MANAGEMENT OF A POSITIVE SURGICAL MARGIN AFTER RADICAL PROSTATECTOMY: DECISION ANALYSIS

0022-5347/00/1641-0093/0 THE JOURNAL OF UROLOGY® Copyright © 2000 by AMERICAN UROLOGICAL ASSOCIATION, INC.®

Vol. 164, 93–100, July 2000 Printed in U.S.A.

MANAGEMENT OF A POSITIVE SURGICAL MARGIN AFTER RADICAL PROSTATECTOMY: DECISION ANALYSIS GARY D. GROSSFELD,* VIDA S. TIGRANI, DAVID NUDELL, MACK ROACH, III, VIVIAN K. WEINBERG, JOSEPH C. PRESTI, JR.,† ERIC J. SMALL‡ AND PETER R. CARROLL§ From the Departments of Urology, Radiation Oncology and Medicine, University of California-San Francisco and Program in Urologic Oncology, University of California-San Francisco-Mt. Zion Cancer Center, San Francisco, California

ABSTRACT

Purpose: We created and tested a decision analysis model to help determine the preferred management of a positive surgical margin(s) after radical prostatectomy. Materials and Methods: We constructed a decision tree modeling surveillance versus immediate prophylactic adjuvant radiation in patients with a positive surgical margin(s) after radical prostatectomy. Literature and institution based estimates were determined for certain factors, including the probability of undetectable prostate specific antigen (PSA) in patients followed expectantly postoperatively and those treated with immediate adjuvant radiotherapy, complications of radiotherapy after prostatectomy and probability of undetectable PSA in those treated with therapeutic radiation for detectable PSA postoperatively. A panel of experts assigned utilities to the various outcomes. Sensitivity analysis was performed to determine threshold values required to change the model outcome. Results: Using average probability estimates from a literature review the decision model recommended initial surveillance. Sensitivity analysis demonstrated that the model depended on the probability of disease recurrence in men followed expectantly after surgery as well as the efficacy of therapeutic radiation. We tested the decision model again for patient groups based on tumor grade, pathological stage, preoperative PSA and number of positive margins. The model recommended initial radiation for patients with low to intermediate grade disease, no evidence of seminal vesicle invasion and multiple positive margins. Conclusions: The results of our decision analysis imply that immediate radiation may be appropriate for patients with a positive surgical margin(s) and a high likelihood of recurrent local rather than distant disease. This model may be useful to physicians and patients who use individual probability estimates and utility values to determine the preferred course of management after surgery. KEY WORDS: prostate, prostatic neoplasms, prostatectomy, radiotherapy, decision support techniques

vesicle invasion or lymph node metastasis. Conversely secondary treatment may be reserved for those with biochemical or clinical evidence of disease recurrence. A specific area of disagreement concerns optimal management of a positive surgical margin. Options include radiation in the immediate postoperative period (adjuvant radiotherapy) or observation with delayed treatment at disease recurrence. Because some patients followed expectantly never have disease recurrence, the dilemma centers on whether to treat some unnecessarily to cure potentially those who will have local recurrence. To make this decision it is important to know the likelihood of disease recurrence in patients with a positive surgical margin who are followed expectantly and in similar men receiving adjuvant radiation, the efficacy of therapeutic radiation administered after disease recurrence and the potential morbidity of radiation in this setting. In the absence of randomized prospective clinical trials addressing these questions, alternative methods of data analysis are required. One such method is the decision analytic model.5 Such a model defines relevant alternatives and outcomes associated with a particular decision making process and provides a quantitative assessment of the marginal benefit of 1 outcome over another.6 In this way a single best course of action may be identified if one exists.5 We constructed and tested a decision analysis model comparing immediate adjuvant radiation versus surveillance with delayed therapeutic radiation as necessary in patients with a

Patterns of resource use after definitive local therapy for prostate cancer are poorly defined. Repeat cancer treatment may be given prophylactically after definitive local therapy in patients at high risk for primary local treatment failure (adjuvant secondary treatment). Alternatively secondary cancer treatment may be given therapeutically to patients in whom primary local treatment failed, as evidenced by disease recurrence (therapeutic secondary treatment). Indications for secondary treatment in either setting remain unclear. Nevertheless, recent studies demonstrated that secondary treatment is relatively common after definitive local therapy for prostate cancer, administered to as many as 25% to 35% of patients within 3 to 5 years of initial treatment.1– 4 For patients undergoing initial treatment with radical prostatectomy adjuvant therapy may be delivered based on adverse pathological characteristics, such as extracapsular disease extension, tumor at the surgical margin(s), seminal Accepted for publication January 18, 2000. * Financial and/or other relationship with Ilex Oncology and TAP Holdings. † Financial and/or other relationship with Mercke and BoehringerIngelheim. ‡ Financial and/or other relationship with Janssen Pharmaceuticals and Agouron. § Financial and/or other relationship with TAP and Anthra. Editor’s Note: This article is the fifth of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 166 and 167. 93

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positive surgical margin(s) at radical prostatectomy. We used literature and institution based data to provide probability estimates for each decision point and tested the model to determine the preferred course of management. MATERIALS AND METHODS

