Identification of patients with prostate cancer who benefit from immediate postoperative radiotherapy: EORTC 22911

Tags: surgical margins, surgical margin, prostate cancer, irradiation, progression-free survival, radiotherapy, J Urol, radical prostatectomy, Gleason score, biochemical recurrence, prostatectomy, hazard ratio, treatment benefit, risk factors, negative margins, University Health Network, pathology, adjuvant radiotherapy, American Society of Clinical Oncology, EORTC, Heterogeneity, Hein Van Poppel, radical retropubic prostatectomy, Theodorus H. Van der Kwast, Department of Urology, Ospedale San Rafaele, Treatment of Cancer, Virga Jesse Ziekenhuis, Cancer, European Association of Urology, National Cancer Institute, Centre Hospitalier Universitaire Grenoble, European Organisation for Research and Treatment of Cancer Data Center, pathology data, Eur J Cancer, Urology, Eisenberger MA, seminal vesicle, Hopital Jean Minjoz, Academisch Medisch Centrum, Department of Radiotherapy and Oncology, Michel Bolla, Laurence Collette Manuscript, JOURNAL OF CLINICAL ONCOLOGY, van der, Treatment effect, Luigi Da Pozzo, Clarian Hlth Partners, Van der Kwast, lateral margins, seminal vesicles, Department of Urology, Universiteits Ziekenhuis Gasthuisberg, Paul Van Cangh, Postoperative Radiotherapy, Laurence Collette, Department of Urology, Department of Radiotherapy, Laurence Collette Provision
Content: VOLUME 25 NUMBER 27 SEPTEMBER 20 2007 Journal of Clinical Oncology
ORIGINAL REPORT
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. Submitted December 21, 2006; accepted June 25, 2007. 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. 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: [email protected] © 2007 by American Society of Clinical Oncology 0732-183X/07/2527-4178/$20.00 DOI: 10.1200/JCO.2006.10.4067
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. Schrцder, and Laurence Collette ABSTRACT 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. J Clin Oncol 25:4178-4186. © 2007 by American Society of Clinical Oncology
INTRODUCTION 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 studies6-9 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
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Benefit of RT Immediately After Prostatectomy
Table 1. Characteristics of the Eligible Patients With and Without Review Pathology
Characteristic
Not Reviewed (n 420)
No. of
Patients
%
Reviewed (n 552)
Wait-and-See (n 280)
Irradiation (n 272)
No. of
No. of
Patients
%
Patients
%
Total (N 972)
No. of
Patients
%
Age, years 65 65 Median Range Other chronic disease Nerve-sparing procedure Clinical T category T0-1 T2 T3 Missing Preoperative PSA, ng/mL 4 to 10 10 to 20 20 Missing Postoperative PSA, ng/mL 0.2 0.2 Missing Review pathology Gleason sum 2-6 7 8-10 Missing Gleason score 3 4 5 6 7 8 9 10 Seminal vesicle invasion No Yes Unknown Extracapsular extension No Focal Extensive Unknown Surgical margins Free Positive Not assessable Pathologic T pT2 pT3a pT3b pT4 Missing
211
50.2
209
49.8
65.0
47.0-75.1
108
25.7
191
45.5
70
16.7
272
64.8
77
18.3
1
0.2
168
40.0
149
35.5
100
23.8
3
0.7
259
61.7
135
32.1
26
6.2
120
42.9
160
57.1
66.0
48.6-75.8
80
28.6
101
36.1
48
17.1
191
68.2
41
14.6
0
0.0
112
40.0
98
35.0
70
25.0
0
0.0
211
75.4
61
21.8
8
2.9
111
39.6
118
42.1
47
16.8
4
1.4
2
0.7
3
1.1
31
11.1
75
26.8
118
42.1
25
8.9
22
7.9
0
0.0
225
80.4
48
17.1
7
2.5
124
44.3
36
12.9
118
42.1
2
0.7
116
41.4
152
54.3
12
4.2
103
36.8
101
36.1
41
14.6
30
10.7
5
1.8
122
44.9
150
55.1
66.2
47.2-75.8
74
27.2
87
32.0
54
19.9
169
62.1
49
18.0
0
0.0
97
35.7
97
35.7
77
28.3
1
0.4
206
75.7
55
20.2
11
4.0
97
35.7
115
42.3
59
21.7
1
0.4
1
0.4
3
1.1
27
9.9
66
24.3
115
42.3
21
7.7
36
13.2
2
0.7
216
79.4
54
19.9
2
0.7
122
44.9
48
17.6
99
36.4
3
1.1
114
41.9
142
52.2
16
5.9
106
39.0
91
33.5
45
16.5
29
10.7
1
0.4
453
46.6
519
53.4
65.5
47.0-75.8
262
27.0
379
39.0
172
17.7
632
65.0
167
17.2
1
0.1
377
38.8
344
35.4
247
25.4
4
0.4
676
69.5
251
25.8
45
4.6
Abbreviation: PSA, prostate-specific antigen.
