progression status. Comorbid processes associated with advanced age will often determine survival. However, morbidity from cancer progres- Treatment alternatives sion may occur for years prior to death. It is therefore reasonable to inform patients not only about and treatment outcomes the risk of dying from prostate cancer, but also about the risk of developing metastatic disease or The following treatment alternatives in current any evidence of tumor recurrence during follow-up. use for managing localized prostate cancer, either Thus, outcomes of cancer-specific metastasis-free alone or in various combinations, were analyzed by and tumor-free survival should be assessed in addi- the AUA Prostate Cancer Clinical Guidelines Panel: tion to overall survival rates.

Page 2 Executive Summary Copyright © 1995, American Urological Association, Inc. Progression rates at 5, 10 and 15 years characteristics as patient age, tumor grade and pelvic lymph node status. For example, patients under- After surgery or radiotherapy, most recurrence or going radical prostatectomy are on average 3 years progression of adenocarcinoma of the prostate will younger than those undergoing external beam ra- become biochemically (PSA) apparent by 5 years, diotherapy and 7 years younger than those reported but a few patients may have lengthy delays before to have been followed with surveillance. the progression becomes clinically apparent. It is therefore important to continue to assess progres- It is striking that only about one in seven patients sion rates to 10 years and beyond. Progression rates reported in the literature was followed even for 5 may or may not influence the patient directly. Many years and that a very small fraction was followed times progression will be defined as the develop- for 10 or 15 years. Estimates of important out- ment of any evidence of tumor. This recurrence is comes—notably survival and progression rates at 5, often asymptomatic and found only through sur- 10 and 15 years—are likely to be inaccurate if such veillance examinations. small numbers of patients are available for analysis. Obviously, either local recurrence or sympto- Tumor grades are relatively comparable in pa- matic metastatic prostate cancer is of extreme im- tients treated actively (with surgery or radiation); portance to patients diagnosed with localized dis- but for patients followed with surveillance, there ease. However, biochemical failures, usually in the are data on very few patients who have high-grade form of rising serum PSA, may also negatively im- tumors. Also, there is scant information on pelvic pact patients from a psychologic standpoint. Men lymph node status in patients receiving external with prostate cancer understand that a rising serum beam radiotherapy or followed with surveillance, PSA often precedes eventual symptomatic recur- leaving open the possibility of dramatic differences rence. in the stages of patients’ tumors. Because of the significant differences among Complications and harms of treatment treatment series and the consequent inability to make meaningful estimates from data available for Treatment-related death, the most serious ad- the treatment outcomes of patient survival and tu- Archivedverse outcome from treatment of prostate cancer, Document— is mor progression, the panel concluded that it would uncommon. Other adverse outcomes from treat- be methodologically unsound to compare treatment ment, such as incontinence, impotence (erectile modalities directly with regard to these outcomes. dysfunction), cystitis, rectal injury and bleeding, are Nevertheless, the panel did decide to present data moreFor common and have Reference variable degrees of nega- results in the form of summaryOnly outcomes tables 3– tive impact on patient well-being. The reported in- 4 (pages 25-26), as well as graphically in Figures 1 cidences and estimates of these adverse outcomes –13 (pages 28-31), to show the range of outcomes are important to a patient making decisions regard- data reported for the different modalities. The ing treatment. Some of the complications are much ranges of frequency reported for the 25 most com- less common today than in older reports because of mon treatment complications are shown in Table 5 newer technology and advancements in technique. (page 27). Frequency rates for the most important It is important to stratify the complications relative of these complications are depicted graphically as to era of treatment. (See Appendix A, Figures A-7 well in Figures 14–16 (page 31). to A-31.)

Analysis of outcomes data from Treatment recommendations the literature The panel was impressed by the massive amount The panel generated its practice policy recom- of literature available on prostate cancer, but the mendations based on the outcome estimates avail- vast bulk of the literature is not usable for extractable and on panel opinion. The recommendations ing and combining data to assess treatment out- were graded according to levels of flexibility based comes and develop practice recommendations. Of on the strength of the evidence and the panel’s as- 12,501 papers reviewed, the panel was able to re- sessment of patient needs and preferences. Three trieve only 165 with acceptable data on outcomes levels—standards, guidelines and options—are de- from treatment of localized prostate cancer. (See fined on page 8. A standard has the least flexibility. page 9 for an explanation of the review process.) A guideline has significantly more flexibility, and Moreover, in these 165 articles, there are significant differences among treatment series regarding such (Continues on page 6)

Copyright © 1995, American Urological Association, Inc. Page 3 Executive Summary Recommendations: Standards • As a standard, an assessment of the patient’s life expectancy, overall health status and tumor characteristics is necessary before any treatment decisions can be made. Life expectancy: Life expectancy, rather than patient age, should be the factor considered in treatment selection. Therefore, the panel did not set a specific chronological cutoff point. When a man’s life expectancy is relatively long, prostate cancer can be a cause of morbidity and mortality. On the other hand, at an advanced patient age, or when life expectancy is relatively short, competing hazards for mortality reduce the chance that a man will suffer from disease progression or die from prostate cancer. (See U.S. Life Expectancy Table in Appendix C.) Health status: The patient’s overall health status is the sum of all conditions and includes both patient and family history as well as the present state of the patient’s well-being and the degree of any coexistent disease. There are two reasons to evaluate the overall health status prior to deciding on an intervention: (1) Overall health status influences life expectancy; (2) overall health status may affect patient response to adverse events resulting from particular Archivedinterventions. Document— Tumor characteristics: The histologic grade and stage of the tumor should be considered when assessing the potential natural history and treatment options for prostate cancer. Small, well-differentiated cancers progress more slowly and are less likely to be life threatening than large, poorly differentiated Fortumors which Reference have a greater potential to be biologically aggressive Onlyand clinically significant. • As a standard, a patient with clinically localized prostate cancer should be informed about the commonly accepted initial interventions including, at a minimum, radical prostatectomy, radiotherapy and surveillance. A discussion of the estimates for benefits and harms of each intervention should be offered to the patient. The panel defines radical prostatectomy to include complete removal of the prostate, vasal ampullae and seminal vesicles. The panel defines radiotherapy to include external beam and/or interstitial (brachytherapy) treatments. Surveillance is defined as periodic monitoring of the patient’s prostate cancer and its effects. The patient should be informed that depending on his condition and initial choice, subsequent interventions may be appropriate. • As a standard, the patient’s preference, based on his attitude toward the course of the disease and the benefits and harms of the different interventions, should be considered in determining his treatment.

Page 4 Executive Summary Copyright © 1995, American Urological Association, Inc. Recommendations: Treatment options Options for management of localized prostate cancer include radical prostatectomy, radiotherapy and surveillance. Radiotherapy includes external beam and interstitial (brachytherapy) treatments. The panel considers these interventions to be options because data from the literature do not provide clear-cut evidence for the superiority of any one treatment. Provided for each option, however, are a description of the patient most likely to benefit from the intervention and a brief summary of the intervention’s advantages and disadvantages. • Radical prostatectomy: Based on the panel’s interpretation of the literature and panel opinion, the patient most likely to benefit from radical prostatectomy would have a relatively long life expectancy, no significant surgical risk factors and a preference to undergo surgery. The major advantage of radical prostatectomy is its potential for total removal of the cancer and “cure” in properly selected patients. “Cure” is defined as lifetime freedom from disease. Potential harms include urinary incontinence and erectile dysfunction. Because the cancer may not be completely eradicated, disease progression may occur. Archived• Radiotherapy: Based onDocument— the panel’s interpretation of the literature and panel opinion, the patient most likely to benefit from radiotherapy would have a relatively long life expectancy, no significant risk factors for radiation toxicity and a preference for radiotherapy. ForThe Reference advantages of radiotherapy are that it has a potential forOnly cure and that it is well tolerated in the majority of men when modern techniques are used. Its principal potential harms include radiation cystitis and proctitis and erectile dysfunction. Because the prostate remains in place, persistence and progression of the disease may occur. • Surveillance: Based on the panel’s interpretation of the literature and panel opinion, patients most likely to benefit from surveillance are those with a shorter life expectancy and/or a low-grade tumor. Benefits of surveillance for low- or intermediate-grade, localized prostate cancer include a lack of treatment-related morbidity with only marginal compromise of disease-specific survival at 5 to 10 years of follow- up. Because the prostate is neither removed nor irradiated, progression of the disease is more likely to occur.

Copyright © 1995, American Urological Association, Inc. Page 5 Executive Summary an option is the most flexible. None of the panel’s despite the effect of age on survival and the signifi- recommendations, however, fits the guideline cate- cant differences in average patient age for different gory defined on page 8. treatment modalities. In still another example, many articles reporting complications from treatment do not report “zero complications.” For instance, an ar- The standard patient ticle may not refer to incontinence in its list of treat- The panel’s recommendations apply to the stan- ment-related complications. Readers are left to dard patient, defined as a man who has clinically lo- wonder whether the complication did not occur or if calized prostate cancer (adenocarcinoma of the it was omitted from the report. prostate). For this report, the panel focused on clini- • Data variability: Examples of variability cal stage T2 (B) disease. Based on the opinion of abound in the literature. For instance, staging meth- the panel, recommendations may also be applied to odology often varies between studies, not only with patients diagnosed with stage cT1c disease (detect- regard to clinical staging versus surgical staging, ed by elevated PSA). The recommendations were but with regard to differences in types of lymph not developed for patients with stage T1a/b (A1/A2) node dissections (not all of which are comparable). or clinical T3-T4 (C) disease. For a detailed discus- Patient populations differ greatly in the literature, as sion of prostate cancer staging, see pages 13-15. do such important factors as means and length of follow-up. • Publication bias: Because not all physicians Literature limitations and publish, case-study results may not be generally representative. Moreover, studies with negative or recommendations for research equivocal results are less likely to be submitted for publication and less likely to be published if submitted. Limitations in the literature Archived Document—Recommendations for future The medical literature for stage T2 prostate cancer is, overall, clearly deficient in usable data on research which to base comparable estimates for outcomes Most research needs can be grouped in three cat- of treatments and to make practice policy recom- egories: (1) new and better methods to diagnose and mendations.For The deficiencies Reference are such that the Pros- manage localized prostate Only cancer; (2) prospective, tate Cancer Clinical Guidelines Panel was unable to randomized, controlled studies of the issues con- develop, based on evidence from the literature, cerning prostate cancer, especially controlled stud- treatment-comparable outcome estimates for the ies of competing treatments for the management of most important outcomes: patient survival and tum- localized prostate cancer; and (3) studies of how or progression at 5, 10 and 15 years. Major limita- prostate cancer and its treatments affect patient tions can be summarized as follows: quality of life. • Few randomized controlled trials: Most of ❶ the data come from case series not subjected to the In the first category, needs for new methods rigors of a carefully performed, prospective, central- of cancer diagnosis and monitoring include the ly controlled clinical trial. Indeed, most of the stud- need for a more sensitive, more specific tumor indi- ies the panel reviewed in its literature search were cator. As clinically useful as serum PSA values have clinical series based on “convenience samples,” pa- become, they lack important properties such as tients available in the clinical setting where the re- prostate-cancer specificity. search was done. The majority of the other limita- Needed also are biochemical, radiographic and/or tions summarized on this page stem from the pau- genetic methods to assist in staging and to deter- city of randomized controlled trials. mine reliably which cancers are biologically aggres- • Insufficient data: Many articles do not report sive and which are clinically insignificant. For de- all outcomes (such as cancer-specific, metastasis- tecting potentially life-threatening cancers while free and tumor-free survival). Also, there are few still localized, it would be useful to have a genetic data on high-grade tumors in patients managed by marker that can identify men likely to develop such surveillance, or on pelvic lymph node status in pa- a tumor in their lifetimes. tients managed by external beam radiotherapy as ❷ In the second category, randomized, prospec- well as surveillance. In another very important ex- tive, controlled studies of competing treatments for ample, many articles do not specify ages of patients managing localized prostate cancer are clearly a

Page 6 Executive Summary Copyright © 1995, American Urological Association, Inc. pressing need, especially comparative studies inves- • Surveillance: Optimal schedule of follow-up tigating surveillance vis-à-vis active treatments. and optimal interventions at evidence of pro- Properly designed efficacy studies of treatment gression. modalities will provide reliable descriptive data for Among the other topics and issues that need to the patients studied. The descriptive factors should be addressed in rigorously designed clinical trials include age, tumor stage, tumor grade, ploidy, PSA, are: performance status and comorbidity, as well as cost • New technologies for the treatment of clinical- factors and validated measures of quality of life ly localized prostate cancer; over the course of a trial. • Trade-offs between survival and quality of End points measured in a trial should include life—including analysis of methods by which risk of local recurrence, risk of disease progression patients make treatment choices and the role (including objective measures of symptoms associ- played by quality-of-life factors in those ated with progression), risk of metastatic disease choices; and risk of prostate cancer death. • Opportunities for chemoprevention of prostate Following are additional suggested study topics cancer including dietary interventions, hor- and issues for each of the three major modalities: monal therapy and retinoid therapy; • Radical prostatectomy: Methods of improv- • New strategies for the use of hormonal treating preoperative staging, reducing the number ments; of patients with extraprostatic disease and re- • Combined therapies for prostate cancer; ducing treatment complications; strategies to • Development and validation of surrogate mea- reduce the cost of the procedure; better ways sures of long-term prostate cancer outcomes to disseminate advances in surgical technique (e.g., validation of PSA failure as a surrogate to the urologic community; treatments for pa- for cancer survival). tients with pathologically proven (pT3) ex- ❸ Finally, the third category of research needs traprostatic disease; and treatments for patients consists of research into how prostate cancer and Archivedwith evidence of serologic (PSA) failure. Document— its treatments affect patient quality of life. Such • Radiotherapy: Ways to reduce treatment mor- research would include the second topic in the bidity; ways to standardize treatment; the role above list: analysis of trade-offs between survival of three-dimensional conformal therapy and of and quality of life and of the role played by quality- radiosensitizers;For strategiesReference to reduce the cost of-life factors in patients’ Only treatment choices. of treatment; optimal treatment at progression; Needed as well are improved methods for involving mature data on long-term follow-up of existing the patient in a meaningful and efficient decision- radiotherapy patients; stage-speciﬁc complica- making process and for providing unbiased infor- tions data on existing series; and PSA and mation to patients and physicians about emerging biopsy data. processes and outcomes of care.

Levels of flexibility are defined as follows (Eddy, Methods and definitions 1992; American Academy of Family Physicians, 1995): The AUA Prostate Cancer Clinical Guidelines • Standard: A policy is considered a standard Panel developed the recommendations in this if the health and economic outcomes of the al- Report on the Management of Clinically Localized ternative interventions are sufficiently well- Prostate Cancer following an explicit approach to known to permit meaningful decisions and development of practice policies (Eddy, 1992). The there is virtual unanimity about which inter- explicit approach attempts to arrive at recommenda- vention is preferred. tions through mechanisms that take into account the • Guideline: A policy is considered a guideline relevant factors for making selections from alterna- if the health and economic outcomes of the in- tive interventions. Such factors include estimation terventions are sufficiently well-known to per- of outcomes from the interventions, consideration mit meaningful decisions and an appreciable of patient preferences regarding those outcomes but not unanimous majority agree on which in- (including costs engendered by the interventions) tervention is preferred. and assessing when possible the relative priority of the interventions for a share of limited health care • Option: A policy is considered an option if resources. Emphasized is the use of scientific evi- (1) the health and economic outcomes of the denceArchived in estimating the outcomes of interventions. Document—interventions are not sufficiently well-known When panel opinion is necessary, the explicit ap- to permit meaningful decisions, (2) prefer- proach calls for an explanation of why it is neces- ences among the outcomes are not known, (3) sary and discussion of the factors considered. patients’ preferences are divided among alternative interventions and/or (4) patients are in- To develop recommendations for this report, the For Referencedifferent about the alternativeOnly interventions. panel made an extensive effort to review the literature on stage T2 (B) prostate cancer from 1966- Standards obviously have the least flexibility. 1993 and to estimate outcomes from the alternative Guidelines have considerably more flexibility, and treatment modalities as accurately as possible. options are the most flexible. In this report, the Unfortunately, the paucity of randomized, con- terms are used to indicate the strength of the rec- trolled trials and lack of comparability among treat- ommendations. A recommendation was labeled a ment series regarding the most important outcomes, standard if the panel concluded that it should be survival and disease progression, made method- followed by virtually all health care providers for ologically sound estimations impossible for com- virtually all patients. A recommendation would be paring alternative treatment modalities. labeled a guideline if the panel thought it appropri- The review of the evidence began with a litera- ate not for all, but for a significant majority of pa- ture search and extraction of data as described on tients. None of the recommendations in this report, page 9. The data available in the literature were dis- however, fits the guideline category. played in evidence tables. From these tables, the Recommendations in this report regarding treat- panel attempted to develop estimates of outcomes ment choices were labeled options mostly because for major treatment alternatives (radical prostatec- of the inability to estimate outcomes meaningfully tomy, radiotherapy and surveillance). In Chapter 3, from the evidence available. Because the evidence outcomes are analyzed in detail. does not permit direct comparison of the most im- The panel generated its practice policy recom- portant outcomes among alternative treatment mendations based on the outcome estimates avail- modalities, the comparative recommendations for able and on expert opinion. The recommendations these modalities are presented as treatment options were graded according to three levels of flexibility rather than as guidelines or standards (page 38). based on the strength of the evidence and the pan- Another reason for labeling a recommenda- el’s assessment of patient needs and preferences. tion an option is that patient preferences may be

Page 8 Copyright © 1995 American Urological Association, Inc. unknown or divided because of complications from During the finely detailed data-extraction pro- the treatment, in which case it is particularly impor- cess, 231 of the 396 stage T2 articles were rejected tant to consider preferences of individual patients in for the following reasons: 6 percent because infor- selecting from among alternative interventions. mation on patients could not be separated according to treatment used; 8 percent because of updated data available in a later paper; 12 percent because information on patients’ cancers could not be separat- Literature search ed according to stage; 16 percent because of absent data; 27 percent because of irrelevant data; and 31 To extract scientific evidence about the outcomes percent for other, miscellaneous reasons. The net from alternative interventions for treating stage T2 result was 165 articles with stage T2 outcomes data (B) prostate cancer, the panel performed a literature extracted (see Appendix A, Figures A-5 and A-6). search utilizing the MEDLINE database. The data- Each of the 165 articles was reviewed and the base was searched several times up to December data extracted separately by two panel members, 1993, using the MESH subject heading “prostatic who then met to resolve any differences. Their re- neoplasms.” All citations recovered were imported sult was entered into a database software system into a bibliographic database software system (PARADOX) by staff, who also verified all data en- (Papyrus Bibliography System; Research Software tries. The data were entered by series. Series in this Design, Portland, Oregon). report are groups of patients stratified by parameters such as primary treatment modality. Members of the panel reviewed abstracts for 12,501 articles on prostate cancer published from Subsequent to data extraction, the panel attempt- 1966 to 1993. Each abstract was independently re- ed to follow a process in which the extracted data viewed by two panel members. If either member would be combined by meta-analysis to yield out- thought the article appeared relevant, it was re- come estimates for alternative treatment modalities. trieved. On the basis of abstract review, 1,453 arti- The meta-analytically derived estimates would then be arrayed in an outcomes table to compare the cles were retrieved. After a summary review of Archived Document—modalities. these articles, the panel found 926 of the 1,453 articles (64 percent) acceptable for detailed review. Of Meta-analysis is a term that has been used in a the 926 articles, 396 were found relevant to stage variety of contexts in the medical literature. In its T2 (B) prostate cancer and were accepted for ex- most general definition, meta-analysis is any pro- tractionFor of outcomes data.Referencecess of utilizing the resultsOnly of multiple studies to determine a final estimate for a given parameter. Figure A-1 in Appendix A of this report shows For this report, the definition was restricted to in- graphically, by year, the number of articles the pan- clude only formal mathematical methods of com- el retrieved on the basis of abstract review. Evident bining the results of multiple studies. Various meth- in this graph is the dramatic increase over time in ods can be used. The techniques employed depend the number of papers published. Figure A-2 shows upon the nature of the studies to be combined, the sources of articles from the English-language litera- degree to which the studies are similar and the ture. Also see Appendix A for the bibliography in types of data available. In its most restrictive defini- Table A-1 of sources of articles from which out- tion, meta-analysis includes only the classical (non- comes data were extracted. (Articles cited in the Bayesian) techniques used to combine randomized text of this report, for referencing particular points controlled trials. discussed, were not necessarily among articles the panel reviewed to extract outcomes data.) Data inadequacy Data extraction As noted previously (page 8), after examining at length the data on management of localized prostate A comprehensive data-extraction form was de- cancer, the panel had to conclude that these data do vised by the panel and staff to capture as much per- not provide sufficient evidence to allow valid com- tinent information as possible from each article. A parisons of treatments. Therefore, meta-analytic sample of the form is in Appendix B. The selected combination by any method is inappropriate. articles were divided among the panel members, A major reason is that the data are from clinical who extracted the data to complete the form. series, and data from clinical series are frequently

Copyright © 1995 American Urological Association, Inc. Page 9 not comparable. Pooling such data can lead to the data recorded, “actual” rates might not accurate- large, uncharacterizable biases. In the case of pros- ly represent the impact of the disease or its treat- tate cancer, the differences between series are espe- ment in the general population. For this reason, the cially significant. For example, it is known that pa- word “actual” when used to denote such data ap- tients who are older are more likely to be found in pears in quotes. series on treatment by surveillance or radiation. Many studies, however, do not specify ages of the patients. In another example, patients in nonran- domized studies will likely have different grades of Treatment complications data disease. Yet, grade data are frequently not available. In still another example, stage data are sometimes The problems that exist with regard to data for based on clinical staging and sometimes on surgical survival and disease progression also exist with re- staging. For patients not undergoing surgery, clini- gard to data for complications of treatment. The cal staging is generally used, whereas authors of lack of randomized trials and differences in patient surgical series frequently reclassify patients based populations and treatment techniques frequently re- on surgical stage. This implies that nonsurgical se- sult in data not generalizable across studies. Dif- ries may include more higher-stage patients. ferences in reporting data add to the problems. For Particularly problematic are survival and disease- example, many investigators do not list all compli- recurrence data (including overall survival, disease- cations in the results sections of their studies. They specific survival, recurrence-free survival and time may list only the complications that occur. Uncom- to recurrence). The problems include differences in mon complications like perioperative death are thus reporting of follow-up, differences in methods of not included in many studies. To use such studies in reporting survival and biases in losses to follow-up. a meta-analysis combining results of multiple studies, a zero rate must be assumed for complications not reported. Otherwise, if data were combined on- Data display for survival ly from those studies where a complication occurs, Archived Document—the estimate of frequency of occurrence would be and disease progression artificially high. Because of the various problems with regard to Having determined that combining the outcomes the complications data, the panel chose not to com- data fromFor different series isReference inappropriate, the panel bine these data from the differentOnly studies in order to debated several methods for displaying the data. estimate frequency of occurrence for alternative These methods included crude combinations in an therapies. The panel elected instead to display the outcomes table, graphs with outcomes and sizes of complications data using the same method as for each study shown or simply graphs with the out- survival and progression data. For each of the most comes from each study. All of these methods have important complications, such as perioperative the disadvantage that the reader might infer differ- death, impotence (erectile dysfunction), rectal in- ences for alternative treatments that cannot be justi- jury and incontinence, a graph indicates the report- fied. ed frequency rates for that complication (see Fig- The panel chose the simplest forms of display ures 14–16, page 31). The data are shown in tabu- (pages 25-26, 28-31). In the graphical displays, the lar form as well (page 27), with reported high and circles indicate the rate reported by each series for low rates to indicate a range but with no mean or overall survival, progression-free survival, metasta- median estimates. In Chapter 3, tables and graphs sis-free survival or disease-specific survival. The are explained in detail. data are also shown in tabular form with the minimum and maximum percentages reported but no mean or median estimates. The tables indicate whether reported results are based upon actuarial Literature citations and panel calculations (life tables or Kaplan-Meier) or wheth- opinions in discussion sections er they are “actual” (observed, nonactuarial), that is, representing a ratio of an actual number of sur- vivors over a denominator that may have some re- The discussion sections in Chapter 2 provide pri- duction for dropouts. As noted on page 23, because marily descriptive and explanatory information many patients are lost to follow-up, die of unknown about the natural history of prostate cancer, the causes or fail to have consistent testing or to have Gleason grading system and systems and methods

Page 10 Copyright © 1995 American Urological Association, Inc. used for clinical staging. Also provided in Chap- tions also include information from more recent ter 2 are individual overview discussions of the studies published in 1994. treatment alternatives analyzed by the AUA Although these discussion sections contain pri- Prostate Cancer Clinical Guidelines Panel: radical marily descriptive and explanatory information, prostatectomy, external beam radiotherapy, brachy- some sections also contain panel opinions based on therapy (interstitial radiotherapy) and surveillance. Advantages and disadvantages of each of these evidence from studies cited in the text of the dis- treatment options are discussed on pages 38-41 of cussion. In particular, the section in Chapter 2 on Chapter 4, following the panel’s treatment recom- staging methods (pages 13–15) contains panel opin- mendations. ions questioning the need to use methods such as Some of the studies cited in the discussion sec- computerized tomography (CT) scan and magnetic tions in Chapters 2 and 4 are in addition to articles resonance imaging (MRI) for patients with clinical- reviewed by the panel for data extraction and analy- ly localized prostate cancer. Reasons for panel sis. Among the additional articles are papers pub- opinions are stated explicitly in this and other sec- lished after December 1993. As noted on page 9, tions, but it should be recognized that no attempt December 1993 was the cutoff date in the literature was made to subject the evidence cited to a rigor- search to obtain articles for the purpose of extract- ous review process like that described on pages 9- ing outcomes data. However, the discussion sec- 10 of this chapter.

Archived Document— For Reference Only

is devoid of carcinomatous change as its compo- Background nents do not include glandular tissue.