We evaluated the decision of immediate adjuvant radiation versus surveillance with delayed radiation as necessary in patients with a positive surgical margin(s) at radical prostatectomy. We chose to examine radiation rather than hormonal therapy because the former is more commonly recommended to patients with an isolated positive surgical margin who are at risk for local rather than distant disease recurrence. Biochemical disease recurrence was used as the end point of treatment failure. Probability estimates for treatment related outcomes were obtained from a review of the literature and data from our institution. When possible, literature based probability estimates were determined for patients with positive surgical margins, excluding those with seminal vesicle invasion and lymph node metastasis. All institution based estimates excluded patients with lymph node metastases. In men who underwent immediate adjuvant radiation serum prostate specific antigen (PSA) was assumed to be undetectable at the time of radiation. Patients did not receive androgen deprivation treatment before, during or after radiation except when disease progressed. We comprehensively reviewed the literature to identify articles on positive margin rates and/or postoperative radiation in patients undergoing radical prostatectomy. From these articles estimates were made of certain factors, including the probability of maintaining undetectable serum PSA in patients with a positive surgical margin(s) followed expectantly postoperatively and those treated with immediate prophylactic adjuvant radiation after surgery, the incidence of moderate and/or severe complications after radiation postoperatively and the probability of maintaining undetectable serum PSA in patients who undergo initial surveillance after surgery but then receive therapeutic radiation at PSA recurrence. To determine the probability of maintaining undetectable PSA in patients with a positive surgical margin(s) followed expectantly after surgery the studies that we reviewed specifically addressed recurrence in those with a positive margin and used serum PSA as the end point of treatment failure (table 1).7–11 When possible, to determine the probability of maintaining undetectable serum PSA after immediate prophylactic adjuvant radiation for a positive surgical margin we considered only patients with a positive margin(s) and undetectable serum PSA before radiation (table 2).12–15 Excluded from study were patients with seminal vesicle invasion and lymph node involvement. Two studies warrant specific mention. In the series of Morris et al 6 of 40 patients with undetectable serum PSA who received adjuvant radiation did not have a positive surgical margin.13 In the study of Zietman et al an indeterminate number of patients with a positive margin had detectable serum PSA before radiation, although most were treated within 3 months of surgery.15 We also reviewed the literature to determine the incidence

of moderate and/or severe complications after postoperative pelvic radiation (table 3).13, 15–22 Adverse effects of radiation in these studies were reported in an inconsistent fashion. Some groups specifically graded complications as mild, moderate or severe, or by the Radiation Therapy Oncology Group scale, while others did not. Many specified the type of complication without providing a measure of severity. Consequently we made a best estimate to determine the percent of moderate and/or severe complications in these studies. In addition, the literature was reviewed to determine the probability of maintaining undetectable serum PSA after therapeutic radiation administered in response to PSA recurrence postoperatively (table 4).12, 13, 19 –25 Only series of therapeutic radiation that included PSA recurrence as an end point for radiation failure were included in our study. In some reports we specifically determined the response rate in men with a positive surgical margin(s) at radical prostatectomy (table 4). Although our literature review represents a comprehensive estimate of the probabilities needed for the decision model, it may be problematic to combine retrospective data from multiple institutions that used different selection criteria before treatment. Also, results in specific patient groups based on pretreatment characteristics were not reliably obtained from these previously published articles. Consequently we reviewed our institutional experience to determine the probabilities in question for all patient with a positive margin(s), and for specific patient subgroups based on preoperative serum PSA, seminal vesicle invasion, prostatectomy Gleason score and number of positive surgical margins. The probability of maintaining undetectable serum PSA in positive margin cases managed expectantly after surgery was determined from a review of radical retropubic prostatectomy at hospitals affiliated with our university. Prostatectomy specimens were serially sectioned at 3 mm. intervals perpendicular to the rectal surface and each section was submitted for pathological analysis. The only exception was in cases of a prostate gland greater than 50 gm., in which every other section was analyzed. Separate margins were shaved from the distal apical and proximal base margins of every specimen. These margins were further sectioned in a radial fashion and submitted completely for pathological analysis. Patients with tumor at the inked surgical resection margin were identified. Those who received adjuvant treatment before disease recurrence, had prostate cancer lymph node involvement or incomplete postoperative PSA data were excluded from analysis, leaving 132 men eligible for study. Median followup in these cases was 46 months postoperatively. Serial PSA was determined at 3 to 4-month intervals and disease recurrence was defined as serum PSA 0.2 ng./ml. or greater on 2 consecutive occasions. Preoperative PSA, prostatectomy Gleason score, seminal vesicle invasion and the number of positive margins were determined in all patients. The 3-year disease-free survival was estimated using the Kaplan-Meier method. The probability of maintaining undetectable serum PSA after adjuvant or therapeutic radiation postoperatively was

TABLE 1. Probability of undetectable PSA with positive margin and no radiation References 7

No. Pts.

124 Paulson 167 Epstein8 9 78 Ohori et al 10 Unknown* D’Amico et al 11 80 Lowe and Lieberman Present series 132 * Excluding Gleason score greater than 7 and/or seminal vesicle invasion.

% Undetectable PSA

Followup (method)

42 57.6 64 50 70 52

5 Yrs. (Kaplan-Meier) 5 Yrs. (Kaplan-Meier) 5 Yrs. (Kaplan-Meier) 2 Yrs. (Kaplan-Meier) 45 Mos. (median) 3 Yrs. (Kaplan-Meier)

DECISION ANALYSIS FOR MANAGEMENT OF POSITIVE MARGIN AFTER PROSTATECTOMY

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TABLE 2. Probability of undetectable PSA after immediate prophylactic adjuvant radiation for a positive margin References

No. Pts.