P for Reviewed v Not Reviewed .048 .477 .0002 .600 .599 .0001
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Van der Kwast et al
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 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 prostatespecific 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
Surgical margins SMSM+
Irradiation Wait-and-See Statistics Events Patients Events Patients (O-E) Variance
29 114 35 142
33 116 -2 15.2 79 152 -27.3 28
HR and CI
Total
64 256 112 268
(25%)
(41.8%)
Heterogeneity 21 = 6.97, P < .01
Extracapsular extension
ECE-
14 122
40 124
-29.4 -15.3
43.3 13.4
ECE+
56 147
78 154 -13 33.1
Total
70 269 (26%)
118 278 (42.4%)
Heterogeneity 21 = 5.34, P = .02
Seminal vesicles invasion
-28.3
46.4
SV-
43 216
86 225 -25.4 31.8
SV+
27 54
29 48 -4.4 13.7
Total
70 270 115 273
(25.9%)
(42.1%)
Heterogeneity 21 = 2.18, P > .1
Gleason sum
6
12 97
31 111
7
31 115
53 118
>7
28 59
32 47
-29.8 -9.8 -13.4 -8.6
45.5 10.7 20.6 13.8
Total
71 271 116 276
(26.2%)
(42%)
Heterogeneity 22 = 0.64, P > .1
Postoperative PSA
-31.8
45.1
0.2 ng/mL > 0.2 ng/mL
47 206 23 55
78 211 -19.9 30.7 35 61 -6.3 14.4
Total
70 261 113 272
(26.8%)
(41.5%)
Heterogeneity 21 = 0.43, P > .1
-26.2
45.1 0.25
0.50
1.00
2.00
4.00
Irradiation Better
Wait-and-See Better
Treatment effect: P < .00000
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.
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Benefit of RT Immediately After Prostatectomy
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
Surgical margins SMSM+
Irradiation Wait-and-See Statistics Events Patients Events Patients (O-E) Variance
25 95 16 98
21 90 1.1 11.2 51 110 -20.3 16.5
HR and CI
Total
41 193 (21.2%)
72 200 -19.2 27.7 (36%)
Heterogeneity 21 = 11.78, P < .001
Extracapsular extension
ECE-
13 99
32 100 -11.8 11.1
ECE+
33 104
46 110 -7.2 19.4
Total
46 203 (22.7%)
78 210 -19 30.5 (37.1%)
Heterogeneity 21 = 3.44, P = .06
Seminal vesicles invasion
SV-
37 175
58 173 -14.1 23.3
SV+
10 30
17 32 -4.8 6.6
Total
47 205 (22.9%)
75 205 (36.6%)
Heterogeneity 21 = 0.07, P > .01
Gleason sum
-18.8
29.9
6
12 82
24 87 -7.5 8.9
7
23 88
37 95 -7.4 14.7
>7
12 35
15 26 -3.9 6
Total
47 205 (22.9%)
76 208 (36.5%)
Heterogeneity 22 = 0.66, P > .1
-18.9
29.6 0.25
0.50
1.00
2.00
4.00
Irradiation Better
Wait-and-See Better
Treatment effect: P < .00000
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-andsee 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.