Prostate cancer is the most commonly diagnosed visceral neoplasm in men. The estimated 244,000 Natural history and new cases diagnosed in the United States in 1995 grade classification represent 36 percent of cancers in men, compared to 14 percent for lung cancer and 10.4 percent for colorectal cancer, the next two most frequently di- Prostate cancer has a wide spectrum of growth agnosed cancers (Wingo, Tong and Bolden, 1995). rates. Many tumors pursue a relatively indolent The 40,400 deaths from prostate cancer anticipated course over a number of years. Others advance rap- in 1995 represent 14 percent of all cancer deaths in idly by local extension and/or metastasis. Evalu- men, placing prostate cancer second only to lung ation of the effect of active intervention must take cancer mortality (33 percent) and ahead of colorec- into account the course the disease would follow if tal cancer mortality (9.4 percent). it were allowed to proceed without interference. Of the malignant conditions that arise primarily Active treatment of a prostatic cancer that is des- within the prostate gland, by far the most frequently tined never to present a clinical problem to the pa- occurring type is adenocarcinoma. Because of the tient would not be expected to improve patient out- Archived Document—comes over treatment by surveillance alone. Pros- rarity of other primary neoplasms within the gland, the terms “prostate cancer” and “carcinoma of the tate cancer aggressiveness, however, does tend to prostate” are generally understood to be synony- increase with time (Adolfsson and Tribukait, 1990). mous with “adenocarcinoma.” Given sufficient time, small localized tumors can be expected to become large, multifocal, nonlocalized Anatomically,For four glandular Reference prostatic regions Only tumors (Whitmore, Warner and Thompson, 1991), are recognized: (1) the transition zone, a bilobar with decreasing likelihood of cure. “Cure” is de- area lying on each side of the distal two-thirds of fined in this report as lifetime freedom from dis- the supramontanal prostatic urethra in the unen- ease. larged state, but which can, following the development of benign prostatic hyperplasia, occupy as Thus, because techniques for distinguishing much as 95 percent of the entire gland volume; (2) rapidly growing from slow growing tumors are still the central zone, which occupies the major portion evolving, patient longevity becomes a major factor of the cephalad half of the prostate; (3) the periph- in determining treatment. Treatment of prostate eral zone, which occupies most of the distal half of cancer depends to a significant degree upon the pa- the gland and (4) the periurethral glands lining the tient’s age, functional level and medical status. urethra. Because a younger, healthier patient may be ex- posed to a longer period of risk for disease progres- Approximately 75 percent of prostatic carcino- sion, metastases and death, consideration of inter- mas arise in the outer gland (a combination of the vention rather than management by surveillance central and peripheral zones), and many of these may be more compelling in this patient. Risks for cancers are multifocal. The remaining 25 percent death from untreated disease are presented in this arise in the transition zone. The volume of the report (pages 40-41), but long-term results are largest area of involvement, if in the peripheral or poorly understood. Of concern is a recent article central zones, correlates with overall tumor stage. suggesting that even low-grade tumors may have as The periurethral glands are rarely involved in ma- high as a 55 percent likelihood of resulting in can- lignant change. cer death within 15 years of follow-up (Aus, Hugo- A nonglandular area, the fibromuscular stroma, sson and Norlén, 1994). The older patient with a lying on the anterior gland surface as well as com- shorter period at risk may have a lesser chance of prising the internal and external urethral sphincters, prostate cancer death. The age at which the risk of

Page 12 Copyright © 1995 American Urological Association, Inc. cancer death reaches an “acceptable” level, so that treatment is unnecessary, is not known. Table 1. TNM and Jewett-Whitmore staging systems Histologic grade is currently one of the most

common methods for classifying tumor aggression STAGE levels, and the most common system currently in Jewett- use is the Gleason grading system based on archi- TNM Whitmore Description tectural criteria (Gleason, 1977). A primary grade TX Tumor cannot be assessed from 1 to 5, with 5 being the most aggressive, is as- T0 No evidence of tumor signed to the pattern occupying the greatest area of T1a A1 Tumor an incidental finding at TURP in- the specimen. A secondary grade is assigned to the volving 5% or less of tissue resected pattern occupying the second largest area. These T1b A2 Tumor an incidental finding at TURP in- two grades are then added to get a Gleason score, volving more than 5% of tissue resected which ranges from 2 to 10. It is generally agreed T1c B0 Nonpalpable tumor identified because of that tumors with a Gleason score ≤ 6 have lower bi- elevated PSA ologic aggressiveness and those with a Gleason T2a B1 Tumor involves one-half of a lobe or score ≥ 7 are biologically aggressive tumors. less T2b B1 Tumor involves more than one-half of a Pathologists can have difficulty, however, distin- lobe, but not both lobes guishing grade 3 histologic patterns from grade 4 T2c B2 Tumor involves both lobes histologic patterns for assigning primary or sec- T3a C1 Unilateral extracapsular extension ondary grades. The distinction is important. Studies T3b C1 Bilateral extracapsular extension relating component grades to spread of cancer have T3c C2 Tumor invades one or both seminal vesi- shown that metastases almost never occur with cles grade 3, but occur often with grades 4 and 5 (Mc- T4a C2 Tumor invades bladder neck and/or ex- Neal, Villers, Redwine, et al., 1990). Consequently, ternal sphincter and/or rectum whereas 3 + 3 = 6 is a favorable Gleason score, 4 + T4b C2 Tumor invades levator muscles and/or is Archived2 = 6 or 2 + 4 = 6 is not. Certainly not favorable Document—fixed to the pelvic sidewall are 4 + 3 = 7, 3 + 4 = 7, 5 + 2 = 7 and 2 + 5 = 7. NX Regional lymph nodes cannot be as- The value of the Gleason system may thus depend, sessed in some cases, on the pathologist’s proper catego- N0 No regional lymph node metastasis rization of grade 3. Still, the system is a vast im- N1 D1 Metastasis in a single lymph node, 2 cm provementFor over earlier, purelyReference descriptive attempts or lessOnly at greatest dimension at classification. N2 D1 Metastasis in a single lymph node more than 2 cm, but not more than 5 cm at Factors such as tumor grade and volume (stage), greatest dimension, or in multiple lymph along with evaluation of nuclear chromatin content nodes none more than 5 cm at greatest and nuclear roundness, allow some prediction of a dimension tumor’s biologic potential. However, at the present N3 D1 Metastasis in a lymph node more than 5 time, such factors are not fully applicable to indi- cm at greatest dimension vidual patients because of the many exceptions that MX Presence of distant metastasis cannot be assessed exist to these predictive indices. M0 No distant metastasis The natural history of untreated prostate cancer M1 D2 Distant metastasis is discussed in detail on pages 18-19 of this chapter in the description of surveillance as a treatment alternative. dergone modifications because of the need to ac- commodate evolving concepts of prostate cancer. Accurate determination of tumor stage is impor- Staging tant, in that therapy is highly dependent upon knowledge of whether or not the tumor is localized to the gland. Clinical staging has improved in re- Several staging systems for prostate cancer have cent years, yet considerable inaccuracy remains. been described in the literature. The two used most This, at times, results in understaging and, to a less- often are the Jewett-Whitmore ABCD system er extent, overstaging as compared with surgical or (Prout, 1973) and the TNM system (Beahrs, Hen- pathologic staging. This has confounded accurate son, Hutter, et al., 1992). Table 1 provides a com- evaluation of treatment modalities based solely up- parison of the two systems. Both systems have un- on clinical staging.

Copyright © 1995 American Urological Association, Inc. Page 13 Methods used in clinical staging Studies indicate that most nonpalpable, PSA-detected prostate cancers are of sufficient volume to of prostate cancer classify them as clinically important (Brendler, Methods available for staging of clinically local- Carmichael, Walsh, et al., 1993; Epstein, Walsh, ized prostate cancer include digital rectal examina- Carmichael, et al., 1994; Oesterling, Suman, tion (DRE), serum prostate speciﬁc antigen (PSA), Zincke, et al., 1993; Scaletscky, Koch, Eckstein, et serum acid phosphatase, transrectal ultrasonogra- al., 1993). There is no evidence that PSA-detected phy (TRUS), computerized tomography (CT) scan prostate cancers are different from small DRE-de- and both body and endorectal magnetic resonance tected tumors. imaging (MRI). For determination of distant metastases, staging methods include CT scan, MRI and Pelvic lymph node dissection radioisotopic bone scan. In the panel’s opinion, based on growing evidence from recent studies, Pelvic lymph node dissection (PLND) has long many of the methods available do not necessarily been considered the gold standard in evaluation of provide useful information and may not be required regional metastases from prostate cancer. Although for patients with clinically localized prostate can- PLND can provide staging information obtainable cer. by no other method, the procedure increases time in surgery and can increase patient morbidity. Poten- tial complications include hemorrhage, lymphocele, CT scan and MRI infection and vascular and neurologic injuries Approximately 50 percent of patients with newly which occur in as many as 20 percent of those pa- diagnosed prostate cancer undergo a CT scan tients undergoing PLND (Donohue, Mani, White- and/or MRI to assess locoregional spread (Stamey sel, et al., 1990; Kavoussi, Sosa, Chandhoke, et al., and McNeal, 1992). Yet, for most patients, these 1993). staging modalities provide little useful information Evidence is mounting that most patients who are and may not be necessary. Capsular perforation, candidates for a radical prostatectomy or radiother- seminalArchived vesicle invasion and pelvic lymph node Document—in- apy have very low risk for positive pelvic lymph volvement most often are microscopic phenomena nodes. One study found that patients with a primary and, if so, cannot be diagnosed by either CT or tumor volume less than 4 cc (1.5-2.0 cm in diame- MRI (Rifkin, Zerhouni, Gatsonis, et al., 1990). ter) do not have lymph node metastases (Stamey, These tests can often detect gross extraprostatic dis- McNeal, Freiha, et al., 1988). Another study noted ease, butFor that degree of spreadReference can usually be deter- that only 6 of 274 patients Only (2 percent) with palpable mined from the serum PSA concentration, DRE or disease in one lobe (clinical stage T2a/T2b) had TRUS at time of biopsy. For these reasons, CT and positive pelvic lymph nodes, in contrast to 23 per- MRI may not be required in the staging evaluation cent of 84 patients with palpable disease in both of patients with clinically localized prostate cancer. lobes (clinical stage T2c) (Walsh, 1988). The Stan- ford group found in patients with clinical stage Prostate cancer detected by PSA T2a/T2b disease that no patients having sextant needle biopsy specimens positive in only one lobe Beginning in 1987, PSA has gradually achieved had positive lymph nodes, and only 8 percent of pa- widespread clinical use, initially as a tumor marker tients having biopsy specimens positive in both for monitoring response to treatment, and more re- lobes had lymph node metastases (Daniels, McNeal cently as an indicator of early, potentially curable and Stamey, 1992). In two other large contempo- prostate cancer (Brawer, Chetner, Beatie, et al., rary series of almost 600 patients, in which the 1992; Catalona, Smith, Ratliff, et al., 1991; Cooner, cancers were detected using PSA screening, the in- Mosley, Rutherford, et al., 1990; Labrie, Dupont, cidence of positive pelvic lymph nodes was approx- Suburu, et al., 1992). imately 5 percent (Danella, deKernion, Smith, et It is well established that serum PSA can identi- al., 1993; Petros and Catalona, 1992). fy patients with prostate cancers not detectable by In a study reviewing 1,632 patients with clinical- DRE, thus increasing the number of nonpalpable ly localized prostate cancer who had undergone bi- prostate cancers being diagnosed. As shown in lateral pelvic lymphadenectomy at the Mayo Clinic, Table 1 in the TNM staging system, “PSA-detect- the overall incidence of positive pelvic lymph ed” cancers are classiﬁed as stage T1c; in the nodes was 12 percent (Bluestein, Bostwick, Berg- Jewett-Whitmore staging system, they are referred stralh, et al., 1994). Using logistic regression analy- to as stage B0 (Stormont, Farrow, Myers, et al., sis, serum PSA was found to be the best predictor 1993). of pelvic lymph node metastases.

Page 14 Copyright © 1995 American Urological Association, Inc. However, the predictive power of serum PSA concentration (less than 10 ng/ml) rarely have could be enhanced considerably by taking into ac- skeletal metastases. count the tumor grade and clinical stage. Using all From the results of these two large clinical stud- three clinical parameters together, a statistical mod- ies, it appears that a staging radionuclide bone scan el was generated that allows the practicing urologist may no longer be necessary for the patient with to accurately estimate the probability of pelvic newly diagnosed, untreated prostate cancer who has lymph node involvement. The model indicates that no skeletal symptoms and a serum PSA concentra- when the serum PSA concentration, tumor grade tion of 10 ng/ml or less. and local clinical stage are below certain levels, the probability of positive lymph nodes is extremely low. A pelvic lymph node dissection may not be necessary (Bluestein, Bostwick, Bergstralh, et al., Treatment alternatives 1994). The evolution of therapeutic modalities for treat- Radionuclide bone scan ment of prostate cancer has been continuous over the past several decades, making it difficult to as- The most sensitive method to detect bony metas- sess the comparative value of each modality. Also, tases is radionuclide bone scan. Of late, evidence the treatment options for a particular patient are has accumulated suggesting that bone scans may be subject to a number of constraints. First is an as- eliminated for selected patients. Based on two sessment of the patient’s life expectancy based up- large-scale clinical studies, Oesterling and col- on actuarial and comorbidity information, his func- leagues have determined that serum PSA concentra- tional status and his own wishes regarding therapy. tion can be used to reliably predict bone scan find- Another important concern is whether the malig- ings in patients with newly diagnosed prostate can- nancy is believed to be confined within the gland or cer. whether it has spread either regionally or distantly. In the first clinical study, the investigators evalu- The following treatment alternatives in current Archivedated, retrospectively, 521 randomly selected pa-Document— use for managing localized prostate cancer, either tients who presented with newly diagnosed, untreat- alone or in various combinations, were analyzed by ed prostate cancer (Chybowski, Larson-Keller, the AUA Prostate Cancer Clinical Guidelines Panel: Bergstralh, et al., 1991). All were evaluated with re- radical prostatectomy, external beam radiotherapy, gard Forto local clinical stageReference as determined by DRE, brachytherapy (interstitial Only radiotherapy) and sur- biopsy tumor grade, serum acid phosphatase, pro- veillance (also known as expectant management, static acid phosphatase concentration, serum PSA watchful waiting or observation). and bone scan findings. Of all the clinical parame- Treatment methods that the panel considered in- ters available to predict the presence of skeletal vestigational are thermotherapy, cryotherapy, andro- metastases, PSA was the best in predicting the re- gen deprivation and chemotherapy. A treatment sults of a radionuclide bone scan. For a serum PSA method was categorized as investigational if the concentration of 10 ng/ml or less, the probability of panel found the number of patients treated inade- skeletal metastases (positive bone scan) is extreme- quate for evaluation and/or if follow-up has been ly low—less than 1.5 percent. inadequate to provide sufficiently precise outcome In order to confirm these initial findings, a sec- estimates. ond investigation was conducted to assess the ability of serum PSA to predict bone scan findings (Oesterling, Martin, Bergstralh, et al., 1993). Treatment alternative: Radical Medical records of 2,064 consecutive patients with (total) prostatectomy prostate cancer were reviewed. Patients with prior treatment (androgen deprivation therapy, radical prostatectomy or radiotherapy) were excluded. As Patient selection with the previous study, irrespective of the tumor Surgical removal of the prostate gland is “cura- grade and local clinical stage, the serum PSA value tive” only if all the tumor is removed. “Cure” is de- was the best predictor of the bone scan results. fined as lifetime freedom from disease. Therefore, Combining tumor grade, local clinical stage or both the appropriate patient for radical prostatectomy with PSA did not enhance the predictive power of has the disease clinically confined to the prostate, PSA. This second investigation also confirmed the with no area of extension beyond the capsule or fix- observation that patients with a low serum PSA ation of the gland and no evidence of regional or

Copyright © 1995 American Urological Association, Inc. Page 15 distant disease. This would include selected patients The bladder neck opening is then contoured as nec- with clinical stage T1 or T2 biopsy-proven tumors. essary to the size of the urethral stump where an Evidence suggests that not all of these patients need end-to-end anastomosis is performed. The princi- to undergo a pelvic lymph node dissection or a ra- ples of the operations are well established, with dionuclide bone scan before radical prostatectomy usual operating times of 2 to 4 hours. Hospitaliza- (see pages 14-15). tions of 3 to 6 days are the rule, and the patient has The appropriate patient also has these character- an indwelling catheter for 10 to 21 days. istics: (1) an expected longevity longer than the expected morbidity of his cancer if left untreated; (2) Treatment alternative: External no significant surgical risk factors; and (3) a will- beam radiotherapy ingness to undergo surgery following a discussion of risks, postoperative side effects, natural history and options (Gibbons, 1993). Technological improvements Advances in radiation oncology over the last sev- Life expectancy of the patient eral years have substantially improved external Although relentless, the growth pattern of inter- beam radiotherapy for prostate cancer. Technologi- mediate- and low-grade prostate cancers (Gleason cal improvements allow the radiation beam to be score ≤ 6) is such that the cancer might not repre- more precisely targeted to the prostate and seminal sent a significant threat to the patient in his lifetime. vesicles, sparing normal tissues to a greater degree An assessment of the patient’s overall health status from harmful effects of radiation. Computer tech- is therefore mandatory before any treatment recom- nology now permits accurate three-dimensional de- mendations can be made. This should include infor- lineation not only of the prostate and seminal vesi- mation regarding age and cause of death of parents, cles, but of the normal rectum, bladder and other structures (conformal therapy). This facilitates indi- familial longevity and diseases (for example, hyper- vidually customized therapeutic blocks, sharply fo- tension, cardiovascular, metabolic), and past and cusing the radiation beam on the target volume. currentArchived health problems. Document— Moreover, recent advances in clinicopathologic Patients with localized prostate cancer might be understanding of the likelihood of seminal vesicle candidates for treatment by surveillance or delayed extension, the location of the prostatic apex, the im- therapy if they have a low-grade tumor and a life portance of day-to-day prostate motion and the expectancyFor of 10 years or lessReference (Whitmore, 1993), therapeutic efficacy of lymphOnly node irradiation have whereas patients with a greater life expectancy all contributed to improvements in external beam might be considered candidates for radical prosta- radiotherapy. The full effects of these advances in a tectomy. therapeutic context will become clearer over the next several years as data from long-term follow-up Performance of radical prostatectomy become available. Radical prostatectomy is performed using either the retropubic or perineal approach. Walsh and as- Patient selection sociates have provided considerable insight into the Patients selected for external beam radiotherapy periprostatic anatomy over the last 10 years, which should have a relatively long life expectancy and no has reduced the complications associated with the significant factors for radiation toxicity. For in- retropubic procedure (Walsh, 1992). Techniques instance, bilateral femoral hip replacements can sig- clude precise control of bleeding from the dorsal nificantly interfere with the delivery of radiothera- vein complex, to allow a more precise anatomic py. In addition, patients with systemic lupus erythe- dissection of the apex, and identifying the branches matosis, other unusual collagen vascular diseases of the pelvic plexus that innervate the corpora cav- and inflammatory bowel diseases such as ulcerative ernosa so that they can be preserved and sexual colitis are candidates for an alternative therapy. function can be maintained. These “nerve-sparing” Known pelvic nodal metastasis is a strong con- techniques have subsequently been incorporated in- traindication to external beam radiotherapy. Stud- to the perineal procedure (Weldon and Tavel, 1988). ies by both Memorial Sloan-Kettering (Fuks, The goal of both the retropubic and perineal ap- Leibel, Wallner, et al., 1991) and the Radiation proaches is to remove the entire prostate gland, Therapy Oncology Group (Hanks, Krall, Pilepich, both seminal vesicles, both ampullae of the vas and et al., 1992) reported that only about 10 percent of the surrounding tissues including the bladder neck. patients with node-positive disease at presentation

Page 16 Copyright © 1995 American Urological Association, Inc. remain free of disease at 10 years, and there is no Whether to include seminal vesicles in target indication of a plateau in the disease-free survival volume is also uncertain. Depending upon the pre- curve. This indicates that node-positive patients, cise characteristics of the stage T2 prostate cancer, with perhaps rare exceptions, cannot be cured us- the risk of seminal vesicle invasion can vary from 5 ing current radiotherapy techniques and may re- to 40 percent (Marks and Anscher, 1992; Mukamel, quire an alternative therapy. deKernion, Hannah, et al., 1987; Oesterling, Brend- Patients likely to benefit most and have the best ler, Epstein, et al., 1987). Most patients with semi- results from external beam radiotherapy are gener- nal vesicle invasion will have minimal involvement ally those who are also ideal candidates for radical (less than 16 percent of the gland). Yet, even in the prostatectomy. Patients with T2a tumors will have most favorable subsets of T2 disease, it is not rare for seminal vesicles to be significantly infiltrated by much better long-term disease-free survival than tumor. patients with T2b or T2c tumors (Glick, Philput, El- Mahdi, et al., 1990; Kaplan, Prestidge, Bagshaw, et For the majority of patients with T2 tumors, the al., 1992; Kuban, El-Mahdi and Schellhammer, seminal vesicles can be included in the target vol- 1989b; Schellhammer, Whitmore, Kuban, et al., ume with minimal added morbidity. However, the 1989). Patients with well-differentiated tumors, nor- volume of irradiated rectum will definitely increase. mal acid phosphatases and PSA values ≤ 10-15 Also, in occasional patients, the seminal vesicles ng/ml have markedly improved outcomes compared extend laterally and posteriorly for a significant dis- to patients with either higher-grade tumors or high- tance, with consequently greater risk of morbidity. er PSA values at time of presentation. This has It is reasonable in such cases to carefully weigh the been well documented (Asbell, Martz, Pilepich, et increased risk of morbidity against the benefits of treating the seminal vesicles, especially if the tumor al., 1989; Duncan, Warde, Catton, et al, 1993; For- is classified in the most favorable substages of T2 man, Zinreich, Lee, et al., 1985; Landmann and disease. Hunig, 1989; Perez, Garcia, Simpson, et al., 1989; Pisansky, Cha, Earle, et al., 1993; Russell, Dunatov, ArchivedHafermann, et al., 1991). Document—Treatment alternative: Brachytherapy (interstitial radiotherapy) Target volume Historically, pelvic lymph nodes were included Patient selection in theFor radiation treatment Reference volume as they were Only Patient selection criteria for brachytherapy are known to be positive in a significant percentage of similar to those for external beam radiotherapy. In patients. Some reports showed improved survival general, operative mortality is low, but complica- when the lymph nodes were treated, versus historic tions are not infrequent (see Table 5, page 27). For controls (Bagshaw, 1984; Epstein and Hanks, 1993; transperineal ultrasound-guided implantation ap- McGowan, 1981); and regional nodal radiotherapy proaches, widely variable complications have been was known to be effective in other types of cancers. reported (Blasko, Ragde and Grimm, 1991; Iversen, However, there are many who now doubt the im- Bak, Juul, et al., 1989; Smalley and Noble, 1992). portance or efficacy of regional pelvic radiotherapy. Although some reports show negligible complica- As noted previously, the most mature reports of pa- tions, longer follow-up and other corroborative se- tients with involved lymph nodes clearly indicate ries are needed (Bertermann, et al., 1991; Blasko, that, at 10 years, the overwhelming majority will Ragde and Grimm, 1991; Bosch, Forbes, Prassvin- have developed metastatic disease (Fuks, Leibel, ichai, et al., 1986; Carey, Lippert, Constable, et al., Wallner, et al., 1991; Hanks, Krall, Pilepich, et al., 1988; Fowler, Barzell, Hilaris, et al., 1979; Iversen, 1992). Moreover, there is no evidence of a plateau Bak, Juul, et al., 1989). in the disease-free survival curves, suggesting that Prior transurethral resection of the prostate radiation to involved pelvic nodes is incapable of (TURP) is a relative contraindication to prostate curing a meaningful number of patients. Finally, brachytherapy. Because patients with prior TURP prospective randomized trials have demonstrated no have a much higher incidence of late urinary com- advantage to pelvic nodal radiation when compared plications (Blasko, Ragde and Grimm, 1991), ex- with the results of prostate radiotherapy alone treme caution in minimizing urethral dose is impor- (Asbell, Krall, Pilepich, et al., 1988; Asbell, Martz, tant. Extensive corpora amylacea also present a the- Pilepich, et al., 1989; Pilepich, Krall, Johnson, et oretical contraindication to implantation with al., 1986). low-energy radionuclides (125I and 103Pd). The high

Copyright © 1995 American Urological Association, Inc. Page 17 electron density of the corpora amylacea may ab- trasound to monitor accurate distribution of the sorb the radiation emitted from these low-energy seeds. Anesthesia may be used, but no open surgery sources. is necessary. The transperineal method provides Finally, patients with high-grade tumors or with more homogeneous delivery of the radiation dose to large tumor volume (expressed either as a volumet- the prostate, but some concern has been expressed ric estimate or as advanced clinical stage) are not about adequately accessing the prostate base and well suited for brachytherapy. No widely utilized seminal vesicles. More important, this method has brachytherapy techniques implant either the semi- not yet produced outcome results with long enough nal vesicles or extracapsular tissue. follow-up to be able to evaluate the potential advantages and risks. In the panel’s opinion, however, there is no evidence that results from the transperi- Techniques neal method are inferior to those from the retropu- Brachytherapy techniques involve two separate bic method. choices: which type of radionuclide and which method of administration. Isotopes can be chosen Treatment alternative: Surveillance from a variety of radionuclides, taking into account such factors as dosimetry scheme, half-life, type of emission and tissue penetration. Brachytherapy may Basis for management by surveillance also be augmented by external beam radiotherapy, The notion that no active treatment can be used as well as by high-technology modifications that for a disease process is not unusual. A classic ex- are still investigational. ample is the common cold. However, for such a There are two methods of administration. In the policy of “no active treatment” or “surveillance” to earlier approach (1965 – 1985), the prostate was ex- be used for a neoplasm in which morbidity or mor- posed retropubically. Then the radionuclide “seeds” tality can occur, one or more of the following crite- were inserted by means of hand-positioning the car- ria must be met: (1) The neoplasm must have a low rier needles, attempting to encompass the entire risk of morbidity and mortality; (2) The impact of prostateArchived mass by gross estimation. Several draw- Document—treatment upon morbidity or mortality must be neg- backs to this method have been reported. One is in- ligible, minimal or of unknown effect; and (3) The ferior control of localized disease when compared harms of treatment must outweigh the benefits. with external beam radiotherapy (Kuban, El-Mahdi With regard to the first criterion, evidence sug- and Schellhammer,For 1989a; Reference Morton and Peschel, gests that low-grade, low-stage Only prostate cancer 1988; Schellhammer, El-Mahdi, Higgins, et al., untreated may not produce any symptoms for pro- 1987; Schellhammer, Whitmore, Kuban, et al., longed periods. Only in some patients will morbidi- 1989; Smalley and Noble, 1992). ty or death from the disease ensue. Autopsies of Errors have also been documented in evaluating men who died from other causes reveal a substan- prostate size, and thus in the numbering and spac- tial number with occult prostate cancer. The rate is ing of seeds (Stone, Forman, Sogani, et al., 1988). as high as 80 percent in older men (Franks, 1954). Because distribution of seeds was difficult, the radi- A study using assiduous sectioning techniques to ation dose was nonhomogeneous (Gore and Moss, investigate young men found carcinoma present in 1983; Kandzari, Belis, Kim, et al., 1982; Sogani, 9 percent, 16 percent and 26 percent of men in their DeCosse, Montie, et al., 1979). Seeds migrated and third, fourth and fifth decades, respectively (Sakr, were usually passed out through the urethra (Som- Haas, Cassin, et al., 1993). merkamp, Rupprecht and Wannenmacher, 1988; Of men with untreated prostate cancer followed Steinfeld, Donahue and Plaine, 1991). Finally, up to 10 years, most series suggest that the majority some authors have been concerned about the low do not die of prostate cancer but with it. Most of doses delivered by 125I and 103Pd (Anderson and these series included older men at a higher risk of Ling, 1991; Dale, 1985; Fowler, 1989, 1991; Small- death from other causes and men with less lethal ey and Noble, 1992). Data the panel extracted on forms of prostate cancer (well differentiated, low complications of brachytherapy were based on this stage). In one series (George, 1988), although 5 pa- earlier, retropubic approach. tients died of prostate cancer, 48 died of other caus- The newer method of administering the radiation es (4 percent versus 40 percent of the study popula- (1984-present) places the seeds much more precise- tion). In another series (Adolfsson, Carstensen and ly via the perineal percutaneous route. This ap- Lowhagen, 1992), of the 38 percent of patients who proach uses a perforated template on the perineum died, 7 percent died of prostate cancer and 31 per- to position the carrying needles and transrectal ul- cent of other causes.

Page 18 Copyright © 1995 American Urological Association, Inc. In regard to the second criterion—that the impact Finally, in a recent decision analysis, treatment of treatment on prostate cancer may be minor— of localized prostate cancer for “cure” was calculat- three bodies of evidence support this contention. ed to result in only minimal improvements in quali- First, using contemporary measures of treatment ef- ty-adjusted life expectancy (Fleming, Wasson, Al- ficacy, many patients with clinically localized pros- bertsen, et al., 1993). The authors stratified patients tate cancer when treated for cure have been shown by age and tumor grade and made estimates of to be at risk for disease recurrence. In the case of treatment efficacy and risk of metastatic disease. radical prostatectomy, a guiding principle holds that Using the highest estimate of a positive effect of if the tumor is confined to the prostate and the pros- treatment on life expectancy as well as the highest tate is removed, likelihood of “cure” (lifetime free- risk of developing metastatic disease, the resultant dom from disease) is high. Unfortunately, the dis- increase in quality-adjusted life expectancy was no ease may not, in fact, be organ confined. In the more than 4 years in the youngest patients studied. United States, as many as 50 percent of patients un- Using the median estimate for the risk of metastatic dergoing radical prostatectomy will be found to disease and the highest efficacy of treatment, the have disease outside the prostate capsule or in the authors found that improvement of quality-adjusted seminal vesicles or to have a positive surgical mar- life expectancy was less than 1 year. With virtually gin (Morton, Steiner and Walsh, 1991; Wahle, all other estimates, treatment had a negative effect Reznicek, Fallon, et al., 1990). These patients have on quality-adjusted life expectancy. a higher risk of disease recurrence than do patients Another study (Beck, Kattan and Miles, 1994), with organ-confined tumors (Paulson, Moul and using more recent data from Chodak, Thisted, Ger- Walther, 1990). ber, et al. (1994), concluded that improvement in quality-adjusted life expectancy for radical prosta- Some patients will be found to have a measur- tectomy compared with surveillance was 1.01, 2.41 able PSA following radical prostatectomy, indicat- and 2.68 years for well-differentiated, moderately ing persistent disease (Stein, deKernion, Smith, et well-differentiated and poorly differentiated tumors, al., 1992). Using PSA as an indicator of failure, pa- respectively. Archivedtients treated with radiotherapy have also been Document— noted to have a high risk of relapse. One article reported that as many as 80 percent of patients treat- The candidate for surveillance ed with radiotherapy have a rising PSA within a There are two general principles in selecting the relatively short period of follow-up (Stamey, Ferrari ideal patient for surveillance: (1) a tumor of low bi- and Schmid,For 1993). Another Reference article reported that if ologic activity (which Onlyposes the lowest threat of PSA and clinical relapse are combined, the risk of metastasis); and (2) a relatively short period of time disease relapse within 4 years following radiothera- at risk for disease progression. py is 40 percent (Zagars and von Eschenbach, With regard to low biologic activity, tumor char- 1993). acteristics thought to be associated with the longest The second body of evidence indicates that a disease-free survival include: low grade, low stage, policy of surveillance alone is often associated with low volume and (because it is often associated with prolonged, morbidity-free survivals. A number of tumor volume) low PSA. investigators have presented the results of a surveil- As to short period at risk, because tumor pro- lance policy for localized prostate cancer (Adolfs- gression will occur in most patients with untreated son and Carstensen, 1991; George, 1988; Johans- prostate cancer, given sufficient time, the ideal pa- son, Adami, Andersson, et al., 1992; Jones, 1992; tient for surveillance has a relatively short life ex- Madsen, Graversen, Gasser, et al., 1988; Rana, pectancy. Methods to estimate life expectancy Chisholm, Christodoulou, et al., 1993; Stenzl and include age (see U.S. Life Expectancy Table in Ap- Studer, 1993; Waaler and Stenwig, 1993; Whit- pendix C), as well as information on other disease more, Warner and Thompson, 1991). It must be processes that the patient may have. These data can noted that many of the patients were older and that, be integrated to establish the period of time at risk in many series, patients with focal disease detected for disease progression and thereby determine on transurethral resection of the prostate (TURP) whether surveillance is an appropriate treatment op- were included (stage T1a). Nevertheless, it is in- tion. structive to recognize that 10-year disease-specific Finally, a patient may choose surveillance for survivals of between 40 and 92 percent were real- management of prostate cancer because of a desire ized, with most studies in the 80 to 90 percent to avoid or defer the side effects of other forms of range. therapy.

