Value of positive resection margins in patients with pT2 prostate cancer. Implications for adjuvant treatment

Actas Urol Esp. 2011;35(5):272---276

Actas Urológicas Españolas www.elsevier.es/actasuro

ORIGINAL ARTICLE

Value of positive resection margins in patients with pT2 prostate cancer. Implications for adjuvant treatment夽 J.E. Rosas-Nava a,∗ , F. Herranz-Amo b , E.V. Pa˜ nos-Fagundo b , E. Lledó-García b , b b F. Verdú-Tartajo , C. Hernández-Fernández a b

Servicio de Urología, Hospital General de México DF, Mexico Servicio de Urología, Hospital General Universitario Gregorio Mara˜ nón, Madrid, Spain

Received 7 December 2010; accepted 2 January 2011 Available online 6 August 2011

KEYWORDS Prostate cancer; Radical prostatectomy; pT2 stage; Prognostic factors; Recurrence; Positive surgical margins; Adjuvant radiotherapy

Abstract Objective: To analyze the impact on the recurrence-free biochemical survival of tumor involvement of surgical resection margins in patients with localized prostate cancer (pT2) in the prostatectomy specimen and its implications for adjuvant treatment. Materials and method: Retrospective study of 536 patients with stage pT2 prostate cancer, treated with radical prostatectomy between 1996 and 2007. Subsequent to the prostatectomy, the following variables were collected: Gleason score, pathological stage, capsular invasion, surgical margins and perineural invasion. We performed a univariate analysis and subsequently adjusted it by means of a Cox proportional hazard model (enter method). Results: 21.7% presented positive surgical margins and 20.9% developed biochemical recurrence after a mean follow-up of 57 months. 37.9% of the patients with pathological involvement of the resection surgical margins presented biochemical recurrence against 16% that did not have it (p < 0.001). In the multivariate analysis, only the surgical margin (p < 0.001) and the Gleason score greater or equal to 8 (p < 0.001) behaved as independent biochemical recurrence factors. On stratifying the series according to these two variables, we found that the patients with positive surgical margins and a Gleason score of ≤7 have a recurrence probability at 5 and 10 years of 35% and 50% against 74% and 87% in the group with positive surgical margins and a Gleason score of ≥8 (p = 0.002). Conclusion: Patients with pT2 prostate cancer, positive surgical margins and a Gleason score of ≥8 will benefit from adjuvant radiotherapy. 50% of the patients with positive margins and a Gleason score of ≤7 will not recur, which means that the indication of adjuvant radiotherapy continues to be controversial. © 2010 AEU. Published by Elsevier España, S.L. All rights reserved.

夽 Please cite this article as: Rosas-Nava JE, et al. Valor de los márgenes quirúrgicos de resección positivos en los pacientes con cáncer de próstata pT2. Implicaciones en el tratamiento adyuvante. Actas Urol Esp. 2011;35:272---76. ∗ Corresponding author. E-mail address: rosas nava [email protected] (J.E. Rosas-Nava).

2173-5786/$ – see front matter © 2010 AEU. Published by Elsevier España, S.L. All rights reserved.

Value of positive resection margins in patients with pT2 prostate cancer

PALABRAS CLAVE Cáncer de próstata; Prostatectomía radical; Estadio pT2; Factores pronóstico; Recidiva; Márgenes quirúrgicos positivos; Radioterapia adyuvante