% Undetectable PSA

McCarthy et al12

12

83%

Followup (method)

Morris et al13

40

81%

3 Yrs. (Kaplan-Meier)

Petrovich et al14

37

85%

5 Yrs. (Kaplan-Meier)

Zietman et al15

55

77%

5 Yrs. (Kaplan-Meier)

Present series

35

80%

3 Yrs. (Kaplan-Meier)

40 Mos. (median)

TABLE 3. Complications of postoperative radiation References

% Moderate ⫾ Severe Complications

Petrovich et al16 Zietman et al15 Eisbruch et al17 Syndikus et al18 Wu et al19 Schild et al20 vander Kooy et al21 Forman et al22 Morris et al13

3 0 12 21 (grade 3 or 4) 15 (grade 2) 6.5 20 (chronic only) 17 (chronic only) 12.5

also determined by reviewing our clinical experience. We analyzed the records of 106 patients with negative lymph nodes who received radiation after radical prostatectomy. Median followup was 37 months after radiation. Adjuvant radiation in 37 cases was based on adverse pathological characteristics and therapeutic radiation in 69 on evidence of biochemical or biopsy proved disease recurrence after radical prostatectomy. Of these patients 35 in the adjuvant group had positive surgical margins and undetectable PSA before radiation, while 47 in the therapeutic group had positive surgical margins. These cases formed the basis of our institutional analysis. Radiation failure was defined as a serum PSA of 0.2 ng./ml. or greater on 2 or more consecutive occasions. Biochemical disease-free survival was calculated in these patients using the Kaplan-Meier method. Complete details of postoperative radiotherapy in these cases have been reported previously.26 Each of us independently assigned a utility value to the various outcomes of the decision model. Values ranged from 0 — death to 1—the most desirable outcome of PSA-free survival after surveillance only. Average values were calculated from our responses and assigned to the decision tree. Figure 1 shows average utility values with their respective outcomes in a decision tree. We constructed a decision analysis model using commercially available computer software that modeled surveillance followed by delayed radiotherapy for PSA recurrence versus immediate prophylactic adjuvant radiation for a positive surgical margin(s) and initially undetectable serum PSA after radical prostatectomy for pathological stages T2 to T3N0M0 disease (fig. 1, A). Using our literature and institutional review we formulated a range of probabilities for each branch of the decision tree. Average value of each outcome in tables 1 to 4 was initially assigned to the appropriate branch of the tree. Expected values of surveillance and immediate adjuvant radiation were calculated by folding back the decision tree (fig. 1, B).5 Sensitivity analysis was performed in which probabilities were varied according to the range of values in tables 1 to 4. For this analysis we adjusted a single probability along the range of possible values determined by the literature review while maintaining the remaining probabilities constant at the average values. In this manner each individual probability was tested to determine the threshold value required to

Comments Pos. margins, excluding seminal vesicle invasion ⫹ lymph node involvement Majority with pos. surgical margins but some had other indications Pos. margins, excluding seminal vesicle invasion ⫹ lymph node involvement Pos. margins, excluding seminal vesicle invasion ⫹ lymph node involvement, majority treated within 3 mos. postop., some had detectable PSA at radiation Pos. margin, no evidence of lymph node involvement

change the optimal decision of the model from no immediate radiation to immediate radiation or vice versa. We tested the decision model again to determine the most appropriate course of action in specific patient subgroups. This analysis used institution based data that determined probabilities based on preoperative serum PSA, seminal vesicle invasion, prostatectomy Gleason score and number of positive surgical margins. We hypothesized that men most likely to benefit from immediate adjuvant radiation were those at high risk for recurrent or persistent local rather than systemic disease. Thus, our subgroup analysis excluded patients with risk factors for distant disease recurrence, such as seminal vesicle invasion, poorly differentiated Gleason grade 8 to 10 disease and/or preoperative serum PSA greater than 15 ng./ml. RESULTS

Tables 1 through 4 list the studies used to determine the probabilities assigned to each branch point in the decision model.7–25 The average 55.9% (range 42% to 70%) estimated probability of maintaining undetectable PSA after expectant management for a positive surgical margin was obtained by reviewing 5 articles7–11 plus our institutional data (table 1). The estimated 81.2% (range 77% to 85%) probability of achieving and maintaining undetectable PSA after immediate prophylactic adjuvant radiation for a positive margin was derived from 4 series in the literature12–15 and our institutional data (table 2). The average 11.9% (range 0% to 21%) probability of a moderate or severe complication after postoperative radiation was obtained by reviewing 9 studies in the literature (table 3).13, 15–22 Furthermore, the average 46.1% (range 23% to 73%) probability of achieving and maintaining undetectable PSA after therapeutic radiation for detectable PSA postoperatively was derived from a review of 9 studies12, 13, 19 –25 plus data from our institution (table 4). Figure 1, A represents the decision model constructed to compare immediate adjuvant radiation versus surveillance and delayed radiation for a positive surgical margin. Using average probability estimates obtained from our literature review the decision model recommended initial surveillance over immediate radiation (calculated expected value 0.801 versus 0.766). Figure 1, B shows the probability estimates for each branch of the decision tree and calculated values for each chance node. We performed sensitivity analysis in which the probability estimate of a single treatment related outcome was varied over the range of probabilities obtained from the literature review (fig. 2). For each probability estimate we determined the threshold value at which the outcome of the decision model changed from recommending surveillance to recommending immediate adjuvant radiation. For example, if the probability of PSA failure after expectant management of a positive surgical margin exceeded 52% (less than 48% probability of maintaining undetectable PSA), immediate adjuvant radiation would be chosen by the model (fig. 2, A). Similarly if the likelihood of PSA failure after therapeutic

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DECISION ANALYSIS FOR MANAGEMENT OF POSITIVE MARGIN AFTER PROSTATECTOMY TABLE 4. Probability of undetectable PSA after therapeutic radiation for detectable PSA following prostatectomy No. Pts.