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Van der Kwast et al
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. Statistics Interactions between the magnitude of the treatment benefit and puta- tive predictive factors were studied by means of the log-rank test for heterogeneity15 and the effects of the predictive factors are represented on Forest plots.16 The following factors were studied: seminal vesicle invasion, extraprostatic extension, surgical margin status and localization (apex, lateral, or both), and Gleason sum ( 6, 7, or 7) assessed by the review pathologist, as well as the postprostatectomy PSA level ( 0.2 v 0.2 ng/mL). Event-free rates were estimated by Kaplan-Meier.17 The statistical significance level was set at .05. RESULTS 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). Overall, there was no statistically significant predictive impact of postoperative PSA and Gleason sum or seminal vesicle invasion (P .1 for each; Figs 1 and 2). The treatment benefit seemed larger in patients without extraprostatic extension (heterogeneity, P .02; Fig 1) when all patients were included in the analysis, but the effect was no longer statistically significant when the analysis was restricted to the patients whose PSA remained more than 0.2 ng/mL after surgery (P .06; Fig 2). 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). Figure 3 displays the Kaplan and Meier curves for biochemical progression-free survival according to margin status and treatment arm: no difference is found between the patients with negative surgical margins in the control and irradiation arm (P .1) and the patients with positive margins in the irradiation arm (P .070), whereas only those with positive margins in the control arm fare significantly worse (P .001). The 5-year biochemical progression-free survival rate was 67.4% (95% CI, 56.1% to 76.3%) and 76.2% (95% CI, 66.1% to 83.6%) for the patients with negative margins in the control and irradiation arm, respectively; it was 77.6% (95% CI, 68.8% to 84.2%)
Table 2. Treatment Effects Within the Subgroups Comparing All Patients With Review Pathology Versus Those With Postoperative PSA 0.2 ng/mL
Characteristic
All Patients
HR
95% CI
Patients With Postoperative PSA 0.2 ng/mL (n 414)
HR
95% CI
SM
Negative
0.87 0.53 to 1.45 1.11 0.61 to 1.99
Positive
0.38 0.26 to 0.55 0.29 0.18 to 0.47
ECE
Negative
0.32 0.19 to 0.55 0.34 0.19 to 0.62
Positive
0.67 0.48 to 0.95 0.69 0.44 to 1.08
Invasion of SVs
Negative
0.45 0.32 to 0.64 0.55 0.36 to 0.82
Positive
0.72 0.43 to 1.23 0.49 0.23 to 1.05
Gleason sum
6
0.40 0.22 to 0.73 0.43 0.22 to 0.83
7
0.52 0.34 to 0.80 0.60 0.36 to 1.01
7
0.54 0.32 to 0.91 0.52 0.23 to 1.16
Postoperative PSA, ng/mL
0.2
0.52 0.37 to 0.74
0.2
0.64 0.38 to 1.08
Abbreviations: PSA, prostate-specific antigen; HR, hazard ratio; SM, surgical margin; ECE, extracapsular extension; SVs, seminal vesicles.
for the patients with positive margins in the irradiation arm but was 48.5% (95% CI, 39.6 to 58.9) for the patients with positive surgical margin in the control arm. The hazard ratio for the treatment benefit in the group with negative surgical margins was 0.87 (95% CI, 0.53 to 1.46; P .601), based on 62 events, and it is 0.38 (95% CI, 0.26 to 0.54; P .0001) in the group with positive surgical margins according to the review pathology. This means that for every 1,000 patients with negative margins, adjuvant irradiation would prevent biochemical relapse by year 5 in 88 patients, whereas irradiating 1,000 patients with positive margins would prevent relapse in 291 patients (P .01).
Alive Progression Free (%)
100
90
80
70
60
50
40
30
SM-: W&S
20
SM-: RT
SM+: W&S
10
SM+: RT
0
1 2 3 45 6 7 8 9
Time (years)
O N No. of patients at risk
SM-: W&S 33 116 109 95
72
53
38
25 19
11
SM-: RT 29 114 105 94
81
62
45
25 16
10
SM+: W&S 79 152 129 107 81
58
40
27 18
8
SM+: RT 35 142 135 125 103 83
62
45 34
12
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.
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Benefit of RT Immediately After Prostatectomy
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. The biochemical progression-free survival by margin status and localization is shown in Figures 5A and 5B for the patients in the control arm and in the postoperative irradiation group: without postoperative irradiation, margin positivity is a strong indicator of poor prognosis (P .001), but this effect is no longer observed when patients are irradiated postoperatively. Of note, the 5-year biochemical progression-free survival rates in patients with negative surgical margin amounts to 64.4% (95% CI, 56.1% to 76.3%) in the control group and 76.2% (95% CI, 66.1% to 83.6%) in the group irradiated postoperatively.
A
Irradiation Wait-and-See Statistics
Events Patients Events Patients (O-E) Variance
Margin free 29 114 Subtotal 29 114 (25.4%)
33 116 33 116 (28.4%)
-2 15.2 -2 15.2
HR and CI
|1-HR| % ± SD 13% ± 24 reduction
Margin apex+ 8
33
Margin lateral+ 20 79
Margin both+ 7
30
17 32 43 89 19 31
Subtotal 35 142
79 152
(24.6%)
(52%)
Heterogeneity 22 = 0.83, P > .1
Total
64 256 (25%)
112 268 (41.8%)
Test for heterogeneity (4 groups) 23 = 7.99, P = .05 Test for heterogeneity (2 groups) 21 = 7.16, P < .01
-5.2 6.2 -14.1 15.4 -8.1 6.2 -27.4 27.8 -29.5 43
63% ± 12 reduction
50% ± 11 reduction
0.25 0.50 1.00 2.00 4.00
Irradiation Better
Wait-and-See Better
Treatment effect (global): P < .00001
B
Irradiation Wait-and-See Statistics
Events Patients Events Patients (O-E) Variance
HR and CI
|1-HR| % ± SD
Margin free 25 95 Subtotal 25 95 (26.3%)
21 90 21 90 (23.3%)
1.1 11.2 1.1 11.2
11% ± 31 increase
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 waitand-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.