273

Valor de los márgenes quirúrgicos de resección positivos en los pacientes con cáncer de próstata pT2. Implicaciones en el tratamiento adyuvante Resumen Objetivo: Analizar el impacto sobre la supervivencia libre de recidiva bioquímica de la afectación tumoral de los márgenes quirúrgicos de resección en los pacientes con cáncer de próstata en estadio localizado (pT2) en la pieza de prostatectomía y su implicación en el tratamiento adyuvante. Material y método: Estudio retrospectivo de 536 pacientes con cáncer de próstata en un estadio pT2 tratados con prostatectomía radical entre 1996 y 2007. Posteriormente a la prostatectomía se recogieron las siguientes variables: score de Gleason, estadio patológico, invasión capsular, márgenes quirúrgicos e invasión perineural. Se realizó un análisis univariante y posteriormente se ajustó mediante un modelo de riesgos proporcionales de Cox (método enter). Resultados: El 21,7% presentó márgenes quirúrgicos positivos y el 20,9% desarrolló recidiva bioquímica con una mediana de seguimiento de 57 meses. El 37,9% de los pacientes con afectación patológica de los márgenes quirúrgicos de resección presentó recidiva bioquímica, frente al 16% de los que no la tenían (p < 0,001). En el análisis multivariante solo el margen quirúrgico (p < 0,001), y el score de Gleason mayor o igual a 8 (p < 0,001) se comportaron como factores independientes de recidiva bioquímica. Al estratificar la serie según estas dos variables encontramos que los pacientes con márgenes quirúrgicos positivos y score de Gleason ≤ 7 tienen una probabilidad de recidiva a los 5 y 10 a˜ nos del 35 y del 50%, frente al 74 y 87% en el grupo con márgenes quirúrgicos positivos y score de Gleason ≥ 8 (p = 0,002). Conclusión: Los pacientes con cáncer de próstata pT2, márgenes quirúrgicos positivos y score de Gleason ≥ 8 se beneficiarán de una radioterapia adyuvante. El 50% de los pacientes con márgenes positivos y un score de Gleason ≤ 7 no presentarán recidiva, por lo que la indicación de radioterapia adyuvante sigue siendo controvertida. © 2010 AEU. Publicado por Elsevier España, S.L. Todos los derechos reservados.

Introduction Prostate cancer (PCa) is the most prevalent tumor in men and is the second leading cause of cancer death. The American Cancer Society (ACS) estimates that in 2010 217,730 cases will be diagnosed (80% located) and that 32,050 patients will die as a result of it.1 Approximately one-third to half of the patients treated with curative intent underwent radical prostatectomy (RP).2,3 During follow-up, one-third of these patients will present an increase in prostate specific antigen (PSA) without clinical or radiological manifestations of metastasis.4 Positive surgical margins (PSMs) were found in the biopsies of about 30% of the patients that underwent PR, which is a bad prognosis factor, and biochemical recurrence and specific mortality increased in 5 years in between 12% and 18%.5,6 The Clinical Guidelines of the European Association of Urology (EAU)7 and the National Comprehensive Cancer Network (NCCN)8 recommend adjuvant radiotherapy in patients with PSMs. The aim of this study is to analyze the impact on biochemical relapse-free survival (BRFS) of tumor involvement of resection surgical margins in patients with localized stage prostate cancer (pT2) in the prostatectomy specimen, and what it entails in adjuvant treatment.

than 3 months. In December of 2009 the database was updated. Patients were classified prior to surgery in accordance with the D’Amico biochemical recurrence risk groups.9 For the pathological stage, we used the 2002 TNM classification of the UICC. No patient received neo or adjuvant therapy. Postoperative follow-up consisted of determining PSA at 3 months, 6 months until the fifth year and annually thereafter. We considered biochemical recurrence (BR) to be persistent or increased PSA after radical prostatectomy above 0.4 ng/ml and increasing in the following determination. We performed a descriptive analysis of the variables analyzed employing the usual statistics for quantitative variables (mean, standard deviation, median, etc.) and qualitative (absolute frequencies, etc.). We used Fisher’s exact test and the chi square test to assess the association between categorical variables. We used the Kaplan---Meier method to assess survival and the long-rank test to assess differences between the different groups with confidence intervals at 95%. We performed a univariate analysis and subsequently adjusted it by means of a Cox proportional hazards model (Enter method). Statistical significance was considered when p < 0.05. All calculations were performed with the SPSS version 15.0 statistical software in Spanish.

Results Materials and methods Between 1996 and 2007, we performed RP in 536 patients with localized PCa (pT2), pN0-Nx and follow-up for more

The 536 patients had mean age of 64 and PSA of 7.5 ng/ml, the other clinical variables are listed in Table 1. After the prostatectomy, 17.7% of the patients had a Gleason score

274 Table 1

J.E. Rosas-Nava et al. Clinical characteristics of patients in the series.

Patients Age (years) PSA (ng/ml)

536 63.3 ± 5.