% Undetectable PSA Durable Response

Followup After Radiation (method)

Hudson and Catalona23 Schild et al20 Wu et al19 McCarthy et al12 Morris et al13 Forman et al22

21 46 53 37 48 47

29 50 23 54 47 73

12.6 Mos. (mean) 5 Yrs. (Kaplan-Meier) 2 Yrs. (Kaplan-Meier) 27.5–36 Mos. (median) 3 yrs. (Kaplan-Meier) 36 Mos. (median)

Cadeddu et al24

30

37

At least 2 yrs.

vander Kooy et al21

30

56

8 Yrs. (Kaplan-Meier)

Coetzee et al25 Present series

45 47

51 41

33 Mos. (mean) 3 Yrs. (Kaplan-Meier)

References

Comments

Biochemical failure defined by PSA increase after nadir Pos. margins, excluding seminal vesicle invasion ⫹ lymph node involvement Biochemical failure defined by PSA increase after nadir Pos. margins Pos. margins, excluding lymph node involvement

FIG. 1. Decision tree for positive surgical margin after radical prostatectomy. A, immediate adjuvant radiation (RT) versus surveillance with delayed radiation as necessary. B, literature based probability estimates derived from tables 1 to 4 applied to each branch and calculated values shown at each chance node with final calculated expected values for surveillance and immediate adjuvant radiation (closed box and circles).7–25 Calculated expected value for surveillance exceeds that of immediate adjuvant radiation. Therefore, using literature based probability estimates model recommends initial surveillance over immediate adjuvant radiation. Open circles represent chance nodes.

radiation exceeded 71% (less than 29% probability of maintaining undetectable PSA), immediate adjuvant radiation would be the recommended treatment course (fig. 2, D). Figure 2, B and C shows that the probability of PSA failure after immediate adjuvant radiation and that of complications after radiation had no effect on the outcome of the decision model over the range of probabilities obtained from the literature. In other words, the model depended on the probability of maintaining PSA-free status after surveillance or therapeutic radiation but not on the probability of maintaining PSA-free status after immediate adjuvant radiation or the likelihood of complications. To change the result of the decision model to favor immediate adjuvant radiation the likelihood of PSA failure after immediate radiation would be less than 13% (data not shown). To determine whether a specific group may benefit from immediate adjuvant radiation we used our institutional data to test the decision model in patient subgroups based on tumor grade, pathological stage, preoperative PSA and number of positive surgical margins. We hypothesized that men with a positive margin at high risk of persistent or recurrent local rather than distant disease after radical prostatectomy would most likely benefit from immediate adjuvant radiation. Such patients may have a single positive surgical margin, low to intermediate grade disease (Gleason score less than 8), no evidence of seminal vesicle invasion and preoperative serum PSA less than 15 ng./ml. Table 5 shows Kaplan-Meier estimates of 3-year PSA-free survival as well as calculated expected values from the decision tree of surveillance and immediate adjuvant radiation in specific pa-

tient subgroups treated at our institution. The probability estimate of complications after radiotherapy as well as the utility value of each outcome were identical to those used in the literature based decision model. Table 5 shows that the recommended course of treatment from the decision model changed in certain patient subgroups. Specifically, the decision model recommended immediate adjuvant radiation for low to intermediate grade disease (Gleason score less than 8) with multiple positive margins, and low to intermediate grade disease with no evidence of seminal vesicle invasion. After analyzing the data on histological tumor grade, again using a Gleason score cutoff of less than 7 to define low and intermediate grade disease, we obtained similar results (data not shown). In men without seminal vesicle invasion irrespective of tumor grade the model provided an equal value for surveillance and immediate adjuvant radiation. Surveillance continued to be the recommended course of treatment in patients with preoperative PSA less than 15 ng./ml. and those with a single positive margin (table 5). DISCUSSION

Tumor is present at the inked surgical margin in 14% to 46% of radical prostatectomy specimens.8 Such a finding is suggestive of residual local tumor in the surgical bed and, therefore, it may be an important risk factor for subsequent disease recurrence.7, 9, 10, 27 However, a positive surgical margin does not imply inevitable disease recurrence in all cases. As many as 70% of such patients remain disease-free without

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FIG. 2. Sensitivity analysis in which probability estimate of single treatment related outcome varied over range of probabilities obtained from literature review.7–25 Final calculated expected values of surveillance (squares) and immediate adjuvant radiation (circles) are plotted as probability estimate in question varied. A, probability of maintaining undetectable PSA with expectant management postoperatively. Thus, if probability of PSA failure after postoperative expectant management exceeds 52% (less than 48% probability of maintaining undetectable PSA), calculated expected value of immediate adjuvant radiation exceeds that of surveillance, and recommendation of model changes to favor immediate adjuvant radiation. B, probability of maintaining undetectable PSA after immediate adjuvant radiation. Calculated expected value for surveillance is always higher than that of immediate adjuvant radiation over range of values obtained from literature review. To change recommendation of model probability of PSA failure after immediate adjuvant radiation must be less than 13% (data not shown). C, probability of moderate and/or severe complications after postoperative radiation. Calculated expected value for surveillance is always higher than that of immediate adjuvant radiation over range of values obtained from literature review. D, probability of maintaining undetectable PSA after therapeutic radiation for detectable PSA postoperatively. Thus, if probability of PSA failure after therapeutic radiation exceeds 71% (less than 29% probability of maintaining undetectable), calculated expected value of immediate adjuvant radiation exceeds that of surveillance, and recommendation of model changes to favor immediate adjuvant radiation. Dashed line represents point at which calculated expected value of immediate adjuvant radiation equals that of surveillance.