Copyright © 1995 American Urological Association, Inc. Page 19 Surveillance in practice physician, including an understanding that should symptoms or signs develop which the patient feels Following the diagnosis of prostate cancer and may be related to the tumor, he should contact the appropriate staging to assure that metastatic disease physician at that time. is not present, treatment alternatives are discussed with the patient. Surveillance is presented as one of One principle of surveillance as a management these treatment options. If the patient elects a pro- modality for localized prostate cancer is that other gram of surveillance, he is informed that the status forms of intervention may be employed at any time. of his prostate tumor will be monitored periodical- For example, if evidence suggests that there is a ly. Monitoring may take any number of forms, but need for further treatment, then radical prostatec- will generally include, as a minimum, DRE and tomy, radiotherapy or other forms of therapy may PSA. The frequency of monitoring is often based be undertaken. (The patient is then no longer a upon a number of factors including measures of the “surveillance patient.”) However, the patient must tumor’s biologic activity (stage, grade, volume, understand at the outset that the delay inherent in PSA) and the age and medical status of the patient. surveillance may compromise the effectiveness of Patients may be informed that periodic monitoring any subsequent treatment, if any should become should also include a close relationship with their necessary.

Archived Document— For Reference Only

For assessing benefits and harms of intervention Types of outcomes for stage T2 (B) prostate malignancy, the AUA Prostate Cancer Clinical Guidelines Panel consid- Outcomes of therapeutic medical interventions ered the following outcomes the most important to may be direct or indirect. Direct outcomes affect the patient: (1) survival at 5, 10 and 15 years patients’ lives directly and are experienced directly. (overall survival, disease-specific survival, progression-free survival and metastasis-free survival); (2) Some direct outcomes, such as pain from treatment, progression rates at 5, 10 and 15 years (metastat- occur immediately and are short-term. Others, such ic, local and biochemical); and (3) complications as impotence (erectile dysfunction), may occur on a of treatment. Although all treatment complications continuing basis over a period of time. Still others, were evaluated, the most important are: death from such as the effect of treatment on life expectancy, treatment, incontinence, impotence (erectile dys- can be considered future outcomes. Patient prefer- function), cystitis, proctitis, major bleeding, pul- ences may differ as to relative benefits/harms be- monary embolism, rectal injury and bladder neck tween different types of direct outcomes, for exam- contracture/urethral stricture. ple, the risk of erectile dysfunction compared with the future benefit of longer life expectancy as a re- Archivedsult of the same treatment. Document—Survival at 5, 10 and 15 years Indirect outcomes are measures, such as the level Clinically localized prostate cancer (stages T1 of serum PSA, that are affected by treatment but and T2) is rarely lethal within the first 5 years after not experienced by patients directly. Such measures diagnosis. The overall death rate during this period may provide data about the probability of future is low and usually secondary to comorbid process- For Referencees. Almost any treatment Only for localized prostate can- outcomes. For example, rising PSA can be of great importance when assessing the effectiveness of cancer would appear to have an excellent survival re- cer treatment and the probability of future progres- sult at 5 years. Survival at 10 years and 15 years al- sion of the disease. lows a more accurate assessment of the influence of prostate cancer and its treatment on patient sur- In treating prostate cancer, differences between vival. direct and indirect outcomes are less important than It is not sufficient to assess survival independent- in treating many other diseases. The major consid- ly of tumor progression status. Comorbid processes eration is where patients place the emphasis with associated with advanced age will often determine regard to impact on their lives. Some patients are overall survival. However, morbidity from cancer concerned with adverse direct outcomes such as progression may occur for years prior to death. It is urinary incontinence or erectile dysfunction to the therefore reasonable to inform patients not only point that they may opt for a less morbid treatment, about the risk of dying from prostate cancer, but al- even if the probability of “cure” (lifetime freedom so about the risk of developing metastatic disease from disease) is notably less than for the rejected or evidence of tumor recurrence. Outcomes of dis- treatment (Singer, Tasch, Stocking, et al., 1991). ease-specific, progression-free and metastasis-free However, for many men with adenocarcinoma of survival should be assessed in addition to overall the prostate, the most compelling reason for seek- survival rates. ing treatment is the hope of “cure.” Given the choice, these men may choose the risk of inconti- Progression rates at 5, 10 and nence or erectile dysfunction for an improved chance of “cure.” They are usually well informed 15 years and recognize the prognostic implications of indi- After surgery or radiotherapy, most recurrence or rect measures such as rising PSA. progression of adenocarcinoma of the prostate will

Copyright © 1995 American Urological Association, Inc. Page 21 become biochemically (PSA) apparent by 5 years, bulk of the literature is not usable for extracting and but a few patients may have lengthy delays before combining data to assess treatment outcomes and the progression becomes clinically apparent. Thus, develop comparative estimates for these outcomes. it is important to continue to assess progression Of 12,501 papers reviewed, the panel was able to rates to 10 years and beyond. Progression rates may retrieve only 165 with acceptable data on outcomes or may not influence the patient directly. Many from treatment of localized prostate cancer. (See times progression will be defined as the develop- page 9 for a discussion of the review process.) ment of any evidence of tumor. This recurrence is Moreover, in these 165 articles, there are significant often asymptomatic and found only through sur- differences among treatment series regarding such veillance examinations. characteristics as patient age, tumor grade and Obviously, either local recurrence or sympto- pelvic lymph node status. The differences are sum- matic metastatic prostate cancer is of extreme im- marized in Table 2 (page 23). portance to patients diagnosed with localized dis- Table 2 makes clear that patients receiving the ease. However, biochemical failures, usually in the various forms of treatment are not similar. For ex- form of rising serum PSA, will also negatively im- ample, patients undergoing radical prostatectomy pact patients from a psychologic standpoint. Men are on average 3 years younger than those undergo- with prostate cancer understand that a rising serum ing external beam radiotherapy and approximately PSA often precedes eventual symptomatic recur- 7 years younger than those reported to have been rence. followed with surveillance. It is also striking that only about one in seven Complications and harms of patients reported in the literature was followed even treatment for 5 years and that a very small fraction was followed for 10 or 15 years. Estimates of important Death from treatment is the most serious (though outcomes, particularly of survival and progression uncommon) immediate adverse outcome for a pa- rates at 5, 10 and 15 years, are likely to be inaccu- tient diagnosed with prostate cancer. Other adverse rate if such small numbers of patients are available outcomesArchived from treatment, such as incontinence, Document— im- for analysis. potence (erectile dysfunction), cystitis, rectal injury Tumor grades are relatively comparable in pa- and bleeding, are much more common and have tients treated actively (by surgery or radiotherapy); variable degrees of negative impact on patient well- but for patients followed with surveillance, there being. The reported incidences and estimates of For Referenceare data on very few patients Only who have high-grade these adverse outcomes are important to a patient tumors. In addition, there is scant information on making decisions regarding treatment. Some of the pelvic lymph node status in patients receiving ex- complications are much less common today than in ternal beam radiotherapy or followed with surveil- older reports because of newer technology and ad- lance, which leaves open the possibility of dramatic vancements in technique. It is therefore important differences in the stages of patients’ tumors. to stratify the complications relative to era of treatment. (See Appendix A, Figures A-7 to A-31.)

Cost, inconvenience and indirect Summary outcomes quality-of-life issues tables and graphs Although such issues as cost and inconvenience are important, no meaningful data are readily avail- Because of the signiﬁcant differences in the liter- able from the literature. These are areas in need of ature among treatment series and the consequent in- future research (see Chapter 5, page 45). ability to make meaningful estimates from available data for the most important outcomes, those of patient survival and tumor progression, the panel concluded that it would be methodologically unsound Variability of outcomes data to compare treatment modalities directly with regard to survival and progression. The panel was impressed by the massive amount Nevertheless, in order to show the range of out- of literature available on the topic of prostate can- comes data reported for the different modalities, the cer. However, as discussed in Chapter 1 and in the panel decided to display results of the data extract- Limitations section (page 42) of Chapter 5, the vast ed. Results are displayed in summary outcomes

TYPE OF TREATMENT Radical External beam Series characteristic prostatectomy radiotherapy Brachytherapy Surveillance Mean age of patients 62.7 65.9 64.5 70 (range: 34-84) (range: 26-92) (range: 36-91) (range: 38-90) Number of patients 9,263 14,205 4,891 913 Number with 5-year follow-up 1,188 (13%) 1,802 (13%) 642 (13%) 400 (44%) Number with 10-year follow-up 759 (8%) 110 (1%) 100 (2%) 46 (5%) Number with 15-year follow-up 530 (6%) 0 0 33 (4%) Mean follow-up 70.2 months 70.3 months 56.5 months 111.6 months (range: 1-372) (range: 1-264) (range: 1-219) (range: 3-298) Tumor grade: well 23.1% 41.2% 38.3% 62.2% differentiated2 (376/1,631) (517/1,256) (427/1,116) (250/402) Tumor grade: moderately well 56.9% 40.6% 51.3% 34.8% differentiated2 (928/1,631) (510/1,256) (572/1,116) (140/402) Tumor grade: poorly 20% 18.2% 10.5% 3% differentiated2 (327/1,631) (229/1,256) (117/1,116) (12/402) Number with PLND 83% 26% 87% 0 (910/1,093) (463/1,756) (1,743/1,997) Series published in 1960’s 5 0 0 0 Series published in 1970’s 6 9 2 0 Series published in 1980’s 21 41 22 0 ArchivedSeries published in 1990’s 23 Document—23 11 6 1 The term “series” here denotes groups of patients stratiﬁed by parameters such as primary treatment modality. One article may have more than one series. Table 2 data are from 169 series in 165 articles. 2 Grading system: Categorization of degree of differentiation is based either on series reports of good, moderate or poor differentiation or on the divisionFor of Gleason sums intoReference 2-4 (well differentiated), 5-7 (moderately well differentiated) or 8-10 (poorly Only differentiated).

tables for survival and tumor progression at 5, 10 The major problem with actual reporting of out- and 15 years. For survival at 5, 10 and 15 years, the comes is that prolonged follow-up is required to results are displayed graphically as well. collect adequate data. Some reports include cohorts of men with a minimum of 5-, 10- or 15-year follow-up. Knowing the outcomes for each patient in a Summary outcomes tables series for the entire follow-up time (5, 10 or 15 The tables indicate the range of the outcomes da- years) has the advantage that the data are indeed ac- ta reported by showing highest and lowest results tual, in contrast to actuarial estimates. Unfortunate- reported (maximum and minimum percentages). ly, the long-term systematic follow-up needed to Because combining data among series was not pos- accurately record these data is exceptionally diffi- sible, given their variability, the panel elected not to cult. Patients are often lost to follow-up or die of present summary statistics (mean or median val- unknown causes, or they fail to have consistent test- ues). ing or to have the data recorded so as to accurately The panel also decided to identify “actual” (ob- assess disease status. Moreover, for later end points served, nonactuarial) data separately from actuarial (such as 15-year disease-speciﬁc survival), the data and to report them separately. Although actuar- number of patients available by then is usually ial reporting is regarded as a more reliable way to small, further weakening the statistical signiﬁcance present treatment outcomes for men with localized of the reported outcomes. For these reasons, the prostate cancer, the data from series reporting “ac- word “actual,” when used to denote “actual” data, tual” data were also retained for review. appears in this report in quotes.

Copyright © 1995 American Urological Association, Inc. Page 23 Actuarial reporting allows earlier analysis of data • Metastasis-free survival: Percent of men sets by using all the information in the database to alive without evidence of metastatic disease estimate or predict longer-term outcomes. As more (overall survival minus those men who are patients survive to the desired end points (5, 10 and alive, but have metastatic prostate cancer). 15 years), the confidence intervals for these esti- • Disease-specific survival: Percent of men mates become narrower. Such a data set is dynamic and more prospective, which eliminates some of the who have not died from prostate malignancy problems inherent in “actual” data. (overall survival plus those men who died from causes other than prostate cancer). A criticism of actuarial data is the inability to predict behavior of cancer for a large number of pa- For Table 4 (page 26), displaying failure/progres- tients based on the outcomes for a few. Also, the sion outcomes data, the outcomes are stratified by validity of long-term patient outcomes depends in types of progression: local, distant, biochemical and part on the number of patients available with total. Prostate cancer recurrence, or disease pro- lengthy follow-up. This type of quality assessment gression, is reported in the literature independent of within actuarial data sets was rarely stated in the survival. For the data-extraction process, the panel publications the panel reviewed during the literature attempted to record the rate of progression or fail- search. ure as a percentage. This percentage was either cal- For both “actual” and actuarial data, the summa- culated or extracted from the article’s text, tables or ry outcomes tables show the number of series in or- graphs. If the percentage was calculated, it repre- der to allow reviewers to estimate the degree to sents the number of men who experienced or were which the data are verifiable. The number of series, found to have progressing cancer, or were found to however, is not the number of independent papers have new evidence of cancer after or while under or reports. As used here, “series” are groups of pa- the chosen therapy—as compared with the total tients within a report stratified by parameters such number of men being monitored. as primary treatment modality or stage of disease. OneArchived report may have more than one series. Document—Progression rates were assessed at 5-, 10- and 15-year intervals. Definitions of progression are These series may be subsets of clinical stage T2 (B) disease. For instance, if a report classified out- vague and vary from paper to paper. For this report, comes within the stage B category according to the panel defined categories of progression as fol- clinical Forstage B1, B2, etc., Reference and reported these data lows: Only separately, by each substage, the panel left the data • Local: Recurrent malignancy in the prostate as separately recorded rather than attempting to or prostate bed. It may vary from tumor on combine outcomes. Therefore, under the broader random biopsies to symptomatic cancer re- category of stage B, there is more variability de- growth. pending upon substages reported. • Distant: Radiographic evidence of cancer at For Table 3 (page 25), which displays survival sites away from the prostate area. Bone and outcomes data, the outcomes are stratified by over- lymph nodes are the most common. Some old- all, progression-free, metastasis-free and disease- er studies used plain films and serum acid specific survival. This stratification is necessary to capture and record the major outcomes as reported. phosphatase to determine distant disease. However, definitions of these survival subgroups • Biochemical: Prostate specific antigen (PSA) are not standardized in the literature. The terms are at present is the most reliable means to deter- used by different authors with some variability in mine prostate cancer recurrence, and contem- their meaning. For this report, the panel used the porary reports are using PSA levels alone to following general definitions: define cancer recurrence. The level of PSA and • Overall survival: Percent of men alive, irre- rate of rise that constitute biochemical failure spective of their disease status or the cause of have not yet been defined. death in those men not alive. • Total: Any evidence of local or distant or bio- • Progression-free survival: Percent of men chemical recurrence. Adding local to distant alive without evidence of disease progression will not suffice since they may be present con- (usually overall survival minus those men who currently. are alive, but with progressing or recurrent disease). (Continues on page 32)

ForRadiation: Reference Only 0 0 0 0 66.7% 92.0% 188.5% 93.0% 42.0% 42.0% 363.1% 0 90.0% 66.1% 86.0% 055.0% 0 93.0% 0 0 0 Radical Overall 7Overall 44.4% 88.0% 6 11Overall 17.0% 67.0% 41.4% 8 70.0% 0 22.2% 0 75.0% 2 31.0% 33.0% 0 Metastasis Free 0 Metastasis Free 0 Metastasis Free 0 Metastasis Free 0 Progression Free 1Progression Free 82.0% 82.0% 5 10Progression Free 25.0% 82.0% 40.0% 1 64.0% 0 70.0% 7 70.0% 50.0% 0 90.0 Disease Specific 5 Disease Specific 3 Disease Specific 3 Disease Specific 5 5 Year - Actuarial 10 Year - Actual 10 Year - Actuarial 15 Year - Actual 15 Year - Actuarial Table 3. Summary outcomes—Descriptive analysis of survival data analysis of survival 3. Summary outcomes—Descriptive Table

Copyright © 1995 American Urological Association, Inc. Page 25 16.0% 0.0% Min %% Max Surveillance Reporting Series 0 0 0 0 0 0 0 3 70.0% 100.0% Number 28.0% 5 24.0% 65.0% 32.0% 4 56.0% 4 28.0% 46.0% 7.0% 0.0% 0.0% Min %% Max Reporting Series 0 0 0 0 0 Number 22.0% 0 20.0% 2 67.0% 85.0% 0 29.0% 7 50.0% 5 12.0% 60.0% 0 13.0% 3 22.0% 40.0% 0 Archived19.5% Document— 7 9.1% 0.0% 8.0% 100.0% 100.0% 0 Min %% Max Radiation

ForReporting Series Reference Only External Beam 1 Number 12.0% 2 11.3% 19 40.0% 15 15.4% 0 100.0% 1 41.0% 41.0% 0 0 1.2% 1.2% 4 0.0% 3.0% 2.5% 5.0% 1.8% 9.8% 7 0.0% 4.0% 4.0% 10 3.8% 4.0% 12.0% 25.9% 9 10.0% 42.0%22.0% 22.0% 1 3 28.0% 28.0% 17.0% 35.1% 4 0 26.0% 74.0% Min %% Max Radical Reporting Series Prostatectomy 0000 0000 0000 0000 0000 0000 Number Total 5 Total 5 Total 4 19.0% 47.0%Total 0 1 17.0% 17.0% 0 Total 5 13.0% 80.0%Total 8 4 15.0% 60.0% 20.0% 2 12.0% 50.0% 0 Local 3 Local Local 3 Local 2 Local 2 Local 1 Distant 1 Distant 1 Distant 1Distant 50.0% 50.0% 1Distant 0 13.0% 13.0% 1Distant 3 14.0% 14.0% 1 27.0% 32.5% 0 15.0% 15.0% 5 1 27.0% 27.0% 3 38.0% 64.0% 3 32.0% 85.0% Biochemical Biochemical 0 Biochemical Biochemical Biochemical Biochemical 5 Year - Actuarial 10 Year - Actual 15 Year - Actual 10 Year - Actuarial 15 Year - Actuarial 5 Year - Actual Table 4. Summary outcomes—Descriptive analysis of failure/progression data analysis of failure/progression 4. Summary outcomes—Descriptive Table

Page 26 Copyright © 1995 American Urological Association, Inc. Range 1 0.8 % 0.8 % 1 3.1 % 3.1 % 3 1.8 % 3.0 % 0 9 0.6 % 16.0 % 7 0.1 % 4.7 % 4% 3.5 % 18.8 10 1.0 % 11.3 % Range Archived Document—0.4 % 2.1 %1.6 % 5 55.0 %0.7 % 13 1.0 % 1.0 % 9.0 % 1.0 % 0 75.0 % 2 6 0 7 0.7 % 76.0 % 2 2.5 % 50.0 % 22 22 0.7 % 80.0 % 10 6.0 % 94.0 % ForRadiation: External Beam Reference Radiation: Brachytherapy Only 100.0 % 6 4.0 % 41.0 % 9 2.0 % 78.0 % Range 4.0 %0.0 % 50.0 % 15.4 % 2 0 0.5 % 1.7 % 4 1.0 % 7.0 % 1.0 %1.0 % 3.0 % 1.0 % 0 80.5 % 14.6 % 0.7 %1.5 % 14.3 % 2 1.5 %0.5 % 9 7 3.7 % 0.7 % 2.4 % 2.4 % 0 3.0 % 16.0 % 14.0 % 3 4 0.5 % 8.0 % 0.1 % 19.0 % 0.2 % 7.7 % 0 0.0 %0.0 % 2.1 % 5.4 % 7 3 0.0 % 0.5 % 0.6 % 6.0 % 3 2 0.0 % 6.3 % 3.0 % 7.4 % Radical Prostatectomy 1 0 9 0.0 % 8.3 % 0 5 0 3 4 1 0 0 3 0.0 % 2.0 % 6 0.7 % 2.0 % 2 0.8 % 3.5 % 8 1.0 % 8.8 % 0 2 0.0 % 0.7 % 3 0.5 % 2.0 % 0 4 1.3 % 14.0 % 14 3.0 % 63.0 % 5 8.5 % 72.0 % 4 4.0 % 16.0 % 6 7.0 % 100.0 % 2 18.0 % 65.0 % 9 0.8 % 7.7 % 0 5 2.0 % 9.0 % 21 0.4 % 12.0 % 5 0.6 % 4.0 % 5 1.0 % 11.5 % 4 1.7 % 12.8 % 5 2.0 % 9.4 % 20 10 19 15 29.0 % 11 0.3 % 15.4 % 3 0.5 % 4.6 % 3 0.0 % 18.8 % Incontinence (severe) 20 Urine leak, fistula Incontinence (stress) Bladder neck contracture 13 Diarrhea Total early Total late Edema, chronic Cystitis Proctitis Urethral stricture Fecal incontinence Lymphocele Incontinence (postradiation)Impotence 0 Bladder outlet obstruction 0 Ureteral obstruction Hematuria Cardiovascular Wound infection Sepsis Pulmonary embolus Major bleeding Rectal injury Colostomy DVT Perioperative death Table 5. Summary outcomes—Treatment complications 5. Summary outcomes—Treatment Table

Figure 2. Overall survival: 2. Overall Figure beam radiotherapy External

Figure 4. Overall survival: 4. Overall Figure Surveillance 100 100 Survival Percentage Survival

Archived Document—Percentage Survival

For Reference20 Only20 15 15 10 10 Year 5 5 0 0 0 0 75 50 25 75 50 25

Figure 1. Overall survival: 1. Overall Figure Radical prostatectomy

Figure 3. Overall survival: 3. Overall Figure (interstitial radiotherapy) Brachytherapy

100 100

Survival Percentage Survival Percentage Survival

100

Figure 6. Progression-free survival: 6. Progression-free Figure beam radiotherapy External survival: 8. Progression-free Figure Surveillance 100 Survival Percentage Survival

Archived Document—Percentage Survival

For Reference20 Only 20 15 15 10 10 Year 5 5 0 0 0 0 75 50 25 75 50 25

Figure 5. Progression-free survival: 5. Progression-free Figure Radical prostatectomy survival: 7. Progression-free Figure (interstitial radiotherapy) Brachytherapy

100 100

Survival Percentage Survival Percentage Survival

Figure 10. Disease-speciﬁc survival:Figure Radical prostatectomy 100 100 Survival Percentage Survival ArchivedPercentage Survival Document— 12. Disease-speciﬁc survival:Figure (interstitial radiotherapy) Brachytherapy

For Reference20 Only 20 15 15 10 10 Year 5 5 0 0 0 0 75 50 25 75 50 25

Figure 9. Metastasis-free survival: 9. Metastasis-free Figure beam radiotherapy External 11. Disease-speciﬁc survival:Figure beam radiotherapy External

100 100

Survival Percentage Survival Percentage Survival

Page 30 Copyright © 1995 American Urological Association, Inc. Impotence Impotence Impotence Urethral Urethral Stricture Stricture Urethral Stricture Cystitis Cystitis Bl Neck Contract Proctitis Proctitis PE Bl Neck Contract Bl Neck Contracture Major Bleeding PE PE Major Incont Severe Major Bleeding Bleeding Incont Stress Incontinence Postradiation (including SI) Incontinence Postradiation (including SI) Death Death Death 0.0 % 0.0 % 80.0 % 60.0 % 40.0 % 20.0 % 80.0 % 60.0 % 40.0 % 20.0 %

Figure 16. Complications:Figure Brachytherapy (interstitial radiotherapy)

Figure 14. Complications:Figure Radical prostatectomy 100.0 % 100.0 % Reported Rates Reported

ArchivedRates Reported Document—

For Reference20 Only Impotence Urethral Stricture 15 Cyst Cystitis Proctitis Proctitis 10 Bl Neck Contract Bl Neck Contracture Major Bleeding Major Bleeding 5 Postradiation Incontinence (including SI) Incontinence Postradiation (including SI) Death Death 0 0 75 50 25 Figure 13. Disease-speciﬁc survival:Figure Surveillance

0.0 %

100 Figure 15. Complications:Figure beam radiotherapy External

80.0 % 60.0 % 40.0 % 20.0 %

Survival Percentage Survival 100.0 % Reported Rates Reported

Copyright © 1995 American Urological Association, Inc. Page 31 Circle graphs tients treated with radical prostatectomy or brachytherapy. Supplementing the tables is a graphical presentation consisting of “circle graphs” for 5-, 10- and Table 3 also shows a tendency toward excellent 15-year survival (overall, progression free, metasta- actuarial disease-specific 5-year survival results for sis free and disease specific) (see Figures 1 – 13, all modalities. In general, the literature would ap- pages 28–31). The graphs represent actuarial data pear to support the premise that, for men with lo- only. In each graph, the result (percentage at 5, 10 calized adenocarcinoma of the prostate, disease- or 15 years) for one series is represented by a small specific survival outcomes tend to be quite good re- gardless of treatment at 5 years, and that follow-up circle at the corresponding point. Whereas the ta- of 10 years or longer is needed to evaluate treat- bles give the number of series and maximum and ment efficacy with regard to preventing death due minimum percentages reported, the graphs also to prostate cancer. show how the reporting series are distributed over this range. It is important to note, however, that The reported ranges between upper and lower graphs do not show either the size of each series or actuarial disease-specific results (maximum and the confidence interval for the indicated percentage. minimum percentages) are similar for each modality. External beam radiotherapy has the widest range, which probably reflects the fact that only 26 Analysis of summary percent of patients (463/1,756) underwent a staging pelvic lymph node dissection (PLND). (See Table outcomes tables A-3 in Appendix A). The proportion of patients undergoing PLND The literature the panel reviewed to extract out- was inconsistent from series to series. The fact that comes data for this report is quite heterogeneous. It few patients in the external beam radiotherapy se- covers nearly 30 years of medical history and con- ries received PLND likely resulted in understaging. tains data from studies representing countries in This could account for the reduced disease-specific Europe,Archived Asia, Africa and the Middle East as well Document— in 5-year survival rate of 63.5 percent at the low end the Western Hemisphere. In part because of the het- of the range, compared with close to 90 percent at erogeneity, methods of reporting are variable—to the low end for the other treatment modalities. For the extent that data reported are not sufficiently prostatectomy and brachytherapy, 83 percent and comparable to provide a sound basis for estimating 87 percent of the patients, respectively, were staged and comparingFor treatment outcomes.Reference This is dis- with PLND before treatment Only (Table A-3). cussed at length in Chapter 1 (Methodology), earli- In the three series reporting 89 to 99 percent dis- er in this chapter (pages 22-24) and in the limita- ease-specific survival at 5 years for men followed tions section (page 42) of Chapter 5. by surveillance, the very good outcome may in part Nevertheless, results displayed in the summary be due to the favorably high proportion of men with outcomes tables do provide some interesting, albeit low- and moderate-grade malignancy. Only 3 per- inconclusive, information regarding major out- cent of men treated by surveillance had high-grade comes of treatments for localized prostate cancer. tumors, compared with 20 percent, 18 percent and The following analysis examines the results dis- 10.5 percent, respectively, for the series reporting played for 5-, 10- and 15-year survival (Table 3, on prostatectomy, external beam radiotherapy and page 25) and for 5-, 10- and 15-year progression or brachytherapy. Men under surveillance were also recurrence/failure (Table 4, page 26). older at diagnosis (see Table 2 on page 23), placing them at increased risk of death from any cause (overall survival). Although age generally affects 5-year survival results overall survival negatively, advanced age may help For 5-year survival, Table 3 shows that more ra- to explain the favorable disease-specific survival diotherapy series reported actuarial outcomes than outcome for surveillance, compared to some inter- reported “actual” outcomes, whereas more prosta- ventional therapy groups. Older men, at greater risk tectomy series reported “actual” numbers than re- of dying from “natural” causes, are at risk for a ported actuarial statistics. These imbalances do not shorter time of dying from prostate malignancy. appear to be important in patients who underwent Progression-free survival is more variable than external beam radiotherapy since the “actual” and disease-specific survival among treatment choices. actuarial outcome results do not differ significantly. In the radiation literature, a wide range of outcomes However, significant differences between “actual” is reported. This is reflected in Table 3, in the wide and actuarial results were evident in series of pa- ranges shown between the lowest and highest

Page 32 Copyright © 1995 American Urological Association, Inc. reported results: from 32 to 93 percent for progres- surveillance, only one series contained 10-year pro- sion-free survival following treatment with external gression-free survival data. Since all patients in this beam radiotherapy and from 38 to 90 percent after series had prostate cancer that went virtually un- brachytherapy. treated, the progression-free percentage obviously Such variability for progression-free survival is depends upon how one defines “progression.” In an indication of the uncertainty found in the pub- general, the variability in 10-year outcomes illus- lished reports. This uncertainty is due in part to dif- trates the pitfalls of attempting to compare progres- ferences in intervals between follow-up and differ- sion-free survival data from retrospective studies. ences in defining and recording progression statis- Reporting of 10-year disease-specific survival tics. The definitions vary from symptomatic local data is less subjective, as reflected in more uniform disease to occult malignancy found on random outcomes and in more closely packed data points in posttreatment biopsy. More recently, PSA has been the graphical displays, although the latter may be used to assess patients for cancer recurrence be- more a reflection of the small number of data points cause increases in serum PSA generally predate (Figures 10-13, pages 30-31). The actuarial disease- clinical evidence of progression. specific survival results shown in Table 3 slightly The progression-free status at 5 years for men favor prostatectomy (86 to 93 percent). However, treated with radical prostatectomy is less variable the less favorable results shown for external beam (81.9 to 92 percent actuarial, 63.6 to 91 percent radiotherapy are likely affected by clinical under- “actual”) than for men managed by radiotherapy or staging without pelvic lymph node dissection. The surveillance. This is partly due to more consistent favorable results for the three surveillance series means of defining recurrence. Without the prostate may be partly due to careful selection of patients in place, the variability associated with posttreat- placed on the surveillance protocol. Also, because ment prostate biopsy and palpable prostatic pro- of advanced age and shorter natural life expectancy, gression is reduced. the time these patients were at risk for dying of Metastasis-free survival is less subjective than prostate cancer was less than that for younger men. Archivedprogression-free survival, and outcome results Document—As noted previously on page 32, this obviously af- would likely be more comparable between groups. fects disease-specific survival data positively, just However, as Table 3 shows, the treatment data as it affects overall survival data negatively. available did not permit evaluation of metastasis- free survival except in a limited number of external beamFor radiotherapy studies. Reference15-year survival Onlyresults The 15-year overall survival data would appear 10-year survival results uncertain following prostatectomy and surveillance, as indicated by the variable results shown in Table Considerably fewer papers reported 10-year sur- 3, with wide ranges between high-end and low-end vival than reported 5-year survival. In most of the (maximum and minimum) percentages. These data, papers reporting 10-year actuarial overall survival, however, are from a limited number of studies, and as Table 3 makes clear, the range of outcomes was quite similar across modalities (radical prostatec- the four reported series under surveillance actually tomy, external beam radiotherapy and surveillance). represent only two studies. Three of the four “se- The few modest differences may be explained by ries” are from stratified cohorts of patients within a the effect of age differences. single study (Number 9351, Appendix A, Table A- 1). Stratification was based on substages of stage For progression-free survival, the 10-year actuar- T2 (B) prostate cancer. The 67 percent shown as a ial results appear excellent following radical prosta- maximum percentage for surveillance represents tectomy, but only one series had extractable data. just the substage B1 data. For external beam radio- Six series reported “actual” data for radical prosta- therapy, the relatively low overall survival results at tectomy. The results shown are variable (31.3 to 69 percent), the wide range reflecting the uncertainty 15 years represent data from two separate, large ac- of the data. Similar uncertainty is noted for the 10 tuarial studies. series reporting actuarial data for 10-year progres- Both actuarial and “actual” disease-specific sur- sion-free survival after external beam radiotherapy vival data from reports of men receiving prostatec- (40 to 64 percent). The seven series reporting 10- tomy indicate a high likelihood of disease-specific year progression-free survival in men receiving survival for as long as 15 years following surgery brachytherapy had the greatest variability (50 to 90 (55 to 93 percent actuarial, 63 to 90 percent “actu- percent). For men whose cancers were managed by al”).

