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Identification of Patients With Prostate Cancer Who Benefit From Immediate Postoperative Radiotherapy: EORTC 22911

Theodorus H. Van der Kwast, Michel Bolla, Hein Van Poppel, Paul Van Cangh, Kris Vekemans, Luigi Da Pozzo, Jean-Francois Bosset, Karl H. Kurth, Fritz H. Schröder, Laurence Collette

Department of Pathology and Laboratory Medicine, Mount Sinai Hospital and University Health Network, Toronto, Canada; Department of Radiotherapy, Centre Hospitalier Universitaire Grenoble; Department of Radiotherapy and Oncology, Hopital Jean Minjoz, Besancon, France; Department of Urology, Universiteits Ziekenhuis Gasthuisberg, Leuven; Department of Urology, Hopital St Luc; Statistics Department, European Organisation for Research and Treatment of Cancer Data Center, Brussels; Virga Jesse Ziekenhuis, Hasselt, Belgium; Department of Urology, Ospedale San Rafaele, Milano, Italy; Department of Urology, Academisch Medisch Centrum, Amsterdam; and the Department of Urology, Erasmus Medisch Centrum Rotterdam, the Netherlands

Address reprint requests to Theodorus H. Van der Kwast, MD, PhD, Department of Pathology, 11th floor, University Health Network, 200 Elizabeth St, Toronto, Ontario, Canada M5G 2C4; e-mail: theo.vdkwast{at}uhn.on.ca

	ABSTRACT

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Purpose The randomized controlled European Organisation for Research and Treatment of Cancer (EORTC) trial 22911 studied the effect of radiotherapy after prostatectomy in patients with adverse risk factors. Review pathology data of specimens from participants in this trial were analyzed to identify which factors predict increased benefit from adjuvant radiotherapy.

Patients and Methods After prostatectomy, 1,005 patients with stage pT3 and/or positive surgical margins were randomly assigned to a wait-and-see (n = 503) and an adjuvant radiotherapy (60 Gy conventional irradiation) arm (n = 502). Pathologic review data were available for 552 patients from 11 participating centers. The interaction between the review pathology characteristics and treatment benefit was assessed by log-rank test for heterogeneity (P < .05).

Results Margin status assessed by review pathology was the strongest predictor of prolonged biochemical disease-free survival with immediate postoperative radiotherapy (heterogeneity, P < .01): by year 5, immediate postoperative irradiation could prevent 291 events/1,000 patients with positive margins versus 88 events/1,000 patients with negative margins. The hazard ratio for immediate irradiation was 0.38 (95% CI, 0.26 to 0.54) and 0.88 (95% CI, 0.53 to 1.46) in the groups with positive and negative margins, respectively. We could not identify a significant impact of the positive margin localization.

Conclusion Provided careful pathology of the prostatectomy is performed, our results suggest that immediate postoperative radiotherapy might not be recommended for prostate cancer patients with negative surgical margins. These findings require validation on an independent data set.

	INTRODUCTION

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Approximately 35% of patients undergoing a radical prostatectomy for their prostate cancer will experience biochemical recurrence within 10 years of surgery.^1-3 The most significant risk factors for biochemical recurrence after prostatectomy are high Gleason score, extraprostatic extension, seminal vesicle invasion, and a positive surgical margin.^4,5 Both smaller nonrandomized studies^6-9 and recently the large randomized controlled trial by the European Organisation for Research and Treatment of Cancer (EORTC)^10,11 have demonstrated convincingly that radiotherapy immediately after prostatectomy in patients with adverse risk factors diminishes their risk of biochemical recurrence and improves local control of the disease. EORTC trial 22911 was initiated in 1992 as a multi-institutional phase III trial to test the hypothesis that immediate radiotherapy after prostatectomy of patients with a pT3N0M0 or prostatic adenocarcinoma with positive surgical margin improves their progression-free survival. Although a preliminary analysis of risk factors showed that patients with any adverse risk factor benefited from postoperative radiotherapy, the patients with positive surgical margins seemed to benefit most.¹¹ The latter preliminary report did not include data on Gleason score, and data of a pathology review were not yet available. Pathologic review of prostatectomy specimens of trial EORTC 22911 showed a comparatively low agreement between the local and review pathologists for the margin status and extraprostatic extension, and the prognostic value of the review assessment was stronger than the local assessment, particularly regarding the status of the surgical margins.¹² Availability of the reviewed data of the prostatectomy specimens of approximately 50% of the patients participating in this trial allowed an additional analysis of the most relevant factors, including Gleason score, pathologic stage, and margin status. This article explores further the relationship between these factors and the magnitude of the benefit from immediate postprostatectomy radiotherapy.