TABLE 5. Probability and calculated expected values in specific subgroups with positive surgical margins based on our institutional data % 3-Yr. PSA-Free Probability

Gleason score less than 8 No seminal vesicle invasion Gleason score less than 8 ⫹ no seminal vesicle invasion Preop. PSA less than 15 ng./ml. Single pos. margin Multiple pos. margins

Decision Analysis Calculated Expected Value Immediate Surveillance Adjuvant Radiation

After Surveillance Only

After Adjuvant Radiation

After Therapeutic Radiation

57 56 56

89 86 90

44 42 43

0.801 0.793 0.795

0.810 0.793 0.816

62 62 31

81 92 70

52 57 26

0.839 0.848 0.626

0.765 0.827 0.702

additional treatment.7–11 Pathological factors, such as the location, extent and number of positive margins, may have an impact on the likelihood of disease recurrence in this setting.11 To our knowledge there is currently no consensus on appropriate management of a positive margin after radical prostatectomy. Treatment options include observation with delayed radiation or androgen deprivation at disease progression, immediate adjuvant radiation or immediate androgen deprivation, usually limited to those at high risk for systemic disease.

To our knowledge to date no published studies have compared immediate versus delayed treatment in a prospective randomized fashion. The Southwest Oncology Group completed a randomized trial of this question but the results are not yet available. Previous series of immediate postoperative radiation were analyzed in uncontrolled fashion. Although some studies indicate that immediate adjuvant radiation may provide a benefit over surveillance with respect to local disease control and biochemical disease-free survival, they were performed in a retrospective fashion without considering disease-free survival in

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DECISION ANALYSIS FOR MANAGEMENT OF POSITIVE MARGIN AFTER PROSTATECTOMY

patients followed expectantly.13, 17, 18, 28 –30 Moreover, none demonstrated a survival advantage for patients treated with immediate radiation. Therefore, any long-term benefit of immediate therapy versus surveillance with respect to disease-free and overall survival remains unknown. Given this lack of prospective information alternative methods of data analysis are required to facilitate decision making for patients and physicians postoperatively. One such method involves the creation of a decision analysis model.5 This model allows the assignment of probabilities and utilities to competing outcomes, and uses these values to calculate the best course of action. For clinical decision making these probabilities may be derived from literature based or institutional estimates and they may be tested by sensitivity analysis to determine which factors are most important to the decision in question. In our study we created such a decision model to compare immediate adjuvant radiation with surveillance and delayed treatment as necessary in men with a positive surgical margin(s) after radical prostatectomy. Probability estimates were derived from a review of the literature and our institution based experience. Using literature based estimates we determined that initial surveillance is the best course of action. The model was most sensitive to the probability of remaining disease-free on surveillance only as well as to the efficacy of radiation delivered in response to disease recurrence. The efficacy of adjuvant radiation and likelihood of complications after radiation did not significantly impact the outcome of the model over the range of probabilities tested. Since we did not reliably determine specific patient characteristics from our retrospective literature review, this literature based result implies that immediate adjuvant radiation may not be appropriate in all patients with a positive surgical margin. However, these data provided no information on which patients if any may be appropriate candidates for early postoperative treatment. To identify specific patient groups that may benefit from immediate radiation we used institution based data to test the decision model. These data were derived from cases in which important clinical characteristics were ascertained. We hypothesized that men with a positive margin(s) most likely to benefit from immediate adjuvant radiation were at risk for persistent or recurrent local rather than distant disease. The results of our decision model supported this hypothesis since the model recommended immediate radiation in patients at risk for local disease recurrence, such as those with low or intermediate grade disease and those without seminal vesicle invasion. This finding appeared to be driven by the improved efficacy of adjuvant radiation in these cases. An alternative hypothesis would be that positive margin cases with high risk disease characteristics, such as high grade Gleason 8 to 10 tumors and/or seminal vesicle invasion, would benefit more from combined treatment with surgery and immediate adjuvant radiation versus surgery only (with delayed treatment as necessary). However, due to the limited number of patients in our series with these high risk disease characteristics we did not test this hypothesis. Interestingly the model continued to favor surveillance in patients with a single positive margin, while it favored immediate radiation in those with multiple positive margins. In men with a single positive margin this result may be explained by the improved PSA-free survival of those followed expectantly and improved efficacy of therapeutic radiation rather than the ineffectiveness of immediate adjuvant radiation. In men with multiple positive margins, PSA-free survival on surveillance, and the efficacy of adjuvant and therapeutic radiation were much lower than in the other groups. Although the model recommended immediate radiation in these patients, alternative treatment strategies may be more appropriate in those at high risk for disease recurrence after surgery.