Copyright © 1995 American Urological Association, Inc. Page 33 5-year progression results The 5-year total progression rates after external beam radiotherapy are variable as well, reflecting For local progression (or disease recurrence or both varying definitions of progression and selected treatment failure), the problem of inconsistent defi- reporting of cohort outcomes. For brachytherapy, nitions invalidates most comparisons of outcome progression data reveal similar variability. Differing data between treatment options. In the case of pros- definitions of progression, technical variability and tatectomy, surprisingly few studies provide local selection bias are the main reasons. progression outcome data that can be meaningfully For surveillance, it can be assumed that all un- extracted. The 5-year local progression rate follow- treated prostate malignancies will grow, although ing prostatectomy, as shown in Table 4, page 26, often slowly. Therefore, progression rates on a bio- ranges widely from a low of 1.8 percent (“actual”) chemical or histologic basis are 100 percent in pa- to a high of 11.3 percent (actuarial). The progres- tients under surveillance. However, clinically im- sion usually includes any palpable or biopsy-proven portant local progression during surveillance is sub- tumor in the prostatic bed or vesicourethral anasto- jectively reported among investigators. For mosis. instance, one study published a 5-year local pro- Distant or metastatic recurrence at 5 years fol- gression rate of 65 percent (95/146) for surveillance lowing prostatectomy is uncommon (1.2 to 4.0 per- (Number 8990, Table A-1). Progression was defined cent). For total 5-year clinical recurrence following as palpable local growth of tumor, and the data prostatectomy, the rate ranges from 3 to 12 percent were corrected to reflect cumulative probability at 5 (“actual”). For total progression, the panel excluded years. By comparison, another study reported a 24 a subset in one of the studies (Number 9175, Table percent local progression rate, but defined local A-1). This subset consists of stage T2 (B) prostate progression as “a change in local tumor category” cancer patients separated by deoxyribonucleic acid (Number 9351, Table A-1). Distant progression (DNA) ploidy pattern. The small population of 10 rates for all studies are less subjective, as reflected patients (4 percent) with aneuploid tumors experi- by more consistent outcomes reporting in Table 4. encedArchived 40 percent metastatic recurrence at 5 years. Document— For biochemical progression, local or otherwise, 10-year progression results the panel at the time of the literature review could find only one study with extractable data regarding The same problems of variability in definitions PSA recurrence (Number 10790, Table A-1). This of progression, selection bias and inaccuracy in 5- study wasFor in the external beamReference radiotherapy litera- year progression data are Onlyproblems in data for long- ture. The biochemical failure rate in the study was er follow-up. Nevertheless, it is apparent from indi- defined as “increasing PSA after treatment.” Other vidual reports that the incidence of disease progression/treatment failure, local or distant, does rise definitions have been proposed, and certainly more with time. The extracted 10-year clinical failure da- data are needed to substantiate this definition. ta reflect rates that are nearly double 5-year rates For 5-year local progression following external for both radical prostatectomy and external beam beam radiotherapy, the actuarial rates in Table 4 radiotherapy. range from 0 to 29 percent. The true rate is obvi- However, no inference can be made from the 10- ously uncertain, which again may be due in part to year total progression/failure rates shown in Table variable definitions of this outcome: symptomatic 4. These results range too widely, reflecting highly disease, palpable growth, prostate biopsy, etc. variable and uncertain data as well as differing pa- The distant progression rate at 5 years following tient populations. external beam radiotherapy is also variable and uncertain. An actuarial rate of 3.8 percent reported in one study represents a group of 26 men with clini- 15-year progression results cal stage B1 and B2 disease followed both by radia- Too few studies of 15-year outcomes are avail- tion oncologists and by urologists in three different able to reasonably estimate failure rates. The data hospitals (Number 6364, Table A-1). The follow-up present in these few studies, however, indicate a studies did not specify routine bone scans or serum stabilization of local and distant progression rates acid phosphatase to assess distant progression. after 10 years for men treated with either radical Also, the period of follow-up ranged from 6 months prostatectomy or external beam radiotherapy. The to 8 years (median 32 months), and the authors did rates continue to rise as expected for patients man- not report the number of men with stage B disease aged by surveillance. A relatively high distant fail- who were followed for at least 5 years. ure rate is reported in three series of men treated

Page 34 Copyright © 1995 American Urological Association, Inc. with brachytherapy. The three series are from the improvements in modern surgical and radiological same report (Number 9879, Table A-1) and repre- techniques. sent substages of stage T2 (B) prostate cancer. Pro- Some of the complications in Table 5 apply to all gression/failure of 64 percent was found in men three treatment modalities, but not necessarily to with substage B3 prostate malignancy. It is obvious the same extent. Stress incontinence, for example, that the 15-year progression data are sparse, vari- is reported by 19 series as a complication of radical able and uncertain. prostatectomy, but by only two series as a complication of external beam radiotherapy. To a considerable degree, each form of therapy has its own spec- Treatment complications trum of complications. In an obvious example, wound infection is a potential complication of pros- summary outcomes table tatectomy, but is reported by zero series under the and graphs noninvasive external beam radiotherapy. For proctitis, a potential complication of radiotherapy, Table 5 shows a zero under prostatectomy. The panel was The variability in the prostate cancer treatment unable to determine that any one therapy has a literature in reporting factors such as grade, stage more significant cumulative risk of complications. and age of the patient—which has a confounding effect on reported data for survival and progres- In the case of complications from external beam sion—has a similar confounding effect on reported radiotherapy, the data shown in Table 5 may over- data for complications from surgery or radiation state the frequency of some complications follow- treatment. The panel chose therefore to display re- ing this treatment, such as proctitis and other rectal sults of the extracted data on treatment complica- toxicity. The reason is that, in abstracting the com- tions in the same manner as for the survival and plications data for external beam radiotherapy, the progression data. panel found very little information specific to stage T2 (B) disease. The panel faced a choice: either in- The complications summary outcomes table clude only series that purely address T2 patients, in Archived(Table 5) on page 27 lists the 25 most commonly Document— reported complications. Under each treatment mod- which case there would essentially be no data, or ality to which a particular complication applies, include radiotherapy series that describe complica- Table 5 displays the number of series reporting the tions in all stages of disease. The panel chose to in- complication and the lowest and highest reported clude all radiotherapy series that describe toxicity For Referencein order to provide at leastOnly rough indications of risk frequencies of occurrence (minimum/maximum percentages). The table does not show mean or me- from therapy. dian estimates of frequency. However, toxicity from radiotherapy is much Graphical displays visually represent the report- more likely in advanced stages of disease, because ed frequency rates for the most important complica- patients reported with stages T3-T4 (C) or M1 (D2) tions (Figures 14 - 16, page 31). Each circle on a tumors are much more likely to have received ra- graph represents one series reporting the complica- diotherapy to regional lymph nodes. Radiation to tion. As in the graphs representing survival out- the entire pelvis and in some cases the para-aortic comes, these graphs are a useful supplement to region is often administered in those with higher- Table 5 in that they show how the reporting series stage disease. Moreover, these patients are often are distributed along the range between the mini- treated with significantly greater doses of radiation mum and maximum percentages. Again, however, it to significantly larger amounts of normal tissue, must be noted that the graphs show neither the size which markedly increases toxicity (Green, Gold- of each series nor the confidence interval for the in- berg, Goldman, et al., 1984; Lawton, Won, Pile- dicated percentage. pich, et al., 1991; Mameghan, Fisher, Mameghan, It should also be noted that the data displayed in et al., 1990; Pilepich, Krall, Sause, et al., 1987; Table 5 and Figures 14– 16, in addition to being Smit, Helle, van Putten, et al., 1990). subject to problems of variability mentioned previ- If the panel had been able to include only the ously, may be subject to publication bias. The pos- complications data for external beam treatment of sibility exists that those centers publishing their re- stage T2 disease, the frequency rates would very sults are mainly centers having low complication likely have been less than what Table 5 shows. rates. The data could also be biased in the other di- Patients clinically judged as having T2 disease (as a rection because many of the series may not be re- group) will generally receive a lower dose of radia- cent enough for reported complications to reflect tion to a smaller volume of tissue.

Copyright © 1995 American Urological Association, Inc. Page 35 Table 5 shows that both obstruction and inconti- Analysis of treatment nence may be more common following surgery. complications summary Cystitis, which most often results in the symptom of urinary frequency, is a potential complication of outcomes table radiotherapy. Radiotherapy is also more likely than surgery to cause bowel/rectal injury. Diarrhea asso- Of the complications listed in Table 5 for treat- ciated with radiotherapy is usually transient. ments of stage T2 prostate cancer, the panel consid- With regard to the important complication of im- ered the most important to be perioperative death, potence (erectile dysfunction) following active major bleeding, pulmonary embolism, inconti- treatment for prostate cancer, the reports are diffi- nence, impotence (erectile dysfunction), rectal in- cult to interpret because of patient selection. This is jury, cystitis, proctitis, bladder neck contracture and an instance in which a patient-related factor, age, urethral stricture. Most often reported are rates of may affect the complications data. The youngest death, incontinence, rectal injury and impotence. (and presumably most potent) patients tend to un- Some surgical series also comment on adverse post- dergo surgery. The oldest patients tend to receive operative events such as bleeding and pulmonary radiotherapy. Few reports have carefully compared embolism. pretreatment and posttreatment potency. For treat- A structured review of the literature (Wasson, ment of erectile dysfunction, patients report favor- Cushman, Bruskewitz, et al., 1993) found reported ably on treatment with pharmacologic erection ther- complication rates within the ranges reported in apy, penile implantation or vacuum devices (Fowl- Table 5. Also, patient attitudes about the impor- er, Barry, Lu-Yao, et al., 1993). tance of such adverse events are now under active With regard to perioperative mortality, death investigation. One study used standardized data col- from treatment is relatively rare following external lection instruments to examine patient attitudes re- beam radiotherapy. Death following surgery, al- garding complications following radical prostatec- though shown to increase with age, is generally less tomy (Fowler, Barry, Lu-Yao, et al., 1993). Reports than 1 percent in men under age 75 (Lu-Yao, byArchived these patients indicated higher rates of stricture Document—McLerran, Wasson, et al., 1993). and incontinence than in most reported series. Signiﬁcant bleeding may be expected to occur Moreover, complete incontinence, bladder neck following radical prostatectomy with a frequency contracture and stricture formation may result from between 1.0 and 11.5 percent. The perineal ap- additionalFor interventions to Referenceameliorate the original proach may have the lowest Only incidence of this com- problem. Patient interviews in the Fowler study in- plication. Finally, pulmonary embolism and sepsis dicate that treatment of these urinary complications, are risks of any operative intervention. Medicare with associated symptoms such as frequent urina- data suggest that the incidence of cardiopulmonary tion, wetness and difficulty in voiding, is often not complications following radical prostatectomy in- very successful. (Age was not related to postsurgi- creases to more than 7 percent in men over age 75 cal incontinence in this study.) (Lu-Yao, McLerran, Wasson, et al., 1993).

The AUA Prostate Cancer Clinical Guidelines prostate). For this report, the panel focused on clin- Panel generated its practice policy recommenda- ical stage T2 (B) disease. Based on the opinion of tions based on the outcome estimates available and the panel, recommendations may also be applied to on panel opinion. As explained in Chapter 1, the patients diagnosed with stage cT1c disease (detect- recommendations were graded according to three ed by elevated PSA). The recommendations were levels of flexibility based on strength of evidence not developed for patients with stage T1a/b and the panel’s assessment of patient needs and (A1/A2) or clinical T3-T4 (C) disease. For a de- preferences. The definitions of these three levels are tailed discussion of prostate cancer staging, see repeated below from Chapter 1: pages 13-15. • Standard: A policy is considered a standard if the health and economic outcomes of the alternative interventions are sufficiently well- known to permit meaningful decisions and Recommendations: Standards there is virtual unanimity about which intervention is preferred. As a standard, an assessment of the patient’s life • Guideline: A policy is considered a guideline expectancy, overall health status and tumor charac- if the health and economic outcomes of the in- teristics is necessary before any treatment decisions terventions are sufficiently well-known to per- can be made. mit meaningful decisions and an appreciable Archived Document—Life expectancy: Life expectancy, rather than pa- but not unanimous majority agree on which intervention is preferred. tient age, should be the factor considered in treatment selection. Therefore, the panel did not set a • Option: A policy is considered an option if specific chronological cutoff point. When a man’s (1) the health and economic outcomes of the life expectancy is relatively long, prostate cancer interventionsFor are notReference sufficiently well-known Only can be a cause of morbidity and mortality. On the to permit meaningful decisions, (2) prefer- other hand, at an advanced patient age, or when life ences among the outcomes are not known, (3) expectancy is relatively short, competing hazards patients’ preferences are divided among alternative interventions and/or (4) patients are infor mortality reduce the chance that a man will suf- different about the alternative interventions. fer from disease progression or die from prostate cancer. (See U.S. Life Expectancy Table in Appen- Obviously, a standard has the least flexibility. A dix C.) guideline has significantly more flexibility, and an option is the most flexible. As noted in the defini- Health status: The patient’s overall health status tions, options can exist because of insufficient evi- is the sum of all conditions and includes both pa- dence or because patient preferences are divided or tient and family history as well as the present state unknown. In the following panel recommendations, of the patient’s well-being and the degree of any those regarding treatment choices were labeled op- coexistent disease. There are two reasons to evalu- tions mostly because of insufficient evidence. None ate the overall health status prior to deciding on an of the following panel recommendations fits the intervention: (1) Overall health status influences above definition of a guideline. life expectancy; (2) overall health status may affect patient response to adverse events resulting from particular interventions. Tumor characteristics: The histologic grade and The standard patient stage of the tumor should be considered when assessing the potential natural history and treatment The panel’s recommendations apply to the stan- options for prostate cancer. Small, well-differentiat- dard patient, defined as a man who has clinically ed cancers progress more slowly and are less likely localized prostate cancer (adenocarcinoma of the to be life threatening than large, poorly differentiat-

Copyright © 1995 American Urological Association, Inc. Page 37 ed tumors which have a greater potential to be biologically aggressive and clinically significant. Advantages and disadvantages As a standard, a patient with clinically localized of treatment options prostate cancer should be informed about the commonly accepted initial interventions including, at a minimum, radical prostatectomy, radiotherapy and surveillance. A discussion of the estimates for bene- Radical prostatectomy fits and harms of each intervention should be of- The major advantage of radical (total) prostatec- fered to the patient. tomy is its potential for “cure” by removing all of The panel defines radical prostatectomy to in- the tumor. “Cure” is defined as lifetime freedom clude complete removal of the prostate, vasal from disease. Total prostatectomy in the properly ampullae and seminal vesicles. The panel defines selected patient will provide disease-free survival radiotherapy to include external beam and/or inter- rates comparable to the expected survival in simi- stitial (brachytherapy) treatments. Surveillance is larly aged men for up to 30 years of observation defined as periodic monitoring of the patient’s pros- (Gibbons, Correa, Brannen, et al., 1989). tate cancer and its effects. The major disadvantage is potential morbidity. The patient should be informed that depending Possible operative morbidity includes the follow- on his condition and initial choice, subsequent in- ing: bleeding, which can require a transfusion; dif- terventions may be appropriate. ficulty with anastomosis of the bladder neck to ure- As a standard, the patient’s preference, based on thra; and rectal injury. These problems will vary his attitude toward the course of the disease and the with the size and anatomy of the patient’s pelvic or- benefits and harms of the different interventions, gans and the experience of the surgeon. Postoperat- should be considered in determining his treatment. ive morbidity includes problems with indwelling catheters, lymphocele, anastomotic stricture, urinary incontinence and impotence (erectile dysfunc- ArchivedRecommendations: Document—tion). Treatment options With regard to impotence, some authors have reported postoperative potency rates in the 70-percent range in patients who were potent preoperatively Options for management of localized prostate (Catalona and Bigg, 1990). If impotence occurs cancer includeFor radical prostatectomy, Reference radiotherapy after surgery (or radiotherapy Only or hormone therapy), and surveillance. Radiotherapy includes external what is lost is erectile function. The sensation of beam and interstitial (brachytherapy) treatments. orgasm may remain intact. In these patients, phar- The panel considers these interventions to be op- macologically induced erections (using self-admin- tions because data from the literature do not pro- istered penile injections) or use of vacuum constric- vide clear-cut evidence for the superiority of any tion devices or penile prostheses can provide effect- one treatment. Described for each option is the pa- ive treatment (Lue, Carroll and Moore, 1989). tient most likely to benefit from the intervention. A number of articles have reported stress urinary Radical prostatectomy: Based on the panel’s incontinence and/or severe urinary incontinence (re- interpretation of the literature and panel opinion, quiring intervention) following radical prostatec- the patient most likely to benefit from radical pros- tomy. The complications summary outcomes table tatectomy would have a relatively long life ex- (Table 5) on page 27 shows a reported low of 4 per- pectancy, no significant surgical risk factors and a cent and a high of 50 percent for stress inconti- preference to undergo surgery. nence and a range from 0 percent to 15.4 percent Radiotherapy: Based on the panel’s interpreta- for severe incontinence. The complications graph tion of the literature and panel opinion, the patient for prostatectomy (Figure 14, page 31) shows how most likely to benefit from radiotherapy would have the reporting series are distributed along these low- a relatively long life expectancy, no significant risk high ranges. factors for radiation toxicity and a preference for For mortality following radical prostatectomy, radiotherapy. Table 5 shows a range from 0 percent to 2.1 per- Surveillance: Based on the panel’s interpretation cent. More than half the series reported 0 percent. of the literature and panel opinion, patients most However, the risk of death from radical prostatec- likely to benefit from surveillance are those with a tomy increases with patient age and was found to shorter life expectancy and/or a low-grade tumor. be 1.4 percent in men aged 75 to 80 and 4.6 percent

Page 38 Copyright © 1995 American Urological Association, Inc. for age 80 and older (Lu-Yao, McLerran, Wasson, the true incidence of cancer remaining in the pros- et al., 1993). tate gland. Biopsies of the radiated gland have re- Pulmonary embolism, in the panel’s review of vealed persistent malignancy in at least 30 percent the literature, occurred in 0.8 percent to 7.7 percent of patients (Kabalin, Hodge, McNeal, et al., 1989; of patients after radical prostatectomy. In a report Kaplan, Prestidge, Bagshaw, et al., 1992; Kiesling, of Medicare patients (Lu-Yao, McLerran, Wasson, McAninch, Goebel, et al., 1980). Recently, TRUS- et al., 1993), investigators found cardiopulmonary guided biopsy series in selected patients suggest complications in 4 percent of men 65 to 69 years of that the true incidence of residual cancer may be age and in 7.4 percent of men 75 to 79 years of much higher than previously reported. age. Other potential complications, such as anasto- Regarding toxicity, external beam radiotherapy, motic stricture, fistula and bowel injuries, occur in- as employed in state-of-the-art radiotherapy centers, frequently. has the advantage of having become a very well- Recent developments in the technique of radical tolerated treatment. Improvements include higher- prostatectomy may have reduced the risks of com- energy radiation beams that can be more precisely plications. Refinements in the understanding of the focused, thus sparing larger amounts of normal tis- surgical anatomy of the prostate have made possi- sue from therapy; improved computer technology ble a more meticulous operation, improved opera- that calculates with greater precision the absorbed tive visualization, reduction in blood loss and im- dose of radiation and helps optimize treatment proved sexual function and urinary continence rates planning; and more sophisticated planning proce- postoperatively. dures that precisely localize both the tumor volume Length of hospitalization has also been signifi- and normal tissues, allowing maximal sparing of cantly reduced in many patients to 3 – 6 days, but normal tissues and ensuring adequate delivery of the total cost for radical prostatectomy has not been dose to the tumor. well described and remains a “moving target” However, there remain many potential complica- (Koch, Smith, Hodge, et al., 1994). tions. The actual incidence of erectile dysfunction Archived Document—for patients receiving radiotherapy (as in series of patients receiving other forms of therapy) may be Radiotherapy underreported. Diarrhea is a potential problem for The advantage of radiotherapy (external beam those patients who receive radiation to regional radiotherapy and brachytherapy) is that it not only lymphatics. Other potential significant complica- has aFor potential for cure, Reference but is well tolerated in the tions include rectal toxicityOnly (proctitis, rectal ulcera- majority of men when modern techniques are used. tion, need for colostomy) as well as bladder com- Its principal potential harms include radiation cysti- plications (hematuria, cystitis, dysfunctional void- tis, proctitis, and erectile dysfunction. Also, because ing). the prostate remains in place, persistence and progression of the disease may occur. Brachytherapy Mature data are only available for the older External beam radiotherapy retropubic brachytherapy techniques. Although External beam radiotherapy can be an effective problems have been reported in these mature brach- treatment in the appropriate standard patient afflict- ytherapy series (page 18), several groups have doc- ed with stage T2 prostate cancer. Notwithstanding umented reasonably satisfactory survival results. caveats regarding survival and disease progression The 5-year survival data are not yet available for data (pages 32-33, 33-34), the results reported in the newer ultrasound-guided transperineal tech- the literature for external beam radiotherapy appear niques. However, as the outcomes analysis on pages reasonably favorable. Although some selected se- 32-33 indicates, the 5-year survival results would ries have reported extremely high PSA failures be expected to be quite good. In general, even (noted in Hanks, 1994), others have demonstrated though sufficiently mature data are not yet available extremely favorable PSA control with long-term to establish superiority of the newer techniques, the follow-up (Hanks, 1994; Hanks, Perez, Kozar, et panel knows of no evidence that the results from al., 1993; Pisansky, Cha, Earle, et al., 1993). these techniques are inferior to results from the old- However, an accurate characterization of the true er techniques. incidence of PSA failure in an unbiased cohort is One clear advantage of the current brachytherapy urgently needed. There is also evidence that clinical methods is patient convenience. Several series of lack of local tumor progression may underestimate TRUS-guided transperineal techniques report that

Copyright © 1995 American Urological Association, Inc. Page 39 the procedures are usually performed with hospital er uropathy have a much greater risk of developing stays of 2 days or less. When permanent radionu- subsequent urinary complications. clides are implanted, there is usually only a moderate amount of postimplantation discomfort, controlled in the overwhelming majority of patients by Surveillance oral pain medications. One advantage of surveillance therapy as a treat- Disadvantages of brachytherapy can include in- ment option for localized carcinoma of the prostate ferior control of localized tumors. Similar to all is its low initial cost. Because most patients can be prostate cancer treatment modalities, brachytherapy followed with DRE and PSA alone, if disease pro- produces markedly improved local control in low- gression does not develop during the patient’s life- stage and low- to moderate-grade disease (Carey, time, the cost of such follow-up may be very low. Lippert, Constable, et al., 1988; Fuks, Leibel, Wall- This advantage is dependent upon the assumption ner, et al., 1991; Giles and Brady, 1986; Kuban, El- that most patients will not develop symptomatic or Mahdi and Schellhammer, 1989a; Morton and Pes- metastatic disease during their lifetimes. If this as- chel, 1988; Smalley and Noble, 1992). sumption is incorrect, the cost advantage may dis- appear as it has been estimated that the cost of Additionally, the importance of long-term fol- treatment for one new case of metastatic prostate low-up cannot be overemphasized. Several series cancer is $70,000 (Littrup, Goodman and Mettlin, have reported that the mean time to local failure in 1993). brachytherapy-treated patients is in the range of 5 to 10 years (Fuks, Leibel, Wallner, et al., 1991; Another major advantage of surveillance for lo- Kuban, El-Mahdi and Schellhammer, 1989a; Small- calized prostate cancer is its avoidance of morbidity ey and Noble, 1992). The exceedingly long time to associated with treatment. Most patients with newly local recurrence seen in series that have adequate diagnosed prostate cancer, because of the current follow-up emphasizes both the indolent natural his- policy of early detection and treatment, have no tory of the disease and the tentative nature of any cancer-related symptoms at diagnosis. Surveillance conclusion reached in studies without follow-up of would allow these men to preserve their quality of Archived Document—life. Conversely, radiotherapy and radical prostatec- 10 to 15 years. tomy are associated with potential complications The ability of brachytherapy to control local dis- including erectile dysfunction, incontinence and in- ease must, therefore, be evaluated on the basis of jury to various organs from treatment (Fleming, series that have sufficient follow-up. Four different Wasson, Albertsen, et al., 1993). reports haveFor compared local Reference tumor control with Only Finally, survival outcomes for at least 10 years brachytherapy versus control with alternative thera- are generally good. As summarized on page 19, pies. Three reported that brachytherapy produced available data suggest that the risk of metastatic inferior local tumor control when compared with disease and prostate cancer death in patients man- either external beam radiotherapy or radical prosta- aged with surveillance alone is not substantially tectomy (Kuban, El-Mahdi and Schellhammer, different from the risk in patients treated for “cure.” 1989a; Morton and Peschel, 1988; Schellhammer, A recent pooled analysis of six series of patients so Whitmore, Kuban, et al., 1989; Smalley and Noble, treated found excellent 10-year disease-speciﬁc sur- 1992). However, differences in other factors such as vivals for patients with well-differentiated and patient selection, rather than the treatment itself, moderately well-differentiated tumors (Chodak, may explain the differences in outcomes. Thisted, Gerber, et al., 1994). On the other hand, With regard to complications, those reported in one study reported that the majority of patients on present brachytherapy series are remarkably hetero- surveillance who survive more than 10 years ulti- geneous. They include impotence (erectile dysfunc- mately die of prostate cancer (Aus, Hugosson and tion), with no convincing evidence of less risk than Norlén, 1994). with external beam radiotherapy (Smalley and Among the disadvantages of surveillance is the Noble, 1992). For the newer, TRUS-guided trans- risk of subsequent, possibly incurable disease. In perineal techniques, rates for the complications re- virtually every series of patients managed by sur- ported to date vary widely (Blasko, Ragde and veillance, some percentage of patients was reported Grimm, 1991; Iversen, Bak, Juul, et al., 1989). to have died of the disease and an additional group In some stage T2 patients, higher complications was reported to have suffered from disease-related have been reported for brachytherapy as compared morbidity. In a pooled analysis, at 10 years of fol- with external beam radiotherapy. Also, patients with low-up, 6 percent, 6.5 percent and 42 percent of a previous transurethral resection or signiﬁcant oth- patients with well-differentiated, moderately well-