	PATIENTS AND METHODS

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Trial Design
The trial design has been described previously.¹⁰ Briefly, eligible patients had to be age 75 years, be untreated previously for their prostate cancer, and had to have histologically proven prostate cancer, pathologic stage pT2-3, based on local pathology reports. They also had to present with at least one of the following risk factors for biochemical and local recurrence: extraprostatic extension of the tumor, positive surgical margins, and/or invasion of seminal vesicles (as assessed by the local pathologist). Radiotherapy began within 16 weeks after surgery, irrespective of the postoperative prostate-specific antigen (PSA) level. Informed consent (written or oral) was obtained from all patients in accordance with national laws. In each participating center the local/national ethics review committee approved the protocol. After undergoing radical prostatectomy, a total of 1,005 patients were randomly assigned to either the wait-and-see arm (n = 503) or the intervention arm (n = 502). Randomization was performed centrally by minimization algorithm after verification of all eligibility criteria with stratification for the treating institution, extraprostatic extension, positive margins, and seminal vesicle invasion. Irradiation started once patients had recovered from surgery and there were no major voiding problems. Postoperative irradiation consisted of 60 Gy administered with conventional techniques and delivered during 6 weeks, as described previously in more detail.¹⁰

Follow-up of the participants of the trial consisted of digital rectal examination and PSA testing at 4, 8, and 12 months after surgery, then every 6 months until the end of the fifth year, then every year until death. Chest radiography and bone scans were done every year or if clinical or biochemical disease progression was suspected. Computed tomography scans and liver ultrasound were used for confirmation of suspected progression. In patients in the wait-and-see arm, subsequent treatment (radiotherapy or other) was delayed until biochemical or clinical failure; radiotherapy was the recommended treatment for local relapse.

The primary trial end point and end point of the present analysis is biochemical progression-free survival, defined as the time from random assignment until the day of first biochemical or clinical progression or start of treatment in the absence of progression, if any, or death as a result of any cause. Biochemical progression was defined as every increase above the lowest postoperative value to a value more than 0.2 ng/mL that was confirmed twice, at minimum 2-week intervals. Local recurrence had to be documented by a digital rectal examination (with or without biopsy) and distant relapse by sonography or radiographic or scintigraphic imaging.

Pathology of Prostatectomy Specimens
The total number of participants of this multi-institutional trial was 1,005, but for practical reasons only the prostatectomy specimens of 566 participants, included by the 11 major participating hospitals were reviewed. Fourteen patients were ineligible, leaving a total of 552 eligible patients (280 in the wait-and-see arm and 272 in the postoperative irradiation arm; Table 1). After formalin fixation, the prostatectomy specimens were totally embedded after inking the outer surface of the specimens using essentially the same protocol for sectioning in all participating hospitals.^13,14 This includes separate embedding of parasagittal sections of the apex and bladder neck margin. Exclusion criteria for pathologic review were hormonal therapy before prostatectomy or incomplete embedding of the prostatectomy. The pathologic review was performed by a single pathologist with experience in urogenital pathology (T.H.V.d.K.) and included the examination of all slides of the radical prostatectomy specimen. In addition to Gleason score, pathologic stage (TNM, 1997), presence of extraprostatic extension, invasion of seminal vesicles, and surgical margin status were recorded. If extraprostatic extension was present, its extent (focal [ie, extending < 1 high power field] or otherwise extensive [ie, > 1 high power field]) and side of the extension were recorded. Extraprostatic extension was defined by either infiltration of the carcinoma of the prostatic pseudocapsule into the direct vicinity, beyond the adipose tissue, or within the neurovascular bundle beyond the outer contour of the adjacent pseudocapsule.¹² Bladder invasion was determined by invasion in the large bundles of smooth muscle, characteristic of the muscularis propria of the urinary bladder. Positive margin status was recorded when tumor cells were present within the inked margin. For positive surgical margin, apical and nonapical (designated as lateral) involvement was distinguished.

	RESULTS

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Comparison of Patient Characteristics
The characteristics of the patients for whom review pathology is available are listed in Table 1. All of these patients were treated in the hospitals that contributed most to the accrual. The patients whose specimens were reviewed centrally had a somewhat better prognosis than those whose specimens were not reviewed centrally (P = .056). The 5-year biochemical progression-free survival rate was 59.9% (95% CI, 54.6% to 65.2%) for the nonreviewed patients compared with 65.8% (95% CI, 61.3% to 70.2%) for the reviewed group. The group excluded from analysis also exhibited some worse prognostic features (Table 1), and more frequent positive margins and invasion of seminal vesicles by local pathology (P = .0025 and P = .0296, respectively).