Our study had certain limitations. Probability estimates were based on a retrospective literature review and our institutional treatment data. Such estimates were subject to well-defined selection biases as well as to limited followup in the cases under consideration. Because participants in these retrospective studies were chosen for early versus delayed radiation based on physician preference, it is likely that those chosen for early adjuvant radiation had worse disease characteristics than those who underwent initial surveillance with delayed radiation for disease recurrence. Moreover, many estimates were based on disease-free survival 3 years after treatment and it is likely that with longer followup more patients in each arm of the decision tree would have disease recurrence. For radical prostatectomy it was recently reported that failure occurs in as many as 23% of cases 5 years or more after surgery.31 While similar estimates of late failure are not available for adjuvant or therapeutic radiation, it is possible that such late failures would influence the outcome of the decision model. Other potential biases in studies include different patient populations, various PSA end points for defining treatment failure, differences in prostatectomy specimen analysis, and variations in treatment technique and radiation dose. For example, some estimates of treatment outcome included only positive margins, while others included additional adverse pathological characteristics, such as seminal vesicle invasion. In addition, disease recurrence was not consistently defined in the various studies. While our institution based estimates included strict criteria to define biochemical disease recurrence (PSA 0.2 ng./ml. or greater on 2 consecutive occasions), others used less strict definitions, such as a serum PSA of 0.4 ng./ml. or greater,9, 14 0.5 or greater7, 18, 25 and 0.6 or greater,12, 23 or increasing PSA after treatment.21, 22 Such differences in the end point of treatment efficacy would have influenced the estimates of treatment outcome. Also, the completeness of prostatectomy specimen sampling likely varied among studies and with time, and such differences would have influenced the determination of surgical margin status. Furthermore, radiation associated morbidity was not reported in a consistent and validated fashion in the literature, rendering estimates of treatment related morbidity uncertain. Specifically to our knowledge the impact if any of immediate radiation on return of sexual function after radical prostatectomy has not been accurately assessed to date. Such potential morbidity may be an important factor in treatment selection after radical prostatectomy, supporting the need for additional research to define treatment related side effects better in this setting. A panel of experts independently assigned utility values to the current decision model. These values were based on personal beliefs regarding the quality and quantity of life that would be associated with each potential outcome. Despite this subjectivity the utilities that we assigned to each outcome never differed by more than 0.1 and the rank order of each set of outcomes was nearly identical for each of us. It is possible that a survey of patients with prostate cancer may have provided different utility values than those assigned by this expert panel. However, for utility values to be useful in a particular patient confronted with a treatment decision the patient must assign personal values to each outcome. Thus, the utility values in our study should only be considered as an example to illustrate how the decision model operates in a given situation. Although limitations of currently available data must be recognized, we created and tested a decision analysis model designed to provide a framework to help patients and physicians in clinical decision making after radical prostatectomy. It is clear that treatment results from a particular center may significantly differ from those used in our study. Thus, for the decision model to be useful in an individual the experience of the treating urologists and radiation oncolo-

DECISION ANALYSIS FOR MANAGEMENT OF POSITIVE MARGIN AFTER PROSTATECTOMY

gists must be incorporated into the model. The most important advantage of our model is that it enables patients and physicians to place a quantitative estimate on the relative value of surveillance and immediate radiation after radical prostatectomy. In the absence of prospective randomized data on the benefit of immediate adjuvant radiation versus surveillance for a positive surgical margin, patients and physicians must use alternative forms of data analysis when deciding between these treatment options postoperatively. Until prospective studies are available, methods such as a decision model may provide insight into the preferred course of management. Given the likelihood of a positive surgical margin after radical prostatectomy and the implications of such a finding with respect to resource use and disease recurrence, we believe that our results warrant additional research into this important clinical issue. CONCLUSIONS

We constructed a decision analysis model comparing immediate adjuvant radiation versus surveillance with delayed radiation as necessary in patients with a positive surgical margin(s) after radical prostatectomy. Using average probability estimates of treatment outcome obtained from a comprehensive literature review and our institution based data, the decision model recommended initial surveillance over immediate radiation. When the model was tested again for specific patient subgroups, it recommended immediate adjuvant radiation in patients at high risk for persistent or recurrent local disease, such as those with a low to intermediate grade tumor and no evidence of seminal vesicle invasion. Sensitivity analysis demonstrated that the model depended on the likelihood of disease recurrence in men followed expectantly after surgery as well as the efficacy of therapeutic radiation. Further research is needed to confirm these results and determine whether adjuvant radiotherapy is appropriate in other groups of patients with adverse disease characteristics. REFERENCES