Page 40 Copyright © 1995 American Urological Association, Inc. differentiated and poorly differentiated tumors, re- for various complications related to progression of spectively, died of their disease (Chodak, Thisted, the tumor. Gerber, et al., 1994). Another study reported on 61 As pointed out on page 20, patients who elect to patients with stages T1-T2 disease managed by sur- pursue a policy of surveillance are free to choose a veillance. Of 8 who died during the period of ob- “curative” intervention at any time during follow- servation, 4 died of prostate cancer (Adolfsson and up. However, if the goal for subsequent intervention Carstensen, 1991). is to time its application prior to the development of Then there is the risk of developing disease-re- extraprostatic disease, evidence indicates that the lated morbidity. The premise of “curative” treat- window of opportunity is very narrow. Data from ment of carcinoma of the prostate is that it will pre- one report suggest that if serum PSA is measured vent not only cancer-related death, but those com- during surveillance, once the value exceeds 5 ng/ml plications related to the tumor that reduce the the risk exceeds 50 percent that the disease is ex- patient’s quality of life. Patients managed with sur- traprostatic (Thompson, Zeidman, Crawford, et al., veillance may be at a higher risk for such cancer-re- 1993). lated morbidities. Among these complications, Additional treatment may be needed. In virtually spinal cord compression is a major concern. This every series of patients treated with surveillance for event can occur in as many as 12 percent of pa- localized prostate cancer, the term “surveillance” tients with metastatic disease and can lead to death included a variety of additional forms of treatment. as well as severe reductions in the patient’s quality Examples include a series of 122 patients (Adolfs- of life (Rubin, Lome and Presman, 1974). Whether son, Carstensen and Lowhagen, 1992). Of these, 45 intervention at the time of diagnosis might prevent percent received endocrine therapy (36 patients), such an outcome could not be predicted. external beam irradiation (12 patients), 125I implan- Other disease-related complications include pain, tation (3 patients) or radical prostatectomy (4 pa- obstructive voiding symptoms, bone fracture ane- tients). In another series, treatment for local pro- mia, ureteral obstruction, uremia, deep venous gression was required for 23 of 120 patients thrombosis and pulmonary embolism. In one paper, (George, 1988). Archived26 of 223 patients followed on a program of sur-Document—It can be seen then that patients followed with veillance developed metastases (Johansson, Adami, surveillance may be at risk for deferring treatment Andersson, et al., 1992). Of these 26 patients, 23 to a later age and, by doing so, either deferring the had a reduction in performance status. Of 19 pa- side effects of treatment or, alternatively, losing the tientsFor who died of prostate Reference cancer, their perfor- opportunity of disease Onlycontrol as well as undergo- mance status decreased for more than 6 months in ing invasive therapy at an age when comorbidities 12, and 13 patients required hospital care for 1 increase. month or more prior to death. Fourteen patients in A major unmeasured disadvantage to a policy of this series required hospital care for local problems surveillance is the patient’s possible anxiety, his due to their tumors. Of 152 patients who did not feeling that “nothing is being done about my pros- develop disease progression, 30 had mild or moder- tate cancer.” Although the patient may intellectually ate local problems and 14 required transurethral re- understand the often confusing data supporting the section of the prostate. Of 71 patients who did de- validity of surveillance therapy, considerable anxi- velop local progression, 60 had local problems ety can be generated in many patients and their (which generally disappeared after treatment with families by a lack of intervention. The psychologic hormone therapy). Twenty-eight of these 71 had re- consequences of cancer risk or diagnosis awareness current local problems during the course of their are well recognized, and clinicians practicing in this disease. ﬁeld are well aware of the overpowering dread that In summary, using surveillance as the primary can be induced by worry about prostate cancer management of patients with locally conﬁned pros- (Lerman, Miller, Scarborough, et al., 1991; Lerman, tate cancer may place a number of patients at risk Rimer and Engstrom, 1991).

case series and lack of randomized controlled trials. Limitations in the prostate These limitations include the large gaps that exist in cancer treatment literature the literature regarding data reported. For example, many articles do not report all outcomes (such as cancer-specific survival, metastasis-free survival The explicit methodology the AUA Prostate and tumor-free survival). There are also few data on Cancer Clinical Guidelines Panel used in its analy- high-grade tumors in patients managed by surveil- sis for this Report on the Management of Clinically lance, or on pelvic lymph node status in patients Localized Prostate Cancer required careful review managed by external beam radiotherapy as well as and interpretation of published reports in the peer- surveillance. In another very important example, reviewed literature. As discussed in Chapter 1, many articles do not specify ages of patients not- many articles were reviewed and most were reject- withstanding the effect of age on survival and the ed for a variety of reasons, including inaccurate re- significant differences in average patient age for porting of data, limited time of follow-up, incom- different treatment modalities. In still another ex- plete description of treatments utilized and poorly ample, many articles reporting complications from defined patient populations. Moreover, the studies treatment do not report “zero complications.” For finally selected for data extraction were not by any instance, an article may not refer to incontinence in means free of deficiencies. its list of treatment-related complications. Readers Archived Document—are left to wonder whether the complication did not Data not based on randomized occur or if it was omitted from the report. controlled trials Data variability All theFor studies finally selectedReference by the panel pro- Only vided useful information, but most were case series Data variability is one of the most frequent limi- not subjected to the rigors of a carefully performed, tations encountered when attempting to combine prospective, centrally controlled clinical trial. Many evidence from multiple studies. This variability of the patient populations were “convenience sam- takes many forms with many causes. Variations be- ples” selected mainly because they were available tween studies because of differences in staging in the clinical settings in which the research was methods are one example. Some articles reviewed conducted. by the panel reported outcomes according to clini- The lack of randomized, controlled trials is a cal stage, others according to surgical stage. Out- problem inherent in the medical literature. comes data from these two classes of articles are Although it can be addressed and responded to, it not comparable. cannot be avoided. Neither can it be dismissed. The Lymph node dissections performed for staging difficulties this problem creates for developing evi- vary between studies. Lymphadenectomy is typical- dence-based practice policy recommendations are ly performed, but the panel could not substantiate especially severe with regard to localized prostate that all procedures reported in the literature were cancer. Because of the particular attributes of this comparable. Both extensive and limited dissections disease, such as high histologic prevalence, yet were carried out by different surgeons. In addition, variable natural history, treatment outcomes data although laparoscopic dissections are becoming from uncontrolled trials can be even less reliable more commonplace, they were not included in the than usual. articles selected. Imaging studies are frequently utilized and are limited not only by the state-of-the-art technology, Insufficient data but by the abilities of radiologists and urologists to Many of the limitations in the literature stem di- interpret a particular study. Laboratories vary as rectly from the previously mentioned plethora of well. Similar studies performed in different facilities,

Page 42 Copyright © 1995 American Urological Association, Inc. using different assays, could yield very different re- sentative. Moreover, studies with negative or equiv- sults. Urologists and radiologists also differ. It can- ocal results are less likely to be submitted for publi- not be assumed that a radiation technique or surgical cation and less likely to be published if submitted. procedure performed by one clinician is comparable to that performed by another. Data limitations in reflecting As laboratories and imaging studies vary, so do pathology reports. Controlled trials often utilize a current techniques central pathology facility, but comparing case series The data available do not always reflect the means comparing varied facilities. Differences exist many changes in treatment modalities that have oc- in preparation of histologic material, especially curred over the past two decades. For instance, ear- with the current emphasis on whole mount prostate ly brachytherapy experience utilizing retropubic preparations. Yet, interpretations of extent of in- implantation techniques with 131I and 198Au had volvement and margin status are highly dependent high failure rates. Newer methods, utilizing differ- on tissue preparation and subsequent pathologic in- ent isotopes (such as iridium) implanted perineally terpretation, which makes comparisions between under ultrasound guidance, are being used with in- studies problematic. Similar variations exist in the creasing frequency, but too few data are currently abilities of pathologists to grade malignancies. Al- available to make efficacy comparisons. though standards have been established, the subjec- Similarly, nerve-sparing techniques are being in- tive component of these interpretations cannot be creasingly applied to radical prostatectomy. Yet, it ignored. must be assumed that this modification has not had Patient populations differ as do the methods by any impact on survival or progression. In addition, which patients are selected for review. For instance, the use of PSA to detect disease recurrence has al- some clinical reports include consecutive patients, tered the definition of treatment failure. Whether whereas many others are based upon informal se- concepts regarding success and failure will now lection factors such as availability for follow-up, re- change because of the availability of this relatively ferral patterns and logistic concerns. Controlled reliable marker is not known. Many questions re- Archivedstudies, because of strict inclusion and exclusion Document—main: Does PSA failure following radical prostatec- criteria, may be preferable but may not be general- tomy or radiotherapy always indicate treatment fail- izable because of the carefully selected patients en- ure? What numeric criteria should be used to estab- rolled. Means and ranges of follow-up often vary as lish PSA failure? What is its impact on survival? well. ForSuch variations willReference not only have an impact Finally, new forms ofOnly therapy continue to evolve. on outcomes, but will influence any conclusions de- Cryotherapy and other ablative techniques are being rived from the studies. developed, but too few data are available to appro- Because selection criteria between studies may priately assess success and failure in order to make differ, with variations in patient population, studies meaningful comparisons with other treatment performed and methods of follow-up, comparisons modalities. of studies may not be reliable. A common problem with prostate cancer case series, for example, is the reporting of endocrine therapy for patients developing recurrence after surgery or radiotherapy. The Recommendations for timing of administration, the form of therapy utilized and the method of reporting may not be clear- future research ly detailed, thus limiting the value of the report. Controlled prospective trials, by contrast, usually Most research needs can be grouped in three cat- specify from the outset the approach to be utilized. egories: (1) new and better methods to diagnose and manage localized prostate cancer; (2) prospec- Publication bias tive, randomized, controlled studies of the issues concerning prostate cancer, especially controlled Publication bias is a problem affecting the avail- studies of competing treatments for the manage- able data to which there may be no immediate solu- ment of localized prostate cancer; and (3) studies of tion. Very simply, because not all physicians pub- how prostate cancer and its treatments affect patient lish, case-study results may not be generally repre- quality of life.

Copyright © 1995 American Urological Association, Inc. Page 43 Needs for new assessment and Recommendations for randomized management methods controlled trials Needs for new methods of cancer diagnosis and It is clear, from the discussions in this report of monitoring include a more sensitive, more specific limitations in the prostate cancer treatment litera- tumor indicator. As clinically useful as serum PSA ture, that a pressing need exists for properly de- values have now become, PSA is not prostate-can- signed and controlled, prospective, randomized cer specific. As a result, it lacks sufficient sensitivi- clinical trials to study effectiveness of competing ty and specificity to be the ideal screening test for treatment modalities for localized disease. In partic- prostate cancer. In addition, although serum PSA ular, randomized, controlled trials are needed to concentration correlates strongly with tumor vol- compare surveillance with the accepted active treat- ume (r = 0.70), it cannot reliably predict tumor ments. stage on an individual basis. Moreover, PSA after Properly designed efficacy studies of treatment androgen deprivation therapy may not always be a modalities will provide reliable descriptive data for reliable indicator of the true tumor status because the patients studied. The descriptive factors should the cell’s ability to express PSA is under hormonal include age, tumor stage, tumor grade, ploidy, PSA, regulation, and androgen-insensitive cells do not performance status and comorbidity, as well as cost produce and secrete PSA to the same degree as an- factors and validated measures of quality of life drogen-sensitive cells. Patients with progressive over the course of a trial. End points measured in a disease after androgen deprivation therapy may in trial should include risk of local recurrence, risk of fact have a low or stable serum PSA concentration. disease progression (including objective measures Needed also are biochemical, radiographic of symptoms associated with progression), risk of and/or genetic methods to reliably determine which metastatic disease and risk of prostate cancer death. cancers are biologically aggressive and which are Following are additional suggested study topics clinically insignificant, so that focused treatment for each of the three major modalities: strategies can be developed such that treatment is • Radical prostatectomy: Methods of improv- initiatedArchived only in those patients with life-threatening Document—ing preoperative staging, reducing the number prostate tumors. of patients with extraprostatic disease and re- For detecting potentially life-threatening cancers ducing treatment complications; strategies to while still localized, it would be useful to have a reduce the cost of the procedure; better ways genetic Formarker that can identifyReference men likely to de- to disseminate advances Only in surgical techniques velop such a tumor in their lifetimes. These men to the urologic community; treatments for pa- could then be monitored with appropriate, compre- tients with pathologically proven (pT3) ex- hensive screening programs. Knowing who is at traprostatic disease; and treatments for patients risk for developing a clinically significant prostate with evidence of serologic (PSA) failure. cancer has tremendous potential not only to in- • Radiotherapy: Ways to reduce treatment crease the probability of detecting prostate cancer morbidity; ways to standardize treatment; the while still organ confined, but to markedly decrease role of conformal therapy and of radiosensitiz- the health care costs associated with unfocused ef- ers; strategies to reduce the cost of treatment; forts at prostate cancer detection. optimal treatment at progression; mature data on long-term follow-up of existing radiothera- Finally, with only 50 to 60 percent of newly di- py patients; stage-specific complications data agnosed prostate cancers currently organ confined, on existing series; and PSA and biopsy data. there is an overwhelming need for an effective systemic therapy for this disease. At the present time, • Surveillance: Optimal schedule of follow-up no curative treatment exists for advanced prostate and optimal interventions at evidence of pro- cancer. None of the currently available chemothera- gression. peutic agents is effective, and androgen deprivation Among the other topics and issues that need to therapy remains a palliative treatment for most pa- be addressed in rigorously designed clinical trials tients. New and creative approaches, such as gene are: therapy, need to be pursued both at the basic sci- • New technologies for the treatment of clini- ence level and in prospective clinical trials. cally localized prostate cancer.

Page 44 Copyright © 1995 American Urological Association, Inc. • Trade-offs between survival and quality of involvement in a meaningful and efficient decision- life—including analysis of methods by which making process and improved methods for provid- patients make treatment choices and the role ing unbiased information to patients and physicians played by quality-of-life factors in those about emerging processes and outcomes of care. choices. • Opportunities for chemoprevention of pros- Further research needs tate cancer and dietary interventions, hormonal therapy and retinoid therapy. With the increasing emphasis on efficient alloca- • New strategies for the use of hormonal treat- tion of health care resources, it will be necessary to ments. develop methods to assess the costs related to treatment of prostate cancer. These include the costs of • Combined therapies for prostate cancer. early detection, of treatment and of complications • Development and validation of surrogate from treatment. It would be useful as well to be measures of long-term prostate cancer out- able to assess the ﬁnancial impact of intervention comes (e.g., validation of PSA failure as a on productive longevity and the costs related to dis- surrogate for cancer survival). ability, long-term care and management of metastatic disease, and to compare these data with similar data regarding the ﬁnancial impact of the disease it- Patient quality of life self. Research is needed for determining how prostate It would also be helpful for future research to cancer and its treatments affect patient quality of have a prostate cancer registry established for all life. Such research would include the second topic prostate cancer cases in the United States. Informa- in the foregoing list: analysis of trade-offs between tion is now available from the Surveillance, Epi- survival and quality of life and how quality-of-life demiology and End Results Program registry, but factors affect patients’ treatment choices. Needed only for a limited number of locations around the Archivedalso are improved methods for enhancing patient Document—country. For Reference Only

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______*Includes articles cited in text. See Table A-1 in Appendix A for a complete listing of articles extracted for analysis.

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1126 1121- 1910 1901- 190 188- 314 312- 1433 1425- 316 308- 379 378- 728 723- 1042 1041- 453 450- 947 944- 91-96 608 604- 646 643- 418 407- 767 761- 1118 1113- 706 695- 374 372- 88-90 97-101 674 672- 406 403- 84-86 treated by radiation therapy resection on prognosis in carcinoma of prostate The adverse influence of prior transurethral prostate lymphadenectomy for high-stage cancer of the Radical retropubic prostatectomy and pelvic adenocarcinoma Extended total excision of prostatic radiotherapy for prostate adenocarcinoma Latent residual tumor following external localized carcinoma of the prostate Radiation therapy in the definitive treatment of Cryosurgery for carcinoma of prostate results and future considerations Telecobalt therapy for prostatic cancer: rationale, carcinoma of the prostate External beam radiation therapy of primary with radical prostatectomy Carcinoma of prostate: treatment and survival Carcinoma of the prostate: a 15-year followup prostate Radical retropubic prostatectomy for cancer of the prostate Total perineal prostatectomy for carcinoma of the overview Radical perineal prostatectomy: a 20-year pre- and postradiation therapy Carcinoma of the prostate. Evaluation biopsies prostate. A report on 15 years of experience Definitive radiation therapy of carcinoma the definitive treatment Prostate carcinoma: external irradiation as prostatic cancer Radical prostatectomy in the treatment of and perspective Radical prostatectomy for carcinoma: a review Indications and results Total perineal prostatectomy for carcinoma. conservative treatment Early prostatic cancer: long-term results with 1935 to 1958 the prostate: survival in 143 cases treated from Radical perineal prostatectomy for carcinoma of treated by total prostatectomy Twenty single nodules of prostate cancer not 15 years after radical excision The palpable nodule of prostatic cancer. Results the prostate Total retropubic prostatectomy for carcinoma of

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Document— Document— Archived McGowan, D.G. Myers, R.P., and Utz, D.C. Zincke, H., Fleming, T.R., Furlow, W.L., Spaulding, J.T., Whitmore, W.F., Jr. Stutzman, R.E., and Goebel, J.L. Nachtsheim, D.A., Jr., McAninch, J.W., Royce, R.K. Perez, C.A., Bauer, W., Garza, R., and W.W. Flocks, R.H., Culp, D.A., and Bonney, O'Donoghue, E.P.N, Milleman, L.A., H.K.A., and Scott, W.W. McLoughlin, M., Hazra, T., Schirmer, Jr. D.A., Castellino, R.A., and Meares, E.M., Bagshaw, M.A., Ray, G.R., Pistenma, Young, J.A., Bohne, A.W. Taylor, W.F., and Titus, J.L. Hanash, K.A., Utz, D.C., Cook, E.N., Hudson, H.C., Howland, R.L., Jr. Belt, E., Schroeder, F.H. F.E. Davis, W.H., Scardino, P.L., and Carlton, Vermund, H. Longley, J.R., Pearlman, C.K., and M.A. Ray, G.R., Cassady, J.R., and Bagshaw, Bagshaw, M.A., Ray, G.R. Culp, O.S., Meyer, J.J. Flint, L.D., Hsiao, J.H. R.J., and Howe, G.E. Feeney, M.J., Mullenix, R.B., Prentiss, H.L., and Dick, A.L. Barnes, R.W., Bergman, R.T., Hadley, R.R., and Eisenberg, H. Berlin, B.B., Cornwell, P.M., Connelly, Cook, G.B., Watson, F.R. and Shelley, W.M. Jewett, H.J., Bridge, R.W., Gray, G.F., Jr., E.F., Gallup, C.A., and Massey, B.D., Jr. Hendricks, E.D., Massey, B.D., Nation, Cross Cancer Institute (multi-site) Mayo Clinic and Foundation Memorial Sloan-Kettering Cancer Center site) Letterman Army Medical Center (multi- site) Mallinckrodt Institute of Radiology (multi- University of Iowa Hospitals and Clinics Hospital The Johns Hopkins University and Stanford University School of Medicine Henry Ford Hospital Medicine (multi-site) Mayo Clinic and the School of Carraway Methodist Hospital (multi-site) University of California Medical Center Savannah Urological Clinic Orange County Medical Center Stanford University School of Medicine Stanford University School of Medicine Mayo Clinic and Foundation Lahey Clinic Medicine (multi-site) University of California School Loma Linda University (multi-site) Hartford Hospital (multi-site) Cancer Research Center Ellis Fischel State Cancer Hospital and Hospital The Johns Hopkins University and Pasadena, California Page A-5 Page 4110 4106 4076 3914 3898 3868 3789 3649 3480 3401 3399 3195 3087 3050 3019 2894 2806 2783 2729 2720 Reference Papyrus Journal of Urology Journal of Urology Physics Radiation Oncology, Biology, International Journal of Medical Society The Journal of the Kansas Journal of Urology Physics Radiation Oncology, Biology, International Journal of Urology Physics Radiation Oncology, Biology, International Journal of Journal of Urology Cancer Cancer Physics Radiation Oncology, Biology, International Journal of Journal of Urology Cancer Urology Physics Radiation Oncology, Biology, International Journal of Urology America Urologic Clinics of North Journal of Urology Journal of Urology Journal 1982 1982 1982 1981 1981 1981 1981 1981 1980 1980 1980 1980 1979 1979 1979 1979 1981 1980 1981 1980 Year 128 128 8 82 126 7 17 7 124 45 45 6 121 43 14 5 17 7 125 124 Vol

509 505- 504 502- 1914 1909- 281 278- 371 366- 819 817- 7-11 890 885- 497 495- 1928 1922- 1911 1906- 1126 1121- 451 447- 1127 1123- 560 555- 1961 1957- 39-43 629 623- 369 365- 859 855- Pages with long-term followup irradiation prostatic biopsy and recurrence patterns Radiotherapy for prostatic carcinoma: post- adenocarcinoma of the prostate Radical surgery versus radiotherapy for irradiation for adenocarcinoma of the prostate Local control and survival after external lymphadenectomy interstitial irradiation and pelvic Prostatic carcinoma. Treatment with I125 tribulations and possible triumphs pelvic lymphadenectomy in 32 patients: trials, with 125iodine and simultaneous extraperitoneal Interstitial irradiation of carcinoma the prostate treatment of prostatic carcinoma Prophylactic pelvic girdle irradiation in the Research Group Veterans Administration Cooperative Urological prostatectomy for stages I and II prostate cancer. VACURG randomized trial of radical carcinoma Radical external radiotherapy for prostatic transurethral prostatic resection Radical retropubic prostatectomy after prostate the definitive management of carcinoma Combined interstitial and external radiotherapy in Radical surgery for prostatic cancer treated by radiation therapy resection on prognosis in carcinoma of prostate The adverse influence of prior transurethral prostatic cancer pelvic lymphadenectomy in the treatment of Complications of 125iodine implantation and Radiation therapy for localized prostate cancer localized carcinoma of prostate Radiation therapy as definitive treatment for report of a randomized study seed implant in prostatic cancer: a preliminary Preoperative extended field radiation with I-125 urologic cancer Lymphocele after pelvic lymphadenectomy for in prostatic cancer The therapeutic role of pelvic lymphadenectomy for adenocarcinoma Transcoccygeal 125iodine prostatic implantation carcinoma: Mayo clinic experience Definitive radiation therapy for prostatic Title

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Document— Document— Archived Snyder, R., and Forsythe, A. Leach, G.E., Cooper, J.F., Kagan, A.R., Research Group Stephani, S., and The Uro-Oncology Paulson, D.F., Lin, G.H., Hinshaw, W., Conceicao, A. Wilson, J.F., Greenberg, M., and Lopes da Rangala, N., Cox, J.D., Byhardt, R.W., E.K. Mebust, W.K., Weigel, J.W., and Reddy, Rao, R., and Leiter, E. Whitehead, E.D., Huh, S.H., Garcia, R.L., Hazra, T.A., Giri, S. Byar, D.P., Corle, D.K. G.N. Beiler, D.D., Wright, D.J., and Reddy, Bass, R.B., Jr., Barrett, D.M. Hudgins, P.T. Guerriero, W.G., Carlton, C.E., Jr., and Walsh, P.C., Jewett, H.J. McGowan, D.G. B.S., and Whitmore, W.F., Jr. Fowler, J.E., Jr., Barzell, W., Hilaris, Hafermann, M.D. Taylor, W.J., Richardson, R.G., and Shehata, W.M. Jazy, F.K., Aron, B., Dettmer, C.M., and A. Charyulu, K., Block, N., and Sudarsanam, Whitmore, W.F., Jr. Sogani, P.C., Watson, R.C., and Morales, P., Golimbu, M. Ambrose, S.S. Carson, C.C., Zincke, H., and Myers, R.P. Cupps, R.E., Utz, D.C., Fleming, T.R., Authors Kaiser Foundation Hospital (multi-site) Duke University Medical Center site) The Medical College of Wisconsin (multi- Medicine The University of Kansas School Beth Israel Medical Center site) Virginia Commonwealth University (multi- National Cancer Institute Clinical Diagnostic Trials Section, Geisinger Medical Center Mayo Clinic and Foundation Baylor College of Medicine (multi-site) Hospital The Johns Hopkins University and Cross Cancer Institute (multi-site) Memorial Sloan-Kettering Cancer Center Virginia Mason Medical Center (multi-site) University of Cincinnati Medical Center University of Miami School Medicine Memorial Sloan-Kettering Cancer Center New York University Medical Center Emory University School of Medicine Mayo Clinic and Foundation Institution Page A-6 Page 6163 6141 5813 5732 Journal of Urology 5642 Journal of Urology 5631 1 1984 5610 Radiotherapy and Oncology 5265 The Prostate 5219 5205 5077 4922 4897 4639 4401 4383 4345 Journal of Urology Journal of Urology 4287 4285 Journal of Urology 4280 4208 Clinical Radiology Urology Urology Cancer Cancer Cancer Urology Urology Physics Radiation Oncology, Biology, International Journal of Physics Radiation Oncology, Biology, International Journal of Medical Association Journal of the Mississippi State Physics Radiation Oncology, Biology, International Journal of Surgery The Canadian Journal of Journal of Surgery Australian & New Zealand 945 1984 95134 1985 134 1985 127 1982 127 1982 127 1982 9612 1986 37 1986 25 1-3 1985 26 1985 11 1985 53 1984 53 1984 25 1984 10 1984 26 1983 51 1983 53 1983 19 1982 20 1982

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Cryosurgery in prostatic cancer: survival cancer Current conflicts in the management of prostatic megavoltage X-ray therapy Radical treatment of prostatic carcinoma by irradiation in the aged Prostate cancer: experience with definitive prostatic carcinoma. Operative experience Radical prostatectomy for stage A2 and B incidence of local failure prostate: 5-year survival free of disease and 125Iodine implantation for carcinoma of the erectile function extraprostatic tumor extension and preservation of Nerve-sparing radical prostatectomy: Iodine-125 implants for carcinoma of the prostate Experience in 163 patients External beam irradiation of prostate cancer. prostate. The University of Arizona experience External beam radiotherapy in cancer of the irradiation biopsy Carcinoma of the prostate: results postimplantation for localized prostatic cancer metastases in patients treated with 125I- resection of the prostate to survival without distant Relationship of pretreatment transurethral MBMC experience and a literature review External beam irradiation for prostate cancer: the of the prostate studies of extended-field irradiation for carcinoma Treatment-related morbidity in phase III RTOG the prostate Interstitial radiotherapy for localized carcinoma of carcinoma. An early phase I/II comparison for patients irradiated localized prostatic Protons or megavoltage X-rays as boost therapy prostate: localized and extended field treatment Radical radiotherapy for carcinoma of the external irradiation for carcinoma of the prostate combined 125iodine seed implantation and Preliminary observations on the results of B2 carcinoma of the prostate Radical perineal prostatectomy for clinical stage implants treated by pelvic lymphadenectomy and 125iodine Clinical results of early stage prostatic cancer Further follow-up of first 100 cases 125I implantation for carcinoma of prostate.