Margin apex+ 4
24
Margin lateral+ 8
52
Margin both+ 4
22
12 25
30 68
9
17
Subtotal 16 98
51 110
(16.3%)
(46.4%)
Heterogeneity 22 = 0.64, P > .1
Total
41 193 (21.2%)
72 200 (36%)
Test for heterogeneity (4 groups) 23 = 12.96, P < .01 Test for heterogeneity (2 groups) 21 = 12.32, P < .001
-3.9 4 -11.9 9.3 -4.6 2.9 -20.4 16.1 -19.3 27.3
72% ± 14 reduction
51% ± 14 reduction
0.25 0.50 1.00 2.00 4.00
Irradiation Better
Wait-and-See Better
Treatment effect (global): P < .001
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Van der Kwast et al
Alive Progression Free (%)
A 100
90
80
70
60
50
40
Positive margin
30
No
Apex only
20
Lateral only
10
Apex + lateral
P = .0001 (df = 1)
0
2
4
6
8
10
Time (years)
Positive margin O N
No. of patients at risk
No
33 116
95
53
25
11
Apex only
17 32
27
16
7
0
Lateral only 43 89
60
32
15
6
Apex + lateral 19 31
20
10
5
2
Alive Progression Free (%)
B 100
90
80
70
60
50
40
Positive margin
30
No
Apex only
20
Lateral only
10
Apex + lateral
P = .5294 (df = 1)
0
2
4
6
8
10
Time (years)
Positive margin O N
No. of patients at risk
No
29 114
94
62
25
10
Apex only
8 33
30
19
8
1
Lateral only 20 79
69
44
27
9
Apex + lateral 7 30
26
20
10
2
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 Radical prostatectomy is an effective therapy for patients with localized low- grade (Gleason score 5 to 6) and intermediate-grade (Gleason score 7) prostate cancer, given that it is associated with excellent long-term prostate cancer­specific survival.18,19 The identification of positive surgical margins is declining in current populations,20,21 but remains stable at approximately 25% to 35% of men with non­ organconfined prostate cancers.21,22 This places them at risk for biochemical and clinical disease recurrence.5 For this reason, several authors advocated the use of immediate postoperative radiotherapy for patients with adverse risk factors in their prostatectomy specimen to reduce the risk of local recurrence and subsequent distant metastasis.9,24-28 Radiotherapy is believed to act by destroying residual carcinoma cells in the surgical wound bed, and therefore this therapy is believed to be particularly effective in patients with positive surgical margins. The effectiveness of radiotherapy in patients with negative margins but who carry any of the other adverse risk factors (ie, extraprostatic
extension, seminal vesicle invasion, and/or high Gleason score) in their prostatectomy specimens remains uncertain. 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
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Benefit of RT Immediately After Prostatectomy
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 series21,30,39,40 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 nega-
tive findings. In a similar vein, it remains uncertain to what extent prostate cancer­specific 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 The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS 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 Schrцder 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 Schrцder, Laurence Collette
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33. Lee HM, Solan MJ, Lupinacci P, et al: Longterm outcome of patients with prostate cancer and pathologic seminal vesicle invasion (pT3b): Effect of adjuvant radiotherapy. Urology 64:84-89, 2004 34. Pound CR, Partin AW, Eisenberger MA, et al: Natural History of progression after PSA elevation following radical prostatectomy. JAMA 281:15911597, 1999 35. Jhaveri FM, Zippe CD, Klein EA, et al: Biochemical failure does not predict overall survival after radical prostatectomy for localized prostate cancer: 10-years results. Urology 54:884-890, 1999 36. Collette L, Burzykowski T, Schroder FH: Prostate-specific antigen (PSA) alone is not an appropriate surrogate marker of long-term therapeutic benefit in prostate cancer trials. Eur J Cancer 42: 1344-1350, 2006 37. Ohori M, Abbas F, Wheeler TM, et al: Pathological features and prognostic significance of pros-
tate cancer in the apical section determined by whole mount histology. J Urol 161:500-504, 1999 38. Fesseha T, Sakr W, Grignon D, et al: Prognostic implications of a positive apical margin in radical prostatectomy specimens. J Urol 158:2176-2179, 1997 39. Watson RB, Civantos F, Soloway MS: Positive surgical margins with radical prostatectomy: Detailed pathological analysis and prognosis. Urology 48:80-90, 1996 40. Pettus JA, Weight CJ, Thompson CJ, et al: Biochemical failure in men following radical retropubic prostatectomy: Impact of surgical margin status and location. J Urol 172:129-132, 2004 41. Palisaar RJ, Graefen M, Karakiewicz PI, et al: Assessment of clinical and pathologic characteristics predisposing to disease recurrence following radical prostatectomy in men with pathologically organ-confined prostate cancer. Eur Urol 41:155161, 2002

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