1. Grossfeld, G. D., Stier, D. M., Flanders, S. C. et al: Use of second treatment following definitive local therapy for prostate cancer: data from the CaPSURE database. J Urol, 160: 1398, 1998 2. Fowler, F. J., Jr., Barry, M. J., Lu-Yao, G. L. et al: Patientreported complications and follow-up treatment after radical prostatectomy. The National Medicare Experience: 1988 –1990 (updated June 1993). Urology, 42: 622, 1993 3. Fowler, F. J., Jr., Barry, M. J., Lu-Yao, G. L. et al: Outcomes of external-beam radiation therapy for prostate cancer: a study of Medicare beneficiaries in three surveillance, epidemiology, and end results areas. J Clin Oncol, 14: 2258, 1996 4. Lu-Yao, G. L., Potosky, A. L., Albertsen, P. C. et al: Follow-up prostate cancer treatments after radical prostatectomy: a population-based study. J Natl Cancer Inst, 88: 166, 1996 5. Sackett, D. L., Haynes, R. B., Guyatt, G. H. et al: clinical epidemiology: a basic science for Clinical Medicine. Boston: Little, Brown and Co., 1991 6. Corwin, H. L. and Silverstein, M. D.: The diagnosis of neoplasia in patients with asymptomatic microscopic hematuria: a decision analysis. J Urol, 139: 1002, 1988 7. Paulson, D. F.: Impact of radical prostatectomy in the management of clinically localized disease. J Urol, part 2, 152: 1826, 1994 8. Epstein, J. I.: Incidence and significance of positive margins in radical prostatectomy specimens. Urol Clin North Am, 23: 651, 1996 9. Ohori, M., Wheeler, T. M., Kattan, M. W. et al: Prognostic significance of positive surgical margins in radical prostatectomy specimens. J Urol, 154: 1818, 1995 10. D’Amico, A. V., Whittington, R., Malkowicz, S. B. et al: A multivariate analysis of clinical and pathological factors that predict for prostate specific antigen failure after radical prostatectomy for prostate cancer. J Urol, 154: 131, 1995

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11. Lowe, B. A. and Lieberman, S. F.: Disease recurrence and progression in untreated pathologic stage T3 prostate cancer: selecting the patient for adjuvant therapy. J Urol, 158: 1452, 1997 12. McCarthy, J. F., Catalona, W. J. and Hudson, M. A.: Effect of radiation therapy on detectable serum prostate specific antigen levels following radical prostatectomy: early versus delayed treatment. J Urol, 151: 1575, 1994 13. Morris, M. M., Dallow, K. C., Zietman, A. L. et al: Adjuvant and salvage irradiation following radical prostatectomy for prostate cancer. Int J Radiat Oncol Biol Phys, 38: 731, 1997 14. Petrovich, Z., Lieskovsky, G., Freeman, J. et al: Surgery with adjuvant irradiation in patients with pathologic stage C adenocarcinoma of the prostate. Cancer, 76: 1621, 1995 15. Zietman, A. L., Coen, J. J., Shipley, W. U. et al: Adjuvant irradiation after radical prostatectomy for adenocarcinoma of prostate: analysis of freedom from PSA failure. Urology, 42: 292, 1993 16. Petrovich, Z., Lieskovsky, G., Langholz, B. et al: Radiotherapy following radical prostatectomy in patients with adenocarcinoma of the prostate. Int J Radiat Oncol Biol Phys, 21: 949, 1991 17. Eisbruch, A., Perez, C. A., Roessler, E. H. et al: Adjuvant irradiation after prostatectomy for carcinoma of the prostate with positive surgical margins. Cancer, 73: 384, 1994 18. Syndikus, I., Pickles, T., Kostashuk, E. et al: Postoperative radiotherapy for stage pT3 carcinoma of the prostate: improved local control. J Urol, 155: 1983, 1996 19. Wu, J. J., King, S. C., Montana, G. S. et al: The efficacy of postprostatectomy radiotherapy in patients with an isolated elevation of serum prostate-specific antigen. Int J Radiat Oncol Biol Phys, 32: 317, 1995 20. Schild, S. E., Buskirk, S. J., Wong, W. W. et al: The use of radiotherapy for patients with isolated elevation of serum prostate specific antigen following radical prostatectomy. J Urol, 156: 1725, 1996 21. vander Kooy, M. J., Pisansky, T. M., Cha, S. S. et al: Irradiation for locally recurrent carcinoma of the prostate following radical prostatectomy. Urology, 49: 65, 1997 22. Forman, J. D., Meetze, K., Pontes, E. et al: Therapeutic irradiation for patients with an elevated post-prostatectomy prostate specific antigen level. J Urol, 158: 1436, 1997 23. Hudson, M. A. and Catalona, W. J.: Effect of adjuvant radiation therapy on prostate specific antigen following radical prostatectomy. J Urol, 143: 1174, 1990 24. Cadeddu, J. A., Partin, A. W., DeWeese, T. L. et al: Long-term results of radiation therapy for prostate cancer recurrence following radical prostatectomy. J Urol, 159: 173, 1998 25. Coetzee, L. J., Hars, V. and Paulson, D. F.: Postoperative prostate-specific antigen as a prognostic indicator in patients with margin-positive prostate cancer, undergoing adjuvant radiotherapy after radical prostatectomy. Urology, 47: 232, 1996 26. Nudell, D. N., Grossfeld, G. D., Weinberg, V. K. et al: Radiotherapy after radical prostatectomy: treatment outcomes and failure patterns. Urology, 54: 1049, 1999 27. Epstein, J. I., Partin, A. W., Sauvageot, J. et al: Prediction of progression following radical prostatectomy. A multivariate analysis of 721 men with long-term follow-up. Am J Surg Pathol, 20: 286, 1996 28. Anscher, M. S. and Prosnitz, L. R.: Postoperative radiotherapy for patients with carcinoma of the prostate undergoing radical prostatectomy with positive surgical margins, seminal vesicle involvement and/or penetration through the capsule. J Urol, 138: 1407, 1987 29. Freeman, J. A., Lieskovsky, G., Cook, D. W. et al: Radical retropubic prostatectomy and postoperative adjuvant radiation for pathological stage C (PCN0) prostate cancer from 1976 to 1989: intermediate findings. J Urol, 149: 1029, 1993 30. Gibbons, R. P., Cole, B. S., Richardson, R. G. et al: Adjuvant radiotherapy following radical prostatectomy: results and complications. J Urol, 135: 65, 1986 31. Pound, C. R., Partin, A. W., Eisenberger, M. A. et al: Natural history of progression after PSA elevation following radical prostatectomy. JAMA, 281: 1591, 1999