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Document— Document— Archived Bagshaw, M.A. Hospital General (multi-site) Western Center Medical LAC/USC Preston, C.I., Duncan, W., and Kerr, G.R. Green, N., Bodner, H., and Broth, E. Fowler, J.E., Jr. Ladaga, L.E., and Schultheiss, T. Schellhammer, P.F., El-Mahdi, A.E., Catalona, W.J., Dresner, S.M. B.M., Kelly, K., and Mate, T.P. Peschel, R.E., Fogel, T.D., Kacinski, Phillips, R. Kurup, P., Kramer, T.S., Lee, M.S., and Heusinkveld, R.S. Aristizabal, S.A., Steinbronn, D., and Freiha, F.S., Bagshaw, M.A. D.L., and Whitmore, W.F., Jr. Fowler, J.E., Jr., Fisher, H.A.G., Kaiser, Steadham, R.E. Reagan, M.T., Smith, R.A., and Stetz, J., Zinninger, M., and Walz, B.J. Asbell, S.O., Plenk, H.D., Johnson, R.J., Pilepich, M.V., Krall, J., George, F.W., and Froud, P. Wilson, J.W.L., Morales, A., Bruce, A.W., E.C., and Suit, H.D. Munzenrider, J.E., Prout, G.R., Parkhurst, T., Verhey, L.J., Goitein, M., Duttenhaver, J.R., Shipley, W.U., Perrone, Nacey, J.N. Schmidt, J.D., and Culp, D.A. A.S., Platz, C.E., Rose E.F., Sall, J.C., Hawtrey, C.E., Loening, S.A., Narayana, Bonney, W.W., Fallon, B., Gerber, W.L., Abadir, R. Edwards, F.M., Weinstein, S.H., and Ross, G., Jr., Borkon, W.D., Landry, L.J., Elder, J.S., Jewett, H.J., and Walsh, P.C. Gnepp, D.R., and Riley, R.S. Kandzari, S.J., Belis, J.A., Kim, J.C., and Whitmore, W.F., Jr. Grossman, H.B., Batata, M., Hilaris, B., Stanford University School of Medicine Eastern Virginia Medical School Medicine Washington University School of Yale University School of Medicine Center (multi-site) Rush-Presbyterian-St. Luke's Medical Center University of Arizona Health Sciences Institute Memorial Sloan-Kettering Cancer Mississippi Baptist Medical Center Medicine (multi-site) Washington University School of Queen's University site) Massachusetts General Hospital (multi- University of Iowa (multi-site) Medicine University of Missouri School Hospital The Johns Hopkins University and West Virginia University Medical Center Memorial Sloan-Kettering Cancer Center Dunedin Hospital Dunedin Stanford University School of Medicine University of Virginia School Medicine Page A-7 Page 7765 7671 7670 7644 7522 7519 7419 7164 6937 6935 6860 6813 6732 6601 6364 6344 6331 6215 6191 Reference Papyrus Oncology American Journal of Clinical Journal of Urology Journal of Urology Physics Radiation Oncology, Biology, International Journal of Supplementum Urology & Nephrology - Scandinavian Journal of Supplementum Urology & Nephrology - Scandinavian Journal of Physics Radiation Oncology, Biology, International Journal of Physics Radiation Oncology, Biology, International Journal of Physics Radiation Oncology, Biology, International Journal of Physics Radiation Oncology, Biology, International Journal of Anticancer Research Radiotherapy and Oncology Biological Research Progress in Clinical & America Urologic Clinics of North Urology Journal of Urology Journal of Urology Australia The Medical Journal of Journal of Urology Journal 1988 1988 1988 1988 1988 1988 1988 1988 1987 1987 1987 1987 1987 1987 1986 1986 1986 1986 1986 Year 11 139 139 14 110 110 15 15 13 13 7 10 243B 14 27 135 135 144 136 Vol

171 166- 994 989- 988 985- 1157 1153- 89-94 95-100 1322 1317- 1316 1307- 1020 1013- 505 499- 399 395- 7-15 386 379- 684 675- 10-16 725 722- 519 517- 628 624- 424 422- Pages patients by Gleason's grading system Comparison of survival black and white Radiation-treated carcinoma of prostate. radiotherapy for stage B2 or C prostate cancer Combined gold seed implantation and external prostate cancer Interstitial gold and external beam irradiation for for stages A2, B, and C prostate cancer Iodine-125 implants versus external beam therapy Radiation therapy for prostatic carcinoma prostatectomy versus placebo. A 15-year follow-up Treatment of localized prostatic cancer. Radical seed implant plus external irradiation Adenocarcinoma of the prostate: radioactive gold carcinoma of the prostate: analysis RTOG 7706 Elective pelvic irradiation in stage A2, B Prostatic carcinoma: limited field irradiation United States prostate cancer with radiation therapy in the A ten year follow-up of 682 patients treated for cancer and disease-free survival Pretreatment transurethral resection of prostate treatment and complications Radiotherapy of prostate carcinoma: results Radiotherapy of stage B2 lesions the prostate cancer Radiotherapy versus surgery for localized prostatic radiation therapy for carcinoma of prostate Comparison of whole pelvis versus small-field prostate external beam irradiation for carcinoma of the combined temporary 192iridium implantation and Preliminary observations on the results of extended field radiation with surgically staged disease undergoing Prostatic carcinoma: 5-year followup of patients complications cancer. An analysis of treatment results and early High-dose radiotherapy for localized prostatic carcinoma following radical prostatectomy for prostatic Patient survival and local recurrence rate Title

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82-84 17-20 1-21 785 779- 246 235- 1424 1420- 1184 1180- 568 561- 498 493- 1382 1377- 1388 1383- 366 361- 566 564- 2420 2415- 2425 2421- 2474 2468- 195 191- 1265 1262- 332 325- 197 191- 709 701-

Patient selection for radical prostatectomy for radical prostatectomy Selection of patients with stage B prostate cancer follow-up external-beam radiation therapy: 5-year minimum Adenocarcinoma of the prostate treated with clinical stage B2 prostate cancer Role of nerve-sparing radical prostatectomy for results 2N0M0 prostatic adenocarcinoma: long-term Radical prostatectomy for clinical stage T1- control and treatment morbidity influence of duration radiotherapy on tumor Carcinoma of the prostate stage B and C: lack fifteen-year follow-up treatment in stages I and II prostatic cancer. A Radical prostatectomy versus expectant primary prostate treated with radiation therapy control in patients with adenocarcinoma of the The effect of overall treatment time on local prostate with radiotherapy the management of adenocarcinoma The role of serum prostatic acid phosphatase in carcinoma of prostate Prognostic significance of DNA ploidy in prostatic cancer: long-term results Total prostatectomy for clinically localized with clinically localized carcinoma of the prostate useful method for reporting survival data in men Cause-specific actuarial survival analysis: a What have we learned 10 years later? I-125 interstitial implantation for prostate cancer. definitive irradiation for prostatic carcinoma Prognosis in patients with local recurrence after prostate External beam radiotherapy for carcinoma of the carcinoma of the prostate Retrospective study of radiotherapy in early prostate radiotherapy for localized carcinoma of the Factors influencing outcome of definitive influence of tumor deoxyribonucleic acid ploidy localized adenocarcinoma of the prostate: prostatectomy for clinically and pathologically Pattern of failure after radical retropubic irradiation carcinoma of the prostate by definitive external Experience in the treatment of localized and survival in 67 patients Radical prostatectomy. Patterns of local failure adenocarcinoma of the prostate The role of radiation therapy in stages A2 and B

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Document— Document— Archived Smith, J.A., Jr. Middleton, R.G., Larsen, R.H. L.T., and Million, R.R. Amdur, R.J., Parsons, J.T., Fitzgerald, W.J. Bigg, S.W., Kavoussi, L.R., and Catalona, P.J. Paulson, D.F., Moul, J.W., and Walther, Lockett, M.A. Lai, P.P., Perez, C.A., Shapiro, S.J., and T.C., Corle, D.K., and Madsen, P.O. Graversen, P.H., Nielsen, K.T., Gasser, L.T., and Million, R.R. Amdur, R.J., Parsons, J.T., Fitzgerald, M.J. Carlton, J.C., Zagars, G.K., and Oswald, McLeod, D.G., and Lynch, J.H. Noguchi, P.D., Jones, R.V., Moul, J.W., Dejter, S.W., Jr., Cunningham, R.E., G.E., and Weissman, R.M. Gibbons, R.P., Correa, R.J., Jr., Brannen, P.C. Lepor, H., Kimball, A.W., and Walsh, Schellhammer, P.F. Kuban, D.A., El-Mahdi, A.M., and Schellhammer, P.F. Kuban, D.A., El-Mahdi, A.M., and Chung, C.T., and Dalal, P.S. Sagerman, R.H., Chun, H.C., King, G.A., Read, G., Pointon, R.C.S. Zivnuska, F., and Lockett, M.A. Perez, C.A., Garcia, D., Simpson, J.R., M.M. Farrow, G.M., Therneau, T., and Lieber, Blute, M.L., Nativ, O., Zincke, H., Cohen, Y., and Robinson, E. Kuten, A., Nitetzky, S., Tatcher, M., P.F. Schellhammer, Johnson, D.E., and Oswald, M.J. Zagars, G.K., von Eschenbach, A.C., Eastern Virginia Medical School Sciences University of Utah Center for the Health University of Florida College Medicine Medicine Washington University School of Duke University Medical Center site) Mallinckrodt Institute of Radiology (multi- site) Veterans Administration Hospital (multi- University of Florida College Medicine Cancer Center The University of Texas M.D. Anderson site) Georgetown University Hospital (multi- The Virginia Mason Clinic Hospital The Johns Hopkins University and Eastern Virginia Medical School Eastern Virginia Medical School site) Mallinckrodt Institute of Radiology (multi- Sciences University of Utah Center for Health site) Mallinckrodt Institute of Radiology (multi- Mayo Clinic (multi-site) Technion-Israel Institute of Technology Hospital (multi-site) The University of Texas M.D. Anderson Christie Hospital (multi-site) Hospital Christie Page A-9 Page 10108 10107 10104 10076 10039 9899 9895 9879 9737 9733 9717 9580 9572 9407 9351 9265 9219 9194 9175 8990 Reference Papyrus Journal of Urology Journal of Urology Journal of Urology Physics Radiation Oncology, Biology, International Journal of British Journal of Urology Journal of Urology Journal of Urology Physics Radiation Oncology, Biology, International Journal of Association Journal of the National Medical Physics Radiation Oncology, Biology, International Journal of Urology Journal of Urology Physics Radiation Oncology, Biology, International Journal of Journal of Urology Cancer Journal of Surgery Australian & New Zealand Urology Physics Radiation Oncology, Biology, International Journal of Archives of Surgery British Journal of Urology Journal 1992 1992 1992 1992 1992 1991 1991 1991 1984 1984 1983 1985 1985 1991 1991 1991 1990 1990 1990 1990 Year 147 147 147 22 69 146 145 21 76 10 21 133 11 145 67 61 35 18 125 65 Vol

890 888- 921 917- 907 905- 568 565- 187 183- 802 798- 1200 1197- 547 537- 61-66 548 541- 457 451- 49-52 2080 2073- 514 512- 1096 1091- 662 658- 227 223- 320 315- 331 327- 614 611- Pages perineal versus retropubic approach Radical prostatectomy: the pros and cons of of prostatic cancer The importance of local control in the treatment retropubic prostatectomy The management of rectal injury during radical advanced prostate cancer etanidazole and radiation therapy in locally of neurotoxicity: results from a phase II trial dose modification of etanidazole on the incidence The efficacy of pharmacokinetic monitoring and carcinoma Deferred treatment in clinically localised prostatic lymphadenectomy treated with and without staging pelvic therapy for prostate cancer: an analysis of patients Complications following external beam radiation prostatectomy: an interim report Cancer control following anatomical radical implantation term results in patients treated with 125I dissemination in carcinoma of the prostate: long- The effect of local control on metastatic cancer External radiation therapy of localized prostatic carcinoma of the prostate Triple course external beam radiotherapy for radiation prostate cancer by interstitial or external beam Pelvic complications after definitive treatment of histological score and early disease-free survival clinical stage, pathological Gleason Operable prostatic carcinoma: correlations among irradiation for carcinoma of the prostate Improving the therapeutic ratio of external beam urinary continence Impact of anatomical radical prostatectomy on cancer Expectant management of localized prostatic localized prostate carcinoma Radiation therapy for the management of adenocarcinoma pelvic lymph node dissection in prostatic Intraoperative and early complications of staging carcinoma of the prostate: volume effect Bowel complications after radiotherapy for cytometric nuclear DNA ploidy analysis Stage B prostate adenocarcinoma. Flow prostatic carcinoma The natural course of low grade, non-metastatic Title

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Document— Document— Archived Paulson, D.F. Frazier, H.A., Robertson, J.E., and M.A., and Cox, R.S. Kaplan, I.D., Prestidge, B.R., Bagshaw, Borland, R.N., Walsh, P.C. Riese, N., and Rose, M.A. Coleman, C.N., Buswell, L., Noll, Lowhagen, T. Adolfsson, J., Carstensen, and N.E., and Johnson, D.E. Greskovich, F.J., Zagars, G.K., Sherman, P.C. Morton, R.A., Steiner, M.S., and Walsh, Hilaris, B.S., and Whitmore, W.F. Begg, C.B., Fair, W.R., Anderson, L.L., Fuks, Z., Leibel, S.A., Wallner, K.E., Reddy, E.K., Giri, S., and Mansfield, C.M. Schellhammer, P.F., and Peeples, W.J. El-Mahdi, A.M., Turalba, C.I.C., Schellhammer, P.F., El-Mahdi, A.M. Fowler, J.E., Jr., Mills, S.E. Order, S.E. Wharam, M.D., Baumgardner, R.A., and Forman, J.D., Zinreich, E., Lee, D.J., P.C. Steiner, M.S., Morton, R.A., and Walsh, Thompson, I.M., Jr. Whitmore, W.F., Jr., Warner, J.A., and Burmeister, B.H., Probert, J.C. Fauver, H.E. Augspurger, R.R., Williams, G., and Donohue, R.E., Mani, J.H., Whitesel, J.A., Watt, W.H., and Tynan, A. Mameghan, H., Fisher, R., J., Therneau, T.M., and Lieber, M.M. Farrow, G.M., Myers, R.P., Zincke, H., Montgomery, B.T., Nativ, O., Blute, M.L., J., Lowhagen, T., and Hedlund, P.O. Adolfsson, J., Ronstrom, L., Carstensen, Authors Duke University Medical Center (multi-site) Stanford University School of Medicine Hospital The Johns Hopkins University and site) Joint Center for Radiation Therapy (multi- Karolinska Hospital (multi-site) Cancer Center University of Texas M.D. Anderson Hospital The Johns Hopkins University and Memorial Sloan-Kettering Cancer Center (multi-site) University of Kansas Medical Center Center Hospitals Eastern Virginia Medical School/Medical Eastern Virginia Medical School University of Virginia School Medicine Hospital The Johns Hopkins University and Hospital The Johns Hopkins University and Memorial Sloan-Kettering Cancer Center Auckland Hospital Center (multi-site) University of Colorado Health Sciences Institute of Radiotherapy (multi-site) Mayo Clinic Karolinska Hospital (multi-site) Institution Page A-10 Page 11400 11201 11108 11104 Journal of Urology 11062 10790 10748 10693 10672 10550 10517 10373 10369 10340 Journal of Urology 10322 10310 European Urology 10303 10251 10184 10183 Journal of Urology 10109 Urology Urology Urology Cancer Cancer Urology Physics Radiation Oncology, Biology, International Journal of Oncology European Journal of Surgical Journal Henry Ford Hospital Medical Urology & Nephrology Scandinavian Journal of Association Journal of the National Medical Physics Radiation Oncology, Biology, International Journal of Research Recent Results in Cancer Physics Radiation Oncology, Biology, International Journal of Physics Radiation Oncology, Biology, International Journal of Urology & Nephrology Scandinavian Journal of Medical Association Journal of the American 932 1-6 24 1993 93149 1993 150 1993 147 1992 9240 1992 24 1992 18 1992 40 1992 26 1992 85 1993 25 1993 126 1993 26 1993 41 1993 42 1993 26 1993 72 1993 72 1993 27 1993 267 1992 39 1992

18-26 43-49 13-20 44-47 488 485- 462 456- 110 108- 234 231- 522 519- 112 109- 667 661- 210 203- 126 122- 591 581- 1299 1291- 907 905- 1725 1709- 224 219- 2196 2191- 887 883- with prostate boost or small field to prostate? Radiation therapy in prostate cancer: whole pelvis techniques: a reduction in acute morbidity of early prostate cancer versus non-conformal Conformal static field radiation therapy treatment cancer Radical prostatectomy for localized prostate carcinoma of the prostate Radical surgery in the treatment of localized with the first 54 patients Radical retropubic prostatectomy: our experience radiotherapy for prostatic cancer: followup Prostate specific antigen after external beam Prostate cancer: results of external irradiation transperineal I-125 prostate implants Short-term morbidity from CT-planned prostate: long-term results Radical prostatectomy for carcinoma of the radiotherapy (1970-1985) Carcinoma of the prostate: results radical Five- and ten-year follow-up Iodine-125 seed implants for prostatic carcinoma. carcinoma of prostate free survival after radiation therapy for localized Prostate-specific antigen to determine progression- carcinoma of the prostate outcome of definitive irradiation for localized Technical and tumor-related factors affecting radical cryosurgical ablation of the prostate Transrectal ultrasound-guided percutaneous prostatectomy following nerve sparing radical retropubic Return of erections and urinary continence 874 patients treated with radiation therapy Prognostic factors in prostate cancer. Analysis of study of 201 cases prostatic carcinoma: a clinical and pathological Radical retropubic prostatectomy for localised prostate Outcome of patients with untreated cancer the untreated prostatic cancer High 10-year survival rate in patients with early, hospitals' experience 1985-1989 Radical prostatectomy: OSU and affiliated cases quality of life. Experience with 620 consecutive Radical retropubic prostatectomy: morbidity and

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Document— Document— Archived Shehata, W.M. Ploysongsang, S.S., Aron, B.S., and and Epstein, B.E. Soffen, E.M., Hanks, G.E., Hunt, M.A., Van-de-Voorde, W., and Baert, L. Van-Poppel, H., Ameye, F., Oyen, R., J.C. J.O., Burks, D.A., Fleming, C., and Cerny, Littleton, R.H., Kirkemo, A.K., Peabody, Telang, D.J., Miles, B.J., Farah, R.N., and Hoisaeter, P.A. Servoll, E., Halvorsen, O.J., Haukaas, S., M.A. Kaplan, I.D., Cox, R.S., and Bagshaw, R.G., Mebust, W.K., and Weigel, J.W. Reddy, E.K., Krishnan, L., Giri, S., Evans, Fuks, Z. Arterbery, V.E., Wallner, K., Roy, J., and Frohmuller, H.G.W., Wirth, M.P. Gospodarowicz, M.K. Munro, A.J., Lakier, R., Gadalla, T., and Duncan, W., Warde, P., Catton, C.N., P.R. Weyrich, T.P., Kandzari, S.J., and Jain, Wright, G.L., Jr., Kolm, P., and Ragle, R. Schellhammer, P.F., El-Mahdi, A.M., M.A. Logsdon, M.D., Lai, P.P., and Lockett, Perez, C.A., Lee, H.K., Georgiou, A., Rubinsky, B., Chang, Z., and Baust, J. Onik, G.M., Cohen, J.K., Reyes, G.D., Catalona, W.J., Basler, J.W. Ayala, A.G. Zagars, G.K., von-Eschenbach, A.C., and Pedersen, K.V., Herder, A. Stenzl, A., Studer, U.E. Krusemo, U.B. S.O.,Bergstrom, R., Holmberg, L., Johansson, J.E, Adami, H.O., Andersson, J.A., and Perez, J. Simon, J., Riemenschneider, H., Nesbitt, Drago, J.R., Badalament, R.A., York, J.P., and Ramon, J. Leandri, P., Rossignol, G., Gautier, J.R., The Christ Hospital (multi-site) Fox Chase Cancer Center Universiteit University Hospitals of the Katholieke Henry Ford Hospital Haukeland University Hospital Stanford University Medical Center University of Kansas Medical Center Memorial Sloan-Kettering Cancer Center site) Urologische Klinik und Poliklinik (multi- Princess Margaret Hospital West Virginia University Medical Center site) Eastern Virginia Medical School (multi- The Center for Urologic Oncology of site) Mallinckrodt Institute of Radiology (multi- Allegheny General Hospital (multi-site) Medicine Washington University School of Cancer Center The University of Texas M.D. Anderson site) Orebro Medical Center Hospital (multi- Ohio State University (multi-site) Saint-Jean Languedoc-Cerou University Hospital University University of Berne Medical Center Page A-11 Page 12539 12442 12404 12374 12343 12322 12241 12210 11972 11946 11941 11939 11936 11875 11850 11710 11645 11511 11402 Reference Papyrus Cancer Journal of Urology British Journal of Urology Journal of Urology Association Journal of the National Medical Urology South African Medical Journal European Urology Journal of Urology European Urology Physics Radiation Oncology, Biology, International Journal of Physics Radiation Oncology, Biology, International Journal of Physics Radiation Oncology, Biology, International Journal of Journal of Urology Supplementum Urology and Nephrology - Scandinavian Journal of Supplementum Urology and Nephrology - Scandinavian Journal of Physics Radiation Oncology, Biology, International Journal of Physics Radiation Oncology, Biology, International Journal of Radiology Journal 1989 1989 1989 1990 1990 1990 1990 1990 1991 1991 1991 1991 1991 1991 1991 1991 1992 1992 1992 Year 63 142 64 143 82 35 78 18 146 19 21 21 21 146 137 138 22 23 184 Vol

2420 2415- 1229 1227- 515 511- 544 538- 193 181- 380 377- 311 309- 119 117- 1045 1040- 283 279- 1103 1099- 939 935- 960 955- 1319 1317- 118 113- 115 109- 939 935- 298 293- 339 333- Pages

What have we learned 10 years later? I-125 interstitial implantation for prostate cancer. prostatectomy Continence following nerve-sparing radical prostatectomy Early post-operative morbidity of total results after 250 patients Nerve-sparing radical prostatectomy: evaluation of prostate cancer Iodine-125 interstitial irradiation for localized radical prostatectomy and nerve-sparing technique institutional experience: comparison of standard Radical prostatectomy 1972-1987 single Radical irradiation for carcinoma of the prostate prostate External-beam radiation for carcinoma of the with clinically localized disease The risk of dying prostate cancer in patients prostate: long-term follow-up of 115 patients Radical prostatectomy for carcinoma of the beam radiation therapy in RTOG 7706 T-2 (A-2,B) prostate cancer treated with external Outcome for lymph node dissection negative T-1b, prostate: analysis of RTOG studies 7506 and 7706 beam irradiation for adenocarcinoma of the Long-term treatment sequelae following external in the definitive treatment of prostate carcinoma External beam irradiation versus a study of 41 patients implantation to control localized prostate cancer: Failure of open radioactive 125iodine the prostate: morbidity and complications Transperineal ultrasound-guided implantation of external irradiation in localized prostatic cancer implantation of 125-I seeds combined with Long term results of ultrasonically guided complications in 321 patients template implant of the prostate: results and Transperineal percutaneous iridium-192 interstitial design and stratification RTOG data for patient management and trial of lymph nodes in prostate cancer: implications Comparison of pathologic and clinical evaluation adjuvant brachytherapy Results of radical perineal prostatectomy with Title

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125 Document— Document— Archived iodine implant Archived Schellhammer, P.F. Kuban, D.A., El-Mahdi, A.M., and O'Donnell, P.D., Finan, B.F. deKernion, J.B. Ritchie, A.W.S., James, K., and Catalona, W.J., Bigg, S.W. F.F. Kumar, P.P., Good, R.R., and Bartone, Nesbitt, J.A. Drago, J.R., Badalament, R.A., and and Sarembock, L.A. Abratt, R.P., Craighead, P.S., Reddi, V.B., Durrant, K.D., and Fellows, G.J. Davies, A.H., Davis, H.L., Ramarakha, P., C.E., Jr., and Scardino, P.T. Lerner, S.P., Seale-Hawkins, C., Carlton, M.P. Frohmuller, H., Theiss, M., and Wirth, Sause, W., and Pilepich, M.V. Perez, C.A., Doggett, S., Rubin, P., Hanks, G.E., Asbell, S., Krall, J.M., Doggett, S.R., and Rubin, P. Cox, J.D., Perez, C.A., Sause, W.T., Asbell, S.O., Shipley, W.U., Hanks, G.E., Lawton, C.A., Won, M., Pilepich, M.V., D.A., and Brady, L.W. Borofski, A.M., Ziegler, J.C., Lightfoot, Koprowski, C.D., Berkenstock, K.G., Weissman, W.D. Gottesman, J.E., Tesh, D.G., and Blasko, J.C., Ragde, H., and Grimm, P.D. H.H. Iversen, P., Rasmussen, F., and Holm, Stidley, C. Khan, K., Thompson, W., Bush, S., and Sause, W.T., and Doggett, R.L.S. Asbell, S.O., Perez, C.A., Rubin, P., Hanks, G.E., Krall, J.M., Pilepich, M.V., R.A., Wen, B.C., and Vigliotti, A.P. Doornbos, J.F., Hussey, D.H., Robinson, Authors Eastern Virginia Medical School Veterans Administration Medical Center UCLA School of Medicine Medicine Washington University School of Medicine University of Nebraska College University College of Medicine, Ohio State Schuur Hospital (multi-site) University of Cape Town and Groote Churchill Hospital Baylor College of Medicine (multi-site) University of Wurzburg Medical School Cancer Center (multi-site) University of Pennsylvania/Fox Chase site) Medical College of Wisconsin (multi- Center (multi-site) Cooper Hospital/University Medical Hospital Medical Center The Tumor Institute of the Swedish Northwest Tumor Institute Herlev Hospital (multi-site) (multi-site) University of New Mexico Cancer Center Fox Chase Cancer Center (multi-site) (multi-site) University of Iowa College Medicine Institution Page A-12 Page Table A-2. Characterization of outcomes data 1 Total Number of Articles Some articles contain data for more than one treatment modality and are therefore included in the totals column. Quality of Life Data Cost Analysis Data Recurrence Data Morbidity Data Survival Data Excellent Excellent Excellent Excellent Excellent Marginal Marginal Marginal Marginal Marginal Absent Absent Absent Absent Absent Useful Useful Useful Useful Useful 1

Radical Prostatectomy

58 Articles % 0%52 90 % 56 % 97 29 50 % 37 64 % 24 41 % 2%7 12 % 1%12 21 % 0%23 40 % 2%13 22 % 15 26 % 2 0 3 % 2 0 % 0 3 % 0 % 4 3 7 % 3 5% 4 5 % 7% 4 7 % 0 0 %

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External Beam External 0 71 100 %

71 Articles % 6%68 96 % 1%36 51 % 28 39 % 21 30 % 0%14 20 % 0%14 20 % 12 17 % 8%34 48 % 7%19 27 % 24 34 % Radiation: 4 6 % 1 1 1 % 0 1 % 0 0 % 0 % 2 3 % 5 7 % 1 1 % 0 0 % Document— Document— Archived Brachytherapy (Interstitial) Brachytherapy 0 34 100 % Radiation: 34 Articles % 4%32 94 % 2%11 32 % 10 29 % 12 35 % 5%12 35 % 4%15 44 % 1%7 21 % 14 8 41 % 24 % 7 21 % 2%4 12 % 0 0 % 0 1 0 % 0 3 % 0 0 % 0 % 2 6 % 1 3 % 0 0 % 0 6 100 % 0 6 100 % Surveillance Articles % 3%5 83 % 2 33 % 7%1 17 % 7%1 17 % 6 3%5 83 % 7%4 67 % 0 % 0 0 % 0 0 0% 0 0% 0 0% 0 0 % 0 0 0 % 0 0 % 0 0 % 0 % 0 0 % 0 0 % Table A-3. Descriptive data analysis Archived

Radiation: Radiation:

Radical Prostatectomy ExternalFor Beam Brachytherapy (Interstitial) Surveillance

Patients by Stage3 and Primary Treatment Modality 1 All Series 2 All Series 2 All Series 2 All Series 2 Total Number of Patients 9,263 14,205 4,891 913 S % x S % Tot x S % x S % x A No A1-A2 separation A 0 A 0 A 0 A 0 Stage A2 A2 0 A2 0 A2 3 1.8 % 89 A2 0 Stage B B 25 25.4 % 2,355 B 46 56.1 % 7,968 B 10 14.5 % 707 B 5 52.6 % 480