Individual Predictive Factors for Benefit of Radiotherapy
We first assessed the interaction between each of the five considered factors and the magnitude of the benefit from radiotherapy in terms of biochemical progression-free survival (Fig 1), and then repeated the analysis on the subset of patients with PSA 0.2 ng/mL after surgery (Fig 2).

View larger version (21K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Forest plot for the individual factors predictive of treatment benefit in all patients. The middle of the square represents the hazard ratio (HR) for postoperative radiotherapy versus a wait-and-see approach in each group. The length of the horizontal bars represents the 95% CI for the HR. The vertical solid line represents no benefit. CIs not crossing that line indicate significant differences. The diamonds represent the HR and CI. The vertical dashed line represents the HR in the whole sample. O, observed; E, expected; PSA, prostate-specific antigen.

View larger version (21K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Forest plot for the individual factors predictive of treatment benefit in patients with postoperative prostate-specific antigen 0.2 ng/mL. The middle of the square represents the hazard ratio (HR) for postoperative radiotherapy versus a wait-and-see approach in each group. The length of the horizontal bars represents the 95% CI for the HR. The vertical solid line represents no benefit. CIs not crossing that line indicate significant differences. The diamonds represent the HR and CI. The vertical dashed line represents the HR in the whole sample. O, observed; E, expected.

Only surgical margin status caused a statistically significant interaction with the treatment effect (heterogeneity, P < .01) to such an extent that the treatment benefit in patients with negative margins is not significant (Figs 1 and 2; Table 2).

View this table: [in this window] [in a new window]   Table 2. Treatment Effects Within the Subgroups Comparing All Patients With Review Pathology Versus Those With Postoperative PSA 0.2 ng/mL

View larger version (18K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Biochemical progression-free survival by surgical margin status and allocated treatment. N, number of patients; O, number of events; SM–/+, surgical margin negative/positive; W&S, wait-and-see group (control); RT, irradiation.

Excluding the patients with PSA more than 0.2 ng/mL immediately after prostatectomy, the hazard ratio for irradiation was 1.11 (95% CI, 0.61 to 1.99; P = .740) for the patients with negative margins and the hazard ratio was 0.29 (95% CI, 0.18 to 0.47; P < .0001) for the patients with positive margins.

Impact of Positive Margin Localization
Except for 28 of the 322 patients with a positive margin, the review pathologist could also classify the localization of the margin positivity: 65 patients had apically positive margin only, 168 had lateral positive margins, and 61 had both lateral and apical positive margins. The distribution was similar in both arms. Figures 4A and 4B show the forest plot of the treatment benefit according to the localization of the positive margins in all assessed patients and in the patients with postoperative PSA 0.2 ng/mL. The two figures show that the magnitude of the treatment benefit does not differ significantly in function of the localization of the positive margin (heterogeneity, P > .1), although there is a trend for a larger benefit in the small group of patients with positive margins in both the apex and the lateral margins.

View larger version (24K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Treatment effect on biochemical progression-free survival by review margin status and localization of the positive margin (A) in all patients and (B) in patients with postoperative prostate-specific antigen (PSA) 0.2 ng/mL. The middle of the square represents the hazard ratio (HR) for postoperative radiotherapy versus wait-and-see approach in each group. The length of the horizontal bars represents the 95% CI for the HR. The vertical solid line represents no benefit. CIs not crossing that line indicate significant differences. The diamond and the vertical dashed line represent the HR in the whole sample and the CI. O, observed; E, expected; SD, standard deviation.

View larger version (18K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 5. Biochemical progression-free survival according to margin status and localization for patients (A) in the control arm and (B) in the immediate postoperative irradiation arm. N, number of patients; O, number of events.

	DISCUSSION

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Our subset analysis of these patients showed that adjuvant radiotherapy reduces the risk of biochemical recurrence specifically in those with positive surgical margins, whereas those with negative margins (irrespective of other risk factors) in general do not seem to benefit. Importantly, our data indicate that about three patients with positive margins need to be treated with adjuvant radiotherapy to prevent one biochemical recurrence. We emphasize here that this conclusion was only reached after a scrutinized central review of the prostatectomy specimens, whereas data from local pathology did not show this marked effect of surgical margin status on radiotherapy outcome.¹⁰ Obviously, this variability in assessment of surgical margin status detracts from the generalized applicability of our findings. It was noted that the level of agreement between local and review pathology varied strongly for the different participating hospitals ( scores between 0.13 and 0.64),¹² which emphasizes the importance of the uniform application of well-established rules regarding the determination of margin status in prostatectomy specimens.²⁹

The somewhat worse pathologic features, including positive margins and invasion of seminal vesicles, of the nonreviewed patient group as compared with the reviewed patients may have biased our results. However, in the population with available pathology review, the treatment benefit was strongest in the patients with adverse pathologic factors, including positive surgical margins, and therefore it is likely that our conclusions remain valid for the entire population.