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DECISION ANALYSIS FOR MANAGEMENT OF POSITIVE MARGIN AFTER PROSTATECTOMY EDITORIAL COMMENT

The optimum treatment of a man with a positive margin following radical prostatectomy remains obscure due to a number of factors, most importantly the recognition that such a pathological finding may not represent failure to eradicate the neoplasm. Alternatively, any cancer cells left behind may not have a significant clinical impact. Thus, clinicians are faced with a dilemma in answering the simple patient question; “Doctor, did you get it all?” The authors have created a decision analysis model to try and determine the preferred treatment of such patients. They proposed the 3 options of surveillance, immediate adjuvant (prophylactic) radiation and delayed therapeutic radiation given after PSA becomes detectable. The authors assigned utilities for the potential outcomes. They used figures from the literature and experience from their institution as model inputs. Using the published literature results, the decision model recommends an initial surveillance of such patients. With testing of the model with various pathological parameters and PSA level, however, the authors concluded that the initial adjuvant radiation would be beneficial to those men with low to intermediate grade disease without evidence of seminal vesicle invasion and multiple positive margins. The authors are to be applauded for performing such an analysis. Potentially the model would help in the management of the large cohort of men with such adverse pathological findings. However, before this model is widely applied I believe several cautions should be raised. We all recognize that there has been a significant stage migration in the presentation of prostate cancer during the last several years, primarily from the use of PSA testing and resulting clinical T1c disease. The majority of articles used for the present study were published in the mid 1990s when patients were diagnosed and treated before widespread PSA testing was used. We can assume that these historical series were comprised of patients with more significant disease than those contemporarily recognized. Thus, extrapolation to present patients may not be appropriate. Median followup in this series is 46 months after surgery. Most of the series from the literature using the model had only 3 years of followup. The long-term affect on biochemicalfree survival following adjuvant radiation may not be fully apprised. The observation (data not provided) that there was no difference in outcome when men with Gleason grade 4 or 5 (score 7 or greater) were compared to patients not exhibiting this well recognized adverse histological finding is surprising. The abundant data from Stanford University1 and elsewhere would call into question this finding. The extraordinary high degree of concordance between the various assignment of utilities associated with various outcomes by the authors suggests an intra-institution bias effect. It would be imperative before this model is applied on a wider basis to have other experts provide their own utilities to determine the risk-to-benefit ratio for adjuvant therapy. All of us who treat men with prostate cancer would certainly welcome a definitive answer to the question of how to treat the positive margin. While I believe this study provides an interesting analytic approach to this dilemma, I am afraid that we will have to wait for the results of the ongoing randomized clinical trials to really know what is best for our patients. Michael K. Brawer Northwest Prostate Institute Seattle, Washington

1. Stamey, T. A., McNeal, J. E., Yemoto, C. M. et al: Biological determinants of cancer progression in men with prostate cancer. JAMA, 281: 1395, 1999 REPLY BY AUTHORS Most studies to date examining the impact of margin status on disease recurrence after radical prostatectomy have demonstrated that a positive margin has an adverse impact on outcome (references 7, 9, 10 and 27 in article).1, 2 We agree that such a finding does not predict disease recurrence in all patients. Thus, a patient who is told he has a positive margin is faced with the question, “What, if anything, should I do now?” The purpose of our study was to provide a framework by which clinicians and patients can address this difficult question. Results from prospective, randomized trials addressing this question are not yet available. Therefore, novel methods of data analysis may help clinicians and patients. The considerable limitations to the data used to construct our model were addressed in the discussion. The studies chosen for inclusion represent the best data currently available. The subjectivity and potential intra-institutional bias of the utility values were also addressed in the discussion. These utility values were assigned to the decision tree only to illustrate how the model performs in a given situation. For the decision model to be useful for a particular patient with a positive margin, that patient must assign his own personal utility values to each outcome of the decision tree and determine the experience of his treating physician with respect to the probabilities associated with each outcome. Therefore, the model may be helpful for individual patients and their physicians. It was our hypothesis that patients most likely to benefit from postoperative radiation for a positive surgical margin were those with recurrent or persistent local rather than distant disease. Thus, the model was not tested for patients with high grade (Gleason 8 to 10) disease. What our data do show is that for men with well to moderately differentiated disease, defined as Gleason score less than 8 in the article, the decision model recommended immediate adjuvant radiation over initial surveillance. When the data were reanalyzed with Gleason score less than 7, defined as well to moderately differentiated disease, similar results were obtained from the decision model. We only analyzed the effect of total Gleason score and not individual Gleason patterns. Moreover, such results do not provide a comparison of outcome based on Gleason grade but they determine the outcome of the decision model when restricting analysis to specific patient subgroups. We and others await the publication of randomized trials and more contemporary information addressing this important issue. 1. Blute, M. L., Bostwick, D. G., Bergstralh, E. J. et al: Anatomic site-specific positive margins in organ-confined prostate cancer and its impact on outcome after radical prostatectomy. Urology, 50: 733, 1997 2. Grossfeld, G. D., Chang, J. J., Broering, J. M. et al: Impact of positive surgical margins on prostate cancer recurrence and use of secondary cancer treatment: data from the CapSure database. J Urol, 163: 1171, 2000