B1 (if separable) B1 4 5.7 % 531 B1 9Reference 4.4 % 628 B1 10 7.7 % 375 B1 1 3.2 % 29 B2 (if separable) B2 7 6.2 % 574 B2 10 8.8 % 1,255 B2 11 18.7 % 915 B2 1 4.1 % 37 B3 Bilat. disease B3 0 B3 1 0.4 % 52 B3 2 1.7 % 82 B3 1 1.0 % 9 B Aneuploid BA 1 0.1 % 10 BA 0 BA 0 BA 0 B Clinical BC 0 BC 5 0.7 % 100 BC 0 BC 0 B Diploid BD 1 1.9 % 177 BD 0 BD 0 BD 0 Pathologic B BP 2 1.3 % 119 BP 5 2.4 % 334 BP 0 BP 0 B Tetraploid BT 1 0.8 % 74 BT 0 BT 0 BT 0 C Clinical & C Pathologic C 0 C 1 0.8 % 108 C 3 2.2 % 106 C 0 C Clinical CC 0 CC 1 1.1 % 150 CC 0 CC 0 All stage D D 0 D 1 0.1 % 12 D 0 D 1 10.7 % 98

Complication/Cost data K 12 38.5 % 3,563 K 11 9.0 % 1,274Document— K 3 3.9 % 191 K 0 Localized A-B L 17 20.1 % 1,860 L 11 7.3 % 1,044 L 7 23.5 % 1,150 L 2 28.5 % 260

Page A-13 Page Localized regional LR 0 LR 7 9.0 % 1,280 LR 12 26.1 % 1,276 LR 0

STAGING Data 1 Reporting Series Reporting Series Reporting Series Reporting Series S % y x y S % y x y S % y x y S % y x y PAP 36 100% 1,421 1,421 51 98% 3,676 3,761 26 100% 1,983 1,983 3 89% 306 343 PSA 11 100% 217 217 5 0% 0 407 2 100% 196 196 0 Bone scan 30 92% 1,289 1,399 48 93% 3,140 3,391 25 99% 1,535 1,549 4 92% 506 552 TRUS/BX 8 86% 134 155 10 44% 39 89 6 100% 276 276 0 CT 5 100% 121 121 20 37% 318 867 10 34% 102 298 1 13% 8 61 MRI 2 0% 0 0 5 3% 14 524 1 0% 0 196 0 PLND 26 83% 910 1,093 26 26% 463 1,756 22 87% 1,743 1,997 1 0% 0 223 TURP 9 18% 28 156 16 14% 175 1,226 5 0% 0 0 0 Re-TURP 0 4 0% 0 407 0 0

Immune markers or scan 0 4Only 0% 0 407 0 0

GRADE Data - Comparable Studies 1 Reporting Series Reporting Series Reporting Series Reporting Series S % Tot x S % Tot x S % Tot x S % Tot x High, Gleasons (8-10) 16 20.0% 327 13 18.2% 229 13 10.5% 117 5 3.0% 12 Mod, Gleasons (5-7) 16 56.9% 928 13 40.6% 510 13 51.3% 572 5 34.8% 140 Low, Gleasons (2-4) 16 23.1% 376 13 41.2% 517 13 38.3% 427 5 62.2% 250 Total: 1,631 Total: 1,256 Total: 1,116 Total: 402

DNA CONTENT Data 1 Reporting Series Reporting Series Reporting Series Reporting Series S % y x y S % y x y S % y x y S % y x y Aneuploid 3 4.2% 14 336 0 0 0 Tetraploid 1 28.4% 74 261 0 0 0 Diploid 3 73.8% 248 336 0 0 0 Page A-14 Page 3 2 1 DEMOGRAPHIC Data B (Stage B) B2 (if separable) disease) (Bilat. B3 B3 B1 (if separable) A2 (Stage A2) A (No A1-A2 separation) FOLLOW-UP Data PROGRESSION Definition Data PATHOLOGY Data The stage codes for this database are: The term "series" denotes patient groups stratified by particular parameters such as stage of disease and treatment modality. One article may have more than one series. the numerator, y denominator. The letter x designates applicable number of patients, the y total patients. For calculating percentages, is ao eTR SaeA 0 Ca on Re-TURP (Stage A) Maximum F/U (months) Minimum F/U (months) Total number of series ubrwt 0y / 65.%79142897 1 ,3 92 0 2 97 6234 46 19.7% 5 522 100 19.2% 4 1,132 110 9.7% 0 8 1,216 1,492 530 759 43.6% 50.9% 14 16 Number with 15 yr F/U Number with 10 yr F/U R elrigms)710 1 1 810 ,4 ,4 06%1026710 5 159 159 100% 7 236 150 64% 10 1,643 1,643 100% 38 412 412 100% 7 DRE (enlarging mass) Maximum age (years) ubrwt rFU2 10 ,8 ,4 56.%1822871 24 4 8 75 0 457 400 87.5% 6 887 642 72.4% 15 2,897 1,802 62.2% 25 1,949 1,188 61.0% 20 Number with 5 yr F/U Minimum age (years) o.smnlvsce 31.%121020 1,002 192 19.2% 13 Pos. seminal vesicles o.ueha agn32.%6 7 0 276 62 22.5% 3 Pos. urethral margin o.cpuemri 00 8 1 0 619 186 30.0% 8 12 Pos. capsule margin Capsule penetration enFU(ots 270.2 12 Mean F/U (months) ipyww RS30 57%162045%4 00 80 46 58% 4 260 186 72% 15 0 0 0% 3 Biopsy w/wo TRUS ubro ains5 7,595 57 Number of patients enae(er)3 62.7 34 Mean age (years) o.badrnc 89 4250 285 54 18.9% 4 Pos. bladder neck oa ypos410 3 3 510 0 0 0%4 450 0 0 0% 5 44 44 100% 9 407 407 100% 25 0 335 335 MRI progression 100% 4 Local symptoms oesa rg 05%4 82 0 1 6 %00610 2 122 122 100% 6 0 0 0% 9 463 418 90% 23 88 49 56% 10 Bone scan prog. Tporsin30 %0010 0 0 0 0% 1 0 0 0% 7 0 0 0% 3 CT progression iigPP99%37362 2 9 4 %00210 5 159 159 0 100% 2 0 0 0 0 0% 0% 5 7 407 0 648 595 0% 92% 5 25 77 376 77 337 100% 90% 4 9 Rising PSA Rising PAP 1 1 RSB 0%4 7910 93 6 6 7 0 379 363 96% 7 39 39 100% 9 47 47 100% 2 TRUS/BX 2 1 BD (B Diploid) BC (B Clinical) BA B (Aneuploid) BP (Pathologic B) (Pathologic BP Radical Prostatectomy y x % y S 59 S y x % y S y x % y S Reporting Series Reporting Series Reporting Series 83 4 ,5 0 1,156 443 38.3% 372.0 84.0 34.0 1.0

D (All stage D) CC (C Clinical) K (Complication/Cost data) (Complication/Cost K BT (B Tetraploid) (B BT C (C Clinical & Pathologic)

670.3 26 311,465 83 965.9 29 y x % y S 84 S y x % y S y x % y S %0470 407 0 0% 4 %0470 407 0 0% 5 Only Reference

For For External Beam Radiation:

Reporting Series Reporting Series Reporting Series

264.0 92.0 26.0 1.0

Document— Document— Archived O Other, define: U Unknown R Recurrence-e.g., following treatment by RRP or RT L (Localized A-B) (Localized L LR (Localized regional) (Localized LR Brachytherapy (Interstitial) 156.5 21 33,912 43 564.5 25 y x % y S 43 S y x % y S y x % y S 0 0 0 0 0 0 Radiation: Reporting Series Reporting Series Reporting Series 219.0 91.0 36.0 1.0 y x % y S 8 S y x % y S y x % y S 623 8 7 0 0 47 395 33 34.7% 4 0 0 70 7 0 0 0 Surveillance Reporting Series Reporting Series Reporting Series 298.0 111.6 90.0 38.0 3.0 Page A-15 Page Table A-4. Actuarial survival data for circle graphs 15B A59. 76B1B 3071 1 B 55.0 53.0 7419 10 48.0 48.0 10 BA 46.0 10 10 BA 41.4 93.0 10 91.0 1 BA 2 BA 10 1 5 BA 90.0 5 B2 0 84.0 BA B1 1 BA B 1 BA 5 2 6732 87.7 BC 5 0 8333 L 93.0 1 6937 BA 1 15 B2 B 8331 BB 90.0 2 15 B 1078 84.0 90.0 1 AB 1 B 8333 15 83.0 6935 B 1 55.0 AA 1 B1 93.0 15 8902 5 88.5 1 BC AA 15 7796 B 5 10 4922 91.2 1 8333 B AA B 10 BA 97.0 81.0 AA 4076 1 10 B AA BA 7670 96.0 5610 2 1 B AA 7644 1 96.0 5 95.0 1 5 BT AB 1 1 8411 5 80.0 AAA BD B2 1 0 8182 90.0 5 5 BA BA 79.0 B 1 9175 AA B1 5 78.0 B 78.0 0 9175 8333 B2 5 AA B AA 1 9175 BAA 5 6937 1 B 3195 5 8182 77.0 1 5 AA 7671 1 BAA L 1 9175 0 77.0 BT B 70.0 8411 BA 76.0 BA 5 1 BD B 82.0 1 9895 92.0 15 B 9175 5 75.0 6163 B 2 BA 72.0 1 5 10 BA 81.9 9175 1 7670 1 5 AA B 8182 BA 72.0 8798 5 AA BA 1 5 9175 5 B B AA B2 B 75.0 1 6141 70.0 1 5 BA 1 1 BA AB B2 69.0 70.0 7164 15 8161 1 7671 7419 60.0 68.0 65.0 BA B 5 B2 1 15 1 1 3195 5 B AA 56.0 66.0 B 15 15 B 5 BA 1 8182 60.0 2690 AA 25.0 55.0 15 BA B 1 8182 60.0 55.0 B 7164 5 L AA A 22.2 BA 8182 15 1 88.0 15 5 1 AB B 1 11402 6935 BA 15 5 5 1078 1 B 78.0 1 10 1 AA BA BT A 75.1 1 B 1077 B1 1 AB BA 10 BA BD 8182 1 A 10 L 1 70.0 70.0 1 9175 B 48.0 3019 B AA 8902 1 1 1 9175 B2 10 10 BA AA 44.4 1 8823 10 B3 7522 B 1 8411 8902 B3 95.0 10 L AB AB B 1 9175 93.0 90.0 3195 L A 8717 5 AB B 2690 1 1 1281 85.0 8318 5 5 B 1 8823 85.0 AAA AB 1 8182 85.0 5 BP 83.0 B AA 9175 5 82.0 B 75.0 0 1 11402 AA 5 5 L 1 8411 AA 68.9 5 8717 5 BP AA 1 L 1281 A 5 1 B AB 11402 1 BT A 9895 1 AB BD 1 8182 BA 1 9175 B2 1 9175 B 9175 B 4345 L 8411 8717 1281 Papyrus DISEASE - SPECIFIC SURVIVAL METASTASIS - FREE SURVIVAL PROGRESSION - FREE SURVIVAL tg r Rx Arm Stage Radical Prostatectomy OVERALL SURVIVAL No Data Year 1 Survival 14 A1 63.0 60.0 10 57.0 10 BA 54.5 10 BA 10 BAA 1 1 BA 1 L 2 B2 1 11941 B 1 10107 B1 89.0 10310 B B 10373 5 10550 85.0 7644 2 BA 1 5 84.0 B1 1 BA B 83.0 10373 5 12539 BAA L 1 5 11936 1 80.0 BA L 80.0 5 12241 B 1 5 10310 BA B1 BA 77.0 2 2690 1 5 B 76.0 BA B2 0 11511 5 10107 1 71.0 L BA 0 11972 B 5 1 11511 L BA B2 61.0 11710 1 6732 5 B 51.4 BA 7765 5 2 BAA BP 1 11511 L 12210 8331 BC 0 BA 5 86.0 No No 86.0 5 BA 0 BC 8331 01 A 533.0 31.0 70.0 15 15 10 BAA BA BA 1 1 1 B B2 B 10310 6732 7796 87.0 5 84.0 BA 5 1 BA 82.0 L 1 5 11941 BP BA 11511 1 B 5219 Papyrus 05 A58. 07 22 B2 10373 82.9 5 BA 1 B 10550

OVERALL SURVIVAL tg r Rx Arm Stage Radiation: External Beam

Only Reference For Year For

2 Survival

Document— Document— METASTASIS - FREE SURVIVAL 80.0 5 BB 1 B 5642 0 LR 11645 Archived 23 21 B2 12539 Papyrus 24 1 0 L L 12343 11972 1 B1 12539 2 1 B2 BP 2 10373 12539 0 L 11936 L 1 11710 2 B1 1 L 11645 11936 L 12343 DISEASE - SPECIFIC SURVIVAL Radiation: Brachytherapy (Interstitial Radiotherapy) PROGRESSION - FREE SURVIVAL tg r Rx Arm Stage OVERALL SURVIVAL Data BC5 BBAC BA10 BBAA 10 BBAA 5 BBAA 5 BBAA 5 BBAB 5 BBBA BA10 BBAA BB5 BBAB 5 BBBA 5 BBAB 10 BBAA 10 BBAA 10 BBAA 5 BBAA 5 BBAB 5 BBAA 5 BBAA 5 BBAA 5 BBAA 5 BBAA 5 BBAA 5 BBAA 5 BBAB 5 BBAC 5 BBAA 5 BBBA 5 BBAA 5 BBAB BA10 BBAA 3 Year 9095 21D1 39.0 15 D 1 B2 9351 69.0 00121L1D1 85.0 10 99.0 D 5 1 D L 1 10251 B 10039 90.0 62.0 90.0 88.0 84.0 5 67.0 D 5 1 D B3 0 9351 L 84.0 10184 57.0 00121L1D589.0 5 D 1 L 10251 50.0 80114L0D1 85.0 84.0 10 10 D D 100.0 0 93.2 1 92.0 L 53.0 B 10184 10 10039 67.0 D 88.0 63.0 15 88.0 39.0 0 15 70.7 15 D 60.0 10 D L 50.0 10 1 D 10184 1 34.0 D 92.0 88.0 B1 D 85.0 2 86.0 10 B3 0 5 84.0 2 9351 5 84.0 B 9351 D 80.0 B D 67.0 5 78.0 B D 8717 1 77.0 5 9351 1 77.0 5 2 8717 D L D 55.0 B1 D 1 52.0 B 10251 1 38.0 9351 1 B2 8717 B 93.0 9351 L 89.9 10039 86.0 10251 78.5 74.0 65.0 50114L0D594.0 5 D 0 L 10184 55.0 Survival 03 050.0 10 D 1 B 10039 08 68.0 5 D 0 B 41.0 10184 10 D 0 L 10184 Papyrus DISEASE - SPECIFIC SURVIVAL METASTASIS - FREE SURVIVAL PROGRESSION - FREE SURVIVAL tg r Rx Arm Stage OVERALL SURVIVAL Surveillance No No Data 4 Year Survival Page A-16 Page 14 A1 86.0 68.0 10 66.1 96.0 10 BA 92.0 10 88.9 5 BA 87.0 BA 1 5 76.0 BA 5 1 5 74.0 BA 1 5 L BA 1 63.5 BA B2 1 5 11941 BA B 1 10107 1 5 L BA 10550 46.0 1 B BAA LR 11941 85.0 85.0 1 B 10550 5 84.0 1 B 5813 5 5 1077 BA L 64.0 5 5265 BA L BA 12241 63.0 2 10 BA 12210 62.0 1 2 10 53.8 BA 53.5 BP 1 10 BAA 52.0 BP 10 11511 10 1 B BA 42.0 11511 10 BAA 1 B 40.0 11511 BA 10 1 40.0 40.0 B BA 11511 0 10 B 93.0 1 85.0 BA 10 10 1 7796 B BA B 7644 5 81.0 0 5 BA BA 80.0 B 10369 78.0 BAA B 1 8333 5 BA 77.0 BC 1 1 5 8257 5 77.0 1 BAA 6937 B2 76.0 1 BA 5 8331 B1 75.0 BA B 10373 5 1 75.0 B 5 10373 BA 1 BAA B 1 5 6935 72.0 B1 5 8615 BA 71.0 72.0 0 1 BA 7796 L 5 68.0 B BA 8333 1 5 5 68.0 BC 11936 1 68.0 BA B BAA 5 8257 66.0 1 BA 5 8331 64.0 B B1 1 5 7644 BA 64.0 1 5 B1 1 BA 10369 5 63.0 BA 3195 BP 1 5 BA B2 2690 60.0 1 BA B 5 11511 60.0 1 BA 59.0 1 8333 B 5 55.0 B2 2 6937 BA 5 49.0 B2 1 5 11400 BA 48.0 B 5 3195 1 BA 38.0 B 2690 5 BA 38.0 B 1 6935 BA 5 BAA 1 5 7164 32.0 B 1 BAA 5 7164 B2 2 1 BA 11511 B1 5 BC 1 BA 10373 10373 B 1 BA B 4076 1 B 11511 B3 2 6141 B3 9265 3195 BP 2690 11511 Ref. Papyrus

METASTASIS - FREE SURVIVAL DISEASE - SPECIFIC SURVIVAL PROGRESSION - FREE SURVIVAL

tg r Rx Arm Stage Radiation: External Beam

Only Reference For For Year

2 % Survival

Document— Document— Archived BAI,ultrasound guided IR, palpably guided Iridium BBBA IR, palpably guided BBAC IR, BBAB Surveillance D 4 3 Interstitial (brachytherapy) (IR) palpably guided IR, BBAA Conformed or 3D technique BB 4 ﬁeld or rotational technique BAC Linear accelerator External beam (EBR) BAB BAA BA Radical perineal prostatectomy 2 (nerve-sparing) RRP Radical retropubic prostatectomy (RRP) AB Radical prostatectomy AAA AA A 1 Treatment codes for Table A-4 (Refer to Table A-3 for Stage codes) Surveillance See treatment codes for curative radiotherapy (RT): Curative radiotherapy Radical prostatectomy: 198 125 125 AU I I Page A-17 Page Table A-5. Complications data for circle graphs eeeIcn 6 AA 0 Severe Incont Severe Incont 264 Severe Incont Proctitis Severe Incont Severe Incont 24.0 % Severe Incont Severe Incont Proctitis Severe Incont Severe Incont A 14.7 % Severe Incont 1 Severe Incont Severe Incont AB Severe Incont 1 666 Severe Incont Stress Incont Stress Incont 5.2 % 498 Stress Incont Stress Incont Stress Incont Stress Incont AA Stress Incont 0 Stress Incont Stress Incont Stress Incont 264 Stress Incont Stress Incont Stress Incont Stress Incont Stress Incont Stress Incont Stress Incont Stress Incont Stress Incont Death Death Death Death Death Death Death Death Death Death Death Death Death Death Death Death Death Death Death Death Cx Name RADICAL PROSTATECTOMY a e Arm Pap Ref 4 AB 1 348 AB 1 308 A AB 1 AA 1 0 666 498 264 10 AA AAA 1 AB 1 1 AAA 11108 AAA 1 11104 0 5732 AA AB 12322 1 1 12374 AA AA 1 12404 AAA 0 AAA 4285 1 1 10303 AAA 10183 AA 2 A 10322 0 AA 1 9407 1 12442 A 10109 1 AB 1301 1 3480 AA 11062 1 AB 1 1273 AA AB 12442 1 AAA 1 AA 1 4285 2 12404 AAA 5732 AAA 2 9407 1 5732 AAA 12442 AA 1 10322 AB 0 AA 2 11104 1 10109 AA AB 10108 1 A 1 10108 1 AA 10108 AAA 1 4285 1 7832 AA AAA 12404 1 1 11104 AA A 0 10303 AB 1 AA 9407 2 AB 2 10109 AA 1 11062 A 1 10108 AB 1 5732 1 5732 3480 1301 1273 Prim. 00%Proctitis Proctitis Proctitis 50.0 % 38.9 % Proctitis 31.5 % Proctitis 19.2 % Proctitis 18.0 % Proctitis Proctitis 13.0 % 12.0 % 11.8 % % Cx Name (%) . Cystitis 2.1 % Bladder Neck Contr. 2.1 % Post Rad Incont 1.0 % 0.0 % 0.0 % 0.0 % . Cystitis Cystitis Cystitis 4.3 % Cystitis 4.0 % Cystitis 3.9 % 2.3 % Cystitis 2.1 % Cystitis Cystitis 2.0 % Cystitis 1.9 % 1.1 % 1.0 % 0.5 % 0.3 % 0.0 % 0.0 % 8.0 % 7.7 % 6.0 % 6.0 % 5.0 % Bladder Neck Contr. 5.0 % 4.0 % Bleeding Major 4.0 % Bleeding Major Bleeding Major 2.0 % Bleeding Major 2.0 % Post Rad Incont 1.4 % 1.0 % Post Rad Incont 1.0 % Post Rad Incont Post Rad Incont 0.6 % Post Rad Incont 0.2 % Incont Stress 0.2 % Incont Stress 0.0 % 0.0 % 0.0 % 0.0 % 0.0 % 0.0 % 0.0 % Death Death Death Proctitis Proctitis Proctitis Proctitis Proctitis Proctitis Proctitis Proctitis Proctitis Proctitis Proctitis Proctitis Death Death Death Death

RADIATION: EXTERNAL BEAM

Only Reference For

a e Arm Pap Ref 891BAB 1 9899 % 22.0 % 29.0 % 19.9 BAA % 14.0 BA 1 % 14.0 BAA 1 0 % 10.7 BA 12210 BA 1 % 10.0 3649 1 % 9265 10.0 BA 1 4383 BA BAA 4383 1 1 5813 11400 6215 BA 0 11939 BA 1 11400 BAB BAA 1 BA 1 1 9733 8161 2160 6364 1 BA 16.0 % 16.0 % 12.0 BA 1 BA 1 6364 4076 891BAB 1 9899 13 BA BA 1 BA 1 BA 1 0 11936 BA 6813 0 BAA 5219 0 1077 BAA % BA 55.0 11939 1 % BA 42.0 1 % 32.0 % 29.7 1 8798 BAB 10748 BAC 1 BAB 5813 2 BA 1 9737 1 11201 11201 9733 1078 BA BA 1 BA 1 BA 1 1 11936 PE BAA 4897 BA 0 5219 % 12.8 1 6813 BA BAB 0 1 8798 BA 6937 BAA 1 11939 BAB 1 9899 1 BA BA 6937 0 1 8161 BA 9899 1 11939 BAA BA 9737 1 BA 1 1 3649 BA BAA 10748 1 BA 0 6813 BA 1 6937 1 11936 BA BA 8798 1 1 7644 6937 10550 6935

Document— Document— Archived Prim. % Cx Name (%) . Cystitis 2.4 % PE 0.7 % Bleeding Major 2.0 % 0.0 % 0.0 % 0.0 % . Bladder Neck Contr. 4.5 % 5.1 % Urethral Stricture Urethral Stricture Urethral Stricture Urethral 5.1 % Cystitis 3.3 % Cystitis 3.0 % 3.0 % Cystitis 2.6 % Cystitis Cystitis 2.0 % Cystitis 2.0 % 1.8 % 0.7 % Bladder Neck Contr. 9.7 % Bladder Neck Contr. 7.8 % 7.0 % PE 5.0 % PE PE 4.5 % PE 2.6 % 1.6 % 2.4 % PE Bleeding Major Bleeding Major 6.9 % Bleeding Major 2.1 % 1.7 % Bleeding Major 2.1 % Post Rad Incont Post Rad Incont 2.0 % Post Rad Incont 2.0 % Post Rad Incont 1.0 % Post Rad Incont 0.4 % Incont Stress 1.7 % Incont Stress 0.5 % Incont Stress 0.6 % Incont Stress 0.4 % 0.2 % 0.2 % Proctitis Proctitis Proctitis Proctitis Proctitis Proctitis Proctitis Proctitis Proctitis Proctitis Cystitis Cystitis Cystitis Proctitis Death Death Death Proctitis Proctitis (INTERSTITIAL RADIOTHERAPY) RADIATION: BRACHYTHERAPY a e Arm Pap Ref 2729 1 BB 44.0 % 44.0 % 29.0 BB % 16.3 1 BB 1 1 BB 2729 BB 0 7670 1 4287 BB 1 4280 BB 3898 0 1 5610 10517 3087 341 6344 0 11645 071BB 0 BB 1 1 10517 1 3087 3898 10693 601 7670 BB 0 0 4280 10517 BB 1 3087 271BB 1 1 0 7671 4287 10517 15 1 11850 2729 1 BB 94.0 % 94.0 % 37.5 0 2 BB 0 BB 1 10517 0 11936 11645 1 2729 BB 4280 1 1 6344 0 11850 4639 11645 BB 0 0 BB 1 4280 BB 1 10517 1 0 4287 7671 BB 4639 BB 1 3914 BB 1 1 5610 0 3898 0 4287 1 10517 1 0 3914 BB 6344 0 BB 1 7670 1 3914 10517 1 1 3087 3087 2 11850 7670 11936 13 2 1 11936 11850 BB33.0 % BBAB 3.0 % BBAA BC26.0 % BBAC BBAC Prim. BA8.3 % BBAA 75.0 % BBBA BB33.0 % BBAB 0.8 % BBAA BA3.0 % 0.0 % BBAA BBAA BBBA BA1.5 % 1.0 % BBAA BBAA BBAC 12.0 % 10.0 % BBAC BBBA BBAC 5.0 % BBAA 4.0 % 2.0 % BBAA BBAA 4.6 % 2.0 % BBAA BBAA 2.0 % BBAC 1.5 % BBAB BBAA BBAA 1.0 % BBBA BBAB BBAA BA2.0 % BBAA BBBA (%) 4.4 % 9.0 % 3.5 % 2.7 % 0.5 % 7.3 % 6.0 % 0.6 % 8.8 % 1.3 % 3.7 % 9.0 % 2.0 % 6.0 % 1.0 % 1.0 % 1.6 % 9.5 % 8.0 % 4.7 % 2.4 % 0.1 % 9.4 % 4.6 % 1.0 % 7.0 % Page A-18 Page Impotence Impotence Impotence Impotence Impotence Impotence Impotence Impotence Impotence Impotence Stricture Urethral Impotence Impotence 14.6 % Impotence Impotence Impotence AA Urethral Stricture 0 Stricture Urethral Urethral Stricture Urethral Stricture 6.8 % Urethral Stricture 264 Urethral Stricture Bladder Neck Contr. Bladder Neck Contr. AB Bladder Neck Contr. 1 Bladder Neck Contr. Bladder Neck Contr. Bladder Neck Contr. 308 Bladder Neck Contr. Bladder Neck Contr. Bladder Neck Contr. Bladder Neck Contr. Bladder Neck Contr. Cystitis Bladder Neck Contr. Cystitis Bladder Neck Contr. 2.9 % PE 1.0 % PE PE Cystitis PE AB PE AA 1 12.0 PE % 0 PE PE 498 PE A 264 Major Bleeding 1 Major Bleeding Major Bleeding Major Bleeding Major Bleeding 666 Severe Incont Severe Incont Severe Incont Severe Incont Severe Incont Severe Incont Cx Name RADICAL PROSTATECTOMY RADICAL 9 B94.1 % 90.0 % AB AB 1 1 498 308 a e Arm Pap Ref 6 AA 0 264 00 AA AAA 1 AAA 1 AAA 1 10303 AA 1 AA 12322 1 AAA 1 11104 1 10183 AAA 12404 AAA 0 5631 AAA 1 8827 AA 1 12374 AAA 1 AB 10322 2 1 12374 AA AA 11108 1 2 10109 AA AB 4285 1 1 10108 5732 AA 12404 AA 1 5732 AAA 1 AA 1 10303 AA 1 11108 AB 1 12322 2 12404 A 10108 AAA 1 Stricture Urethral 10108 AAA 1 AA 1 3.1 % 11062 AA 0 AA 10322 0 AA 2 11104 AB 1 10183 AA 1 10109 0 5732 AA AB 3480 1 1 1273 AA 264 AAA 1 10303 AA 1 AB 4285 0 1 12404 A 11104 1 10109 1273 AA AA 11062 1 2 A AA 1 12404 1 AA 5732 A 1 11062 1 12442 3480 8925 Prim. 100.0 % 86.8 % 70.4 % 65.0 % 56.3 % 52.0 % 52.0 % 44.2 % 42.1 % 41.4 % Impotence 39.8 % 30.8 % 29.0 % Stricture Urethral Stricture Urethral 13.0 % 11.4 % Cystitis 11.5 % Cystitis Cystitis Cystitis 15.4 % 13.0 % Cystitis 12.0 % 11.0 % % Cx Name (%) 7.7 % Urethral Stricture Urethral Stricture Urethral Stricture Urethral 7.7 % 5.5 % Stricture Urethral 3.9 % Stricture Urethral Stricture Urethral 2.6 % Stricture Urethral 2.0 % Cystitis 1.0 % 1.0 % 0.8 % . Im Im Im 9.0 % Im 8.0 % Im 7.7 % 2.0 % 2.0 % Stricture Urethral Stricture Urethral Stricture Urethral 9.1 % Stricture Urethral 9.0 % 8.0 % Stricture Urethral 7.0 % Stricture Urethral Stricture Urethral 5.6 % Stricture Urethral 5.1 % Stricture Urethral 5.0 % 3.0 % 0.5 % Cystitis 5.6 % Cystitis 1.0 % Cystitis 6.0 %

potence potence potence potence potence

RADIATION: EXTERNAL BEAM

Only Reference For

a e Arm Pap Ref 1877 1 BA 41.0 % 41.0 BA 1 1877 BA BA 1 1 5813 4383 Im % 65.0 Im BAC Im Im 2 % 22.0 % 21.0 % 12.5 11201 BAA % 12.0 BA 0 BA 1 1 BA 9265 1 4383 4897 3649 3649 1 BA 12.0 % 12.0 BA 1 3649 BA 0 11939 Im Im % 29.3 % 26.0 BAA Im BAB 1 1 % 12.0 8161 9733 BA 1 6364 21 BAA BA 1 BA 1 BA 1 1 12210 BAA BA 5219 1 % BAA 80.0 1 6813 BAB 1 4076 1 10748 BAB 9737 1 6141 9899 11201 1078 1 BA 29.2 % 29.2 % 26.7 % 15.0 BA BA 1 BAA 1 BA 0 1 1078 BAA 1142 1 8798 4076 12210 BA BAB 1 BA 1 BAA 1 0 11400 BA 9733 BAB 1 6937 0 8798 BA BA 1 BA 0 1078 1 1623 11936 4110 4897 Im % 30.0 Im % 25.0 BA 1 BA 1 7522 % 11.0 4383 BA 1 11400