It is conceivable that additional adverse factors related to development of biochemical and clinical recurrence, such as high Gleason score and seminal vesicle involvement,^30,31 may have negated the effect of adjuvant radiotherapy as a result of their association with an increased risk of distant metastasis.³² This would suggest that the postoperative irradiation is not able to prevent the occurrence of metastasis any longer, given that the systemic dissemination of tumor cells already has occurred before therapy in these patients. However, a few studies on relatively small series of patients showed a beneficial effect of postoperative radiotherapy for biochemical recurrence in patients with invasion of their seminal vesicles.^28,33 These retrospective studies were compromised by the presence of an excess of other risk factors in the patients who did not receive radiotherapy and by hormonal manipulation. In our study, Gleason score continued to be a powerful prognosticator for biochemical progression in the radiotherapy arm, but we noted that a beneficial effect was obtained in patients with positive surgical margins, both for high Gleason score prostate cancers and those with seminal vesicle invasion (Fig 5). However, our data suggest that the latter subset of patients with both positive margins and seminal vesicle invasion may have less benefit of adjuvant radiotherapy compared with the entire group of patients with positive surgical margins.

Prostate cancer differs from most other malignancies because of its slowly developing nature: nonradical resection of prostate cancer is not always followed by rapid biochemical recurrence; likewise, a local recurrence does not necessarily evolve toward systemic spread and death as a result of the disease. A biochemical recurrence is reported in approximately 30% to 75% of patients with positive surgical margins.^5,20,21 The strong variation reported in literature is likely due to additional factors such as Gleason score distribution and stage distribution of the patients under study, as well as interobserver variation for determination of margin status. It has also been noted that the majority of patients with biochemical recurrence will not develop a local recurrence or distant disease,^21,34 and biochemical progression is by some considered a poor surrogate marker for disease progression.^35,36 Local growth can lead to anxiety of the patient and to additional treatment.

Some studies claimed that apex positivity is less likely to result in biochemical or local recurrence,^37,38 but this was not substantiated by other series^21,30,39,40 and also not in our patient group. In addition, we did not show a difference in treatment benefit for patients with only apex positivity as compared with those with positive lateral margins. Those with both apex and lateral margin positivity seemed to benefit more than those with positivity at one of the sites, emphasizing the predictive impact of positive surgical margins. Unfortunately, we were not able to perform subgroup analysis for actual clinical recurrence of disease, given that the number of events was too small. Some controversy exists in the literature with regard to the clinical significance of surgical margin status as the sole adverse risk factor. Although most but not all studies have shown that positive surgical margin status represents an independent risk factor for biochemical recurrence, in addition to Gleason sum, preoperative PSA, and pathologic stage,^5,21 it is not certain that positive surgical margins add to the risk of actual local recurrence or systemic disease. Those few studies reporting on prognosticators for clinical recurrence so far failed to demonstrate any independent prognostic impact of surgical margin status,^3,21 but their relative short follow-up periods may have contributed to these negative findings. In a similar vein, it remains uncertain to what extent prostate cancer–specific or metastases-free survival of the various subsets of patients with positive margins will be influenced by adjuvant radiotherapy. These pertinent questions may be solved when longer follow-up data of the participants of our trial EORTC 22911 become available.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Michel Bolla, Hein Van Poppel, Laurence Collette

Provision of study materials or patients: Michel Bolla, Hein Van Poppel, Paul Van Cangh, Luigi Da Pozzo, Karl H. Kurth, Kris Vekemans, Jean-Francois Bosset, Fritz Schröder

Collection and assembly of data: Theodorus H. Van der Kwast, Michel Bolla, Laurence Collette

Data analysis and interpretation: Theodorus H. Van der Kwast, Michel Bolla, Laurence Collette

Manuscript writing: Theodorus H. Van der Kwast, Laurence Collette

Final approval of manuscript: Theodorus H. Van der Kwast, Michel Bolla, Hein Van Poppel, Paul Van Cangh, Luigi Da Pozzo, Karl H. Kurth, Kris Vekemans, Jean-Francois Bosset, Fritz Schröder, Laurence Collette

	NOTES

 
Supported by Grants No. 5U10 CA11488-21 through 5U10 CA11488-37 from the National Cancer Institute (Bethesda, MD) and by a grant from the Ligue Nationale contre le Cancer (Grenoble, France). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

Presented in part at the Annual Meeting of the European Association of Urology, April 6, 2006, Paris, France, and the Congress of the American Urological Association, May 23, 2006, Atlanta, GA.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted December 21, 2006; accepted June 25, 2007.

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