Document— Document— Archived Prim. % Cx Name (%) 8.9 % 8.0 % 4.6 % 2.0 % 2.0 % 1.7 % 1.5 % 1.5 % 1.4 % 1.0 % 0.4 % 4.7 % 4.0 % 6.0 % 6.0 % 6.0 % 4.7 % 3.9 % 3.7 % 2.9 % 2.5 % 2.3 % Urethral Stricture Urethral Stricture oe Refer to Table A-4 footnote for treatment codes. Note: potence potence potence potence potence potence potence potence potence (INTERSTITIAL RADIOTHERAPY) RADIATION: BRACHYTHERAPY RADIATION: a e Arm Pap Ref 491 7419 5642 1 BB 78.0 % 78.0 BB 1 5642 BB 0 1 0 4280 10693 10517 4287 1 BB 50.0 % 50.0 % 25.0 BB BB 1 1 4287 2729 0 3914 15 1 11850 3898 1 BB 12.5 % 12.5 1 BB 1 6344 3898 BBAB BA3.8 % BBBA BBAA BA2.0 % BBAA Prim. BBBA BC61.3 % BBAC (%) 4.0 % 5.6 % 2.0 % 8.8 % Page A-19 Page

Reported Rates Reported Rates 100.0 % 100.0% Figure A-9. Articles reporting severe incontinence as a complication of Figure A-7. Articles reporting death as a complication of radical 20.0 % 40.0 % 60.0 % 80.0 % 20.0% 40.0% 60.0% 80.0% 0.0 % 0.0% 1965 9517 9518 9519 1995 1990 1985 1980 1975 1970 1965 aia rsaetm,by year radical prostatectomy, by year prostatectomy, 1970 1975 Year Reported Year Reported 1980 1985

1990

Only Reference For

1995

Document— Document— Reported Rates Reported Rates Archived 100.0 % 100.0% Figure A-8. Articles reporting stress incontinence as a complication of radical Figure A-10. Articles reporting major bleeding as a complication of radical 20.0 % 40.0 % 60.0 % 80.0 % 20.0% 40.0% 60.0% 80.0% 0.0 % 0.0% 1965 9517 9518 9519 1995 1990 1985 1980 1975 1970 1965 rsaetm,by year prostatectomy, rsaetm,by year prostatectomy, 1970 1975 Year Reported Year Reported 1980 1985 1990 1995 Page A-20 Page

Reported Rates Reported Rates 100.0 % Figure A-11. Articles reporting pulmonary embolus as a complication 100.0 % 20.0 % 40.0 % 60.0 % 80.0 % Figure A-13. Articles reporting urethral stricture as a complication of 20.0 % 40.0 % 60.0 % 80.0 % 0.0 % 0.0 % 9517 9518 9519 1995 1990 1985 1980 1975 1970 1965 9517 9518 9519 1995 1990 1985 1980 1975 1970 1965 frdclpottcoy by year of radical prostatectomy, aia rsaetm,by year radical prostatectomy,

Year Reported Year Reported

Only Reference For

Document— Document— Reported Rates Reported Rates Archived 100.0 % Figure A-12. Articles reporting bladder neck contracture as a complication 100.0 % 20.0 % 40.0 % 60.0 % 80.0 % Figure A-14. Articles reporting impotence as a complication of radical 20.0 % 40.0 % 60.0 % 80.0 % 0.0 % 0.0 % 9517 9518 9519 1995 1990 1985 1980 1975 1970 1965 9517 9518 9519 1995 1990 1985 1980 1975 1970 1965 frdclpottcoy by year of radical prostatectomy, rsaetm,by year prostatectomy, Year Reported Year Reported Page A-21 Page

Reported Rates Reported Rates 100.0 % 100.0 % Figure A-17. Articles reporting major bleeding as a complication of external Figure A-15. Articles reporting death as a complication of external 20.0 % 40.0 % 60.0 % 80.0 % 20.0 % 40.0 % 60.0 % 80.0 % 0.0 % 0.0 % 9517 9518 9519 1995 1990 1985 1980 1975 1970 1965 1995 1990 1985 1980 1975 1970 1965 emrdohrp,by year beam radiotherapy, by year beam radiotherapy,

Year Reported Year Reported

Only Reference For

Document— Document— Reported Rates Reported Rates Archived 100.0 % 100.0 % Figure A-18. Articles reporting bladder neck contracture as a complication Figure A-16. Articles reporting postradiation incontinence as a complication 20.0 % 40.0 % 60.0 % 80.0 % 20.0 % 40.0 % 60.0 % 80.0 % 0.0 % 0.0 % 9517 9518 9519 1995 1990 1985 1980 1975 1970 1965 1995 1990 1985 1980 1975 1970 1965 fetra emrdohrp,by year of external beam radiotherapy, by year of external beam radiotherapy, Year Reported Year Reported Page A-22 Page

Reported Rates Reported Rates 100.0 % 100.0 % Figure A-21. Articles reporting urethral stricture as a complication Figure A-19. Articles reporting proctitis as a complication of external 20.0 % 40.0 % 60.0 % 80.0 % 20.0 % 40.0 % 60.0 % 80.0 % 0.0 % 0.0 % 9517 9518 9519 1995 1990 1985 1980 1975 1970 1965 1995 1990 1985 1980 1975 1970 1965 fetra emrdohrp,by year of external beam radiotherapy, emrdohrp,by year beam radiotherapy,

Year Reported Year Reported

Only Reference For

Document— Document— Reported Rates Reported Rates Archived 100.0 % 100.0 % Figure A-22. Articles reporting impotence as a complication of Figure A-20. Articles reporting cystitis as a complication of external 20.0 % 40.0 % 60.0 % 80.0 % 20.0 % 40.0 % 60.0 % 80.0 % 0.0 % 0.0 % 9517 9518 9519 1995 1990 1985 1980 1975 1970 1965 1995 1990 1985 1980 1975 1970 1965 xenlba aiteay by year external beam radiotherapy, by year beam radiotherapy, Year Reported Year Reported Page A-23 Page

Reported Rates Reported Rates 100.0% 100.0% Figure A-23. Articles reporting death as a complication of Figure A-25. Articles reporting major bleeding as a complication 20.0% 40.0% 60.0% 80.0% 20.0% 40.0% 60.0% 80.0% 0.0% 0.0% 1965 1965 rcyhrp,by year brachytherapy, fbahteay by year of brachytherapy, 1970 1970 1975 1975 Year Reported Year Reported 1980 1980 1985 1985

1990 1990

Only Reference

1995 1995 For

Document— Document— Reported Rates Reported Rates Archived 100.0% 100.0% Figure A-26. Articles reporting pulmonary embolus as a complication Figure A-24. Articles reporting postradiation incontinence as a 20.0% 40.0% 60.0% 80.0% 20.0% 40.0% 60.0% 80.0% 0.0% 0.0% 1965 1965 fbahteay by year of brachytherapy, by year complication of brachytherapy, 1970 1970 1975 1975 Year Reported Year Reported 1980 1980 1985 1985 1990 1990 1995 1995 Page A-24 Page

Reported Rates Reported Rates 100.0% 100.0% Figure A-29. Articles reporting cystitis as a complication of Figure A-27. Articles reporting bladder neck contracture as a 20.0% 40.0% 60.0% 80.0% 20.0% 40.0% 60.0% 80.0% 0.0% 0.0% 1965 1965 rcyhrp,by year brachytherapy, opiaino rcyhrp,by year complication of brachytherapy, 1970 1970 1975 1975 Year Reported Year Reported 1980 1980 1985 1985

1990 1990

Only Reference

1995 1995 For

Document— Document— Reported Rates Reported Rates Archived 100.0% 100.0% Figure A-30. Articles reporting urethral stricture as a complication Figure A-28. Articles reporting proctitis as a complication of 20.0% 40.0% 60.0% 80.0% 20.0% 40.0% 60.0% 80.0% 0.0% 0.0% 1965 1965 fbahteay by year of brachytherapy, by year brachytherapy, 1970 1970 1975 1975 Year Reported Year Reported 1980 1980 1985 1985 1990 1990 1995 1995 Page A-25 Page

Reported Rates 100.0% Figure A-31. Articles reporting impotence as a complication of 20.0% 40.0% 60.0% 80.0% 0.0% 1965 rcyhrp,by year brachytherapy, 1970 1975 Year Reported 1980 1985

1990

Only Reference

1995 For

Document— Document— Archived

Page B-1 Page pedxB Data abstraction form Appendix B:

Only Reference For

Document— Document— Archived

Page B-2 Page

Only Reference For

Document— Document— Archived

Page B-3 Page

Only Reference For

Document— Document— Archived Page C-1 Page pedxC ..life expectancy table U.S. Appendix C: ore ainlCne o elhSaitc.VtlSaitc fteUie tts 94 o.2 ieTbe,Scin6 ytsil,M,1994. MD, Section 6. Hyattsville, Vol. 2. Life Tables, 1994, National Center for Health Statistics. Vital Statistics of the United States, Source: g aeMl aeMale Male Male Male Age 41. 591. 13.7 14.3 14.8 15.4 14.6 15.9 15.2 16.5 15.8 17.1 16.4 15.9 17.8 17.0 16.6 18.4 17.6 17.3 19.0 18.3 18.0 19.7 15.8 18.9 18.7 20.4 16.4 19.6 21.1 19.4 17.1 20.3 21.8 20.2 17.8 21.0 22.5 21.0 18.5 21.7 64 21.7 23.2 22.4 63 19.2 22.5 24.0 23.2 62 20.0 23.3 24.7 23.9 61 20.7 24.2 25.4 60 21.5 24.7 25.0 26.2 22.3 25.5 25.8 27.0 59 23.1 26.3 26.7 27.7 58 23.9 27.0 28.5 57 27.6 24.7 27.8 29.3 56 28.4 25.5 28.6 30.1 55 29.3 26.4 29.4 54 30.2 30.3 53 27.2 31.1 31.1 52 28.1 32.0 31.9 51 28.9 32.9 50 29.8 33.8 30.7 34.7 49 31.5 35.6 48 32.4 47 33.3 46 34.2 45 35.1 44 43 42 41 40 l ae WieTtlBlack Total White All races xetto flf tsnl er fae yrc n e:Uie tts 1990 United States, by race and sex: Expectation of life at single years of age,

All Other

Only Reference For

Document— Document— Archived g aeMl aeMale Male Male Male Age 55252535.0 5.3 5.7 6.0 6.3 5.3 6.7 5.6 5.9 7.1 6.3 7.4 6.7 5.2 7.8 7.0 5.5 8.2 5.9 8.6 7.4 6.3 9.0 7.8 6.7 5.2 8.3 7.1 5.6 8.7 9.4 5.9 9.1 7.5 9.9 6.3 9.5 7.9 10.3 6.7 8.4 10.7 85 7.1 10.0 8.9 84 11.2 10.5 9.4 83 7.5 11.7 10.9 9.9 82 7.9 12.2 11.4 81 8.4 10.4 12.7 80 8.9 11.9 11.0 13.2 9.4 12.4 11.5 79 9.9 12.9 12.1 78 10.4 13.5 77 12.7 10.9 14.0 76 13.3 11.5 75 13.9 12.0 74 14.6 73 12.6 15.2 72 13.2 71 13.8 70 14.5 15.1 69 68 67 66 65 l ae WieTtlBlack Total White All races All Other

Page I-1 Page

aaiaeuce n,9–10 and, inadequacies data stetetatraie ,5 5 8 39 38, 15, 5, 2, alternative, treatment as

aaetato o,9 for, extraction data ehooia mrvmnsi,7 6 44 16, 7, in, improvements technological

aadslyfrsria n ies rgeso n,10 and, progression disease and survival for display data agtvlm n,17 and, volume target

Prostate Cancer Clinical Guidelines Clinical Cancer Prostate uvvldt o,2,2–0 2 33 32, 28–30, 25, for, data survival

tgn f –,13–15 1–2, of, staging rgeso aafr 6 34 26, for, data progression

aua itr f ,12–13 1, of, history natural ain eeto o,5 61,38 16–17, 5, for, selection patient

otlt rm ,1 ,1,3,4,41 40, 37, 12, 4, 1, i, from, mortality ofra hrp n,7 6 44 16, 7, and, therapy conformal

rwhrt f ,12–13 1, of, rate growth opiain rm ,1,2,3,3,39 36, 35, 27, 17, 5, from, complications

eeto f i of, detection datgsaddsdatgso,5 39 5, of, disadvantages and advantages

akrudo,12 12 1–2, of, background Radiotherapy also See radiotherapy. beam External

ciﬁc stages ciﬁc

rciedsucin ,3 ,2,2,2,3,3,3,3,40 39, 38, 36, 31, 27, 22, 21, 5, 3, 2, dysfunction, Erectile

Clinically localized prostate cancer; spe- cancer; prostate localized Clinically also See cancer. Prostate

Survival See survival. Progression-free

ae,3 12,2,34–35 26, 21–22, 3, rates,

Survival See survival. Disease-specific aeois(oa,dsat iceia,ttl,dfiiin f 24 of, definitions total), biochemical, distant, (local, categories

oioigwt,2,40 20, with, monitoring nlsso aa 6 34–35 26, data, of analysis

eeto sn,i using, detection rgeso,3 ,2,3,40 33, 21, 8, 3, Progression,

lnclsaiguig ,14 2, using, staging clinical rcii,5 1 7 1 5 6 39 36, 35, 31, 27, 21, 5, Proctitis,

evclmhnd iscin(LD,2 4 2 42 32, 14, 2, (PLND), dissection node lymph Pelvic Digital rectal examination (DRE) examination rectal Digital

irha 7 6 39 36, 27, Diarrhea, P

Mortality See Death.

D Survival See survival. Overall

Treatment outcomes Treatment See Outcomes.

ytts ,3 ,2,2,2,3,3,3,39 38, 36, 31, 27, 22, 21, 5, 3, 2, Cystitis, O

rohrp,2 5 43 15, 2, Cryotherapy,

otfcos 2 0 45 40, 22, factors, Cost ainlIsiue fHat NH,i (NIH), Health of Institutes National

optrzdtmgah C)sas ,14 2, scans, (CT) tomography Computerized

N tions

Only Reference

speciﬁc complications; Treatment complica- Treatment complications; speciﬁc See For Complications.

ramn eae,2 ,2,2,2,3,3,38–39 36, 31, 27, 22, 21, 3, 2, related, treatment

ooetlcne,1 12 1, cancer, Colorectal

rmpott acr ,1 ,1,3,4,41 40, 37, 12, 4, 1, i, cancer, prostate from

eomnain o uuersac n –,43–45 6–7, on, research future for recommendations

Mortality

iiain frsac n ,91,42–43 9–10, 6, on, research of limitations

Survival See survival. Metastasis-free

eeto aefr i for, rate detection

eaaayi,dﬁiino,9 of, deﬁnition Meta-analysis,

Document— Document— Archived 12 1–2, for, information Archived background

antcrsnneiaig(R) ,14 2, (MRI), imaging resonance Magnetic

Stage T2 (B) T2 Stage

Prostate cancer; Prostate also See cancer. prostate localized Clinically

Staging See staging. Clinical

yp oe stre oue(aiteay,16–17 (radiotherapy), volume target as nodes Lymph hmteay ,1,44 15, 2, Chemotherapy,

(PLND)

Pelvic lymph node dissection node lymph Pelvic also See 42. dissection, node Lymph

ugcne,1 12 1, cancer, Lung

stetetatraie ,5 5 38–40 15, 5, 2, alternative, treatment as ramn eeto ae n ,1–3 6 37 16, 12–13, 4, on, based selection treatment

ehiusfr 8 43 18, for, techniques siaino,19 of, estimation

uvvldt o,2,2–0 32 28–30, 25, for, data survival ieepcac,21 expectancy, Life

rgeso aafr 6 34–35 26, for, data progression

ain eeto o,5 71,38 17–18, 5, for, selection patient

opiain rm ,1,2,3,40 31, 27, 17, 5, from, complications

eetWimr AC)saigsse,1 3 14 13, 1, system, staging (ABCD) Jewett-Whitmore

datgsaddsdatgso,5 39–40 5, of, disadvantages and advantages

Radiotherapy also See Brachytherapy.

leig(ao) ,3 1 2 7 1 6 8 39 38, 36, 31, 27, 22, 21, 3, 2, (major), Bleeding

Brachytherapy See radiotherapy. Interstitial lde ekcnrcue ,2,2,3,3,38 36, 31, 27, 21, 2, contracture, neck Bladder

Urinary incontinence Urinary See Incontinence. (PSA)

Erectile dysfunction Erectile See Impotence. Prostate speciﬁc antigen speciﬁc Prostate also See 44. 6, markers, Biochemical

I B

elhsau,tetetslcinbsdo,4 37 4, on, based selection treatment status, Health nrgndpiain ,1,44 15, 2, deprivation, Androgen

H mrcnJitCmite(N)saigsse,1 3 14 13, 1, system, staging (TNM) Committee Joint American

Prostate cancer Prostate also See 12. 1, Adenocarcinoma,

culadataildt,ueo,1,23–24 10, of, use data, actuarial and Actual lao rdn ytm 13 system, grading Gleason

G A Index

Page I-2 Page

rnr notnne ,3 ,2,2,2,3,3,3,3,3,40 39, 38, 36, 35, 31, 27, 22, 21, 5, 3, 2, incontinence, Urinary ramn opiain f 36 of, complications treatment

uvvlrt n,2 7 33 17, 2, and, rate survival

rtrlsrcue ,2,2,3,3,38 36, 31, 27, 21, 2, stricture, Urethral

eiwo ieaueo,8 9 8, on, literature of review

U rgeso n,3,35 34, and, progression

iiain nltrtr o,6 for, literature in limitations

eeto aea,i at, rate detection ramn eeto ae ncaatrsiso,1,37–38 17, of, characteristics on based selection treatment

Stage T2 (B) T2 Stage

tg eemnto f –,13–15 1–2, of, determination stage

ramn ucmsfr 2 for, outcomes treatment

rwhrt f ,12–13 1, of, rate growth uvvlrt n,2 17 2, and, rate survival

eeto aea,i at, rate detection rdn,13 grading,

Stage T1 (A) T1 Stage

Clinically localized prostate cancer prostate localized Clinically also See Tumors.

tg 1(2,i 35 i, (D2), M1 Stage

tnad,4 37–38 4, standards, Stage T1c Stage See BO. Stage

pnlcr opeso,41 compression, cord Spinal eeso,3 ,37 6, 3, of, levels

eu cdpopaae ,1,1,1,24 17, 15, 14, 2, phosphatase, acid Serum

lentvs 5 alternatives,

eia eils ,1–8 38 16–18, 4, vesicles, Seminal

Treatment recommendations Treatment

aiblt fdt n –0 2 2 42–43 32, 22, 9–10, on, data of variability

ye f ,3 1 22 21, 3, 2, of, types Progression also

See 43. 40, 34, 33, 26, 24, 22, 21, 19, 3, disease, of Recurrence alsadgah umrzn,22–32 summarizing, graphs and tables

etlijr,2 ,2,2,2,3,3,39 36, 35, 27, 22, 21, 3, 2, injury, Rectal

rmaalbeltrtr,3 22 3, literature, available from

stetetatraie ,5 5 38–40 15, 5, 2, alternative, treatment as

nlsso umr also,32–35 of, tables summary of analysis uvvldt o,2,2–0 2 33 32, 28–30, 25, for, data survival

eomnain o eerho,7 44 7, on, research for recommendations Treatment outcomes Treatment

rgeso aafr 6 34–35 26, for, data progression

rbeswt aafr 0 35 10, for, data with problems

ain eeto o,5 61,38 16–18, 5, for, selection patient

ucmsdt o,1,2,3,35–36 31, 27, 10, for, data outcomes

ento f ,38 4, of, deﬁnition

41 opiain rm ,1,2,3,3,3,3,40 39, 36, 35, 31, 27, 17, 5, from, complications Only Reference For

datgsaddsdatgso,5 39–40 5, of, disadvantages and advantages ramn opiain,2 ,5 1 2 7 1 53,3,3,40, 39, 38, 35–36, 31, 27, 22, 21, 5, 3, 2, complications, Treatment

radiotherapy

rnueha eeto ftepott TR) 7 9 40 19, 17, (TURP), prostate the of resection Transurethral

Brachytherapy; External beam External Brachytherapy; also See Radiotherapy.

rnrca lrsngah TU) ,1,1,39–40 17, 14, 2, (TRUS), ultrasonography Transrectal ainciebn cn ,1,16 15, 2, scan, bone Radionuclide

stetetatraie ,5 5 38–39 15, 5, 2, alternative, treatment as Radiotherapy, complications from complications Radiotherapy, See radiotherapy. from Toxicity

Document— Document—

Archived 33 32, 28–29, 25, for, data Archived survival

N tgn ytm ,1,14 13, 1, system, staging TNM

eomnain o eerho,7 3 44 43, 7, on, research for recommendations

hrohrp,2 15 2, Thermotherapy,

rgeso aafr 6 34 26, for, data progression

efrac f 6 43 16, of, performance T

ain eeto o,1–6 38 15–16, for, selection patient

ain g n,3 and, age patient

ae,2 ,2,2,28–33 25, 21, 3, 2, rates,

vrl uvvlrtsfr 28 for, rates survival overall

pcfi) entoso,24 of, definitions specific), ev-prn ehius 6 9 43 39, 16, techniques, nerve-sparing

ieepcac n eiinfr 16 for, decision and expectancy life aeois(vrl,porsinfe,mtsai re disease free, metastasis free, progression (overall, categories

ento f ,38 4, of, deﬁnition

nlsso,2,32–33 25, of, analysis

opiain rm 7 1 5 6 38–40 36, 35, 31, 27, from, complications

uvvl ,8 0 1 40 21, 10, 8, 3, Survival, datgsaddsdatgso,5 38–39 5, of, disadvantages and advantages

aia rsaetm,4 38 4, prostatectomy, Radical stetetatraie ,5 5 8 40–41 38, 15, 5, 2, alternative, treatment as

aito ytts ,3 ,2,2,2,3,3,3,39 38, 36, 31, 27, 22, 21, 5, 3, 2, cystitis, Radiation uvvldt o,2,2–1 2 3 40 33, 32, 28–31, 25, for, data survival

eomnain o eerho,7 44 7, on, research for recommendations

rgeso aafr 6 34 26, for, data progression

ult flf,7 2 1 45 41, 22, 7, life, of Quality

ain eeto o,1,38 19, for, selection patient

ai o aaeetb,18–19 by, management for basis

datgsaddsdatgso,5 40–41 5, of, disadvantages and advantages umnr moim ,2,2,3,3,39 36, 31, 27, 21, 2, embolism, Pulmonary

scooia atr,3 1 41 21, 3, factors, Psychological Surveillance

Radical prostatectomy Radical See Prostatectomy.

Urinary incontinence Urinary See incontinence. urinary Stress

speitro evclmhnd eatss 14–15 metastases, node lymph pelvic of predictor as

tnadptet ,37 6, patient, Standard oioigporsinwt,2,2,3,4,45 40, 33, 24, 20, with, progression monitoring

odtriercrec,3 9 4 3 43 33, 24, 19, 3, recurrence, determine to ehd sdfr –,14–15 1–2, for, used methods

eeto sn,i 4 3 44 43, 14, i, using, detection

mrvmnsnee,1 ,7 3 44 13, 7, 2, 1, needed, improvements

lnclsaiguig ,2 3 4 5 44 15, 14, 13, 2, 1, using, staging clinical

specific stages specific also See Staging. Prostate specific antigen (PSA) antigen specific Prostate

ramn opiain aaad 10 and, data complications treatment tg 3T C,i 5 37 35, i, (C), T3-T4 Stage

ehd n entoso,8–9 of, deﬁnitions and methods

tg 1,1 ,14 6, 1, T1c, Stage

ieauesace sdi,9 in, used searches literature

tg 2() 17 (C), T2 Stage

10–11

literature citations and panel opinions in discussion sections in, sections discussion in opinions panel and citations literature ramn ucmsfr ,23 2, for, outcomes treatment American Urological Association, Inc.

Board of Directors (1995 – 1996)

Charles F. McKiel, Jr., MD* Gerald Sufrin, MD* Joseph N. Corriere, Jr., MD Jack W. McAninch, MD* Thomas P. Ball, Jr., MD* David M. Drylie, MD C. Eugene Carlton, Jr., MD* Lloyd H. Harrison, MD* G. James Gallagher William R. Turner, Jr., MD* Lawrence W. Jones, MD* Richard J. Hannigan Roy J. Correa, Jr., MD* Harry E. Lichtwardt, MD Thomas D. Brockman Harry C. Miller, Jr., MD* Abraham T. K. Cockett, MD Melanie H. Younger Dennis J. Card, MD* H. Logan Holtgrewe, MD E. Darracott Vaughan, Jr., MD* Winston K. Mebust, MD *Voting member Joseph C. Cerny, MD* Martin I. Resnick, MD

Practice Parameters, Guidelines and Standards Committee (1995 – 1996)

Winston K. Mebust, MD, Chair Drogo K. Montague, MD Linda D. Shortliffe, MD, Consultant Joseph W. Segura, MD, Vice-Chair Glenn M. Preminger, MD Edward S. Tank, MD, Consultant Reginald C. Bruskewitz, MD Joseph A. Smith, MD Claus G. Roehrborn, MD, Facilitator Jack S. Elder, MD Ian M. Thompson, Jr., MD Roy J. Correa, Jr., MD, Ex-officio Thomas C. Fenter, MD Charles E. Hawtrey, MD, Consultant Charles F. McKiel, Jr., MD, Ex-officio ArchivedJohn B. Forrest, MD John D. McConnell,Document— MD, Consultant William R. Turner, Jr., MD, Ex-officio Health Policy Department Staff and Consultants

Stephanie Mensh Lisa Emmons Randolph B. Fenninger Director Health Policy Manager Washington Liaison SuzanneFor Boland Pope ReferenceTracy Kiely Justine GermannOnly Guidelines Coordinator Health Policy Information Assistant Legislative Associate Julie Bowers Betty Roberts William Glitz Administrative Assistant Health Policy Assistant Public Relations Consultant Kim Hagedorn Megan Cohen Karen Costanzo Health Policy Projects Coordinator Government Relations Coordinator University of Texas, Robin Hudson Roger Woods Southwestern Medical School Secretary Government Relations Assistant

This Report on the Management of Clinically Localized Prostate Cancer was developed by the Prostate Cancer Clinical Guidelines Panel of the American Urological Association, Inc. This Report is intended to furnish to the skilled practitioner a consensus of clear principles and strategies for quality patient care, based on current professional literature, clinical experience and expert opinion. It does not establish a fixed set of rules or define the legal standard of care, pre- empting physician judgment in individual cases. An attempt has been made to recommend a range of generally acceptable modalities of treatment, taking into account variations in resources and in patient needs and preferences. It is recom- mended that the practitioner articulate and document the basis for any significant deviation from these parameters. Finally, it is recognized that conformance with these guidelines cannot ensure a successful result. The parameters should not stifle innovation, but will, themselves, be updated and will change with both scientific knowledge and technological advances. American Urological Association, Inc. Prostate ontheManagementofLocalized Cancer Report 1000 Corporate Boulevard Linthicum, Maryland 21090

Archived Document— For Reference Only December 1995

ISBN 0-9649702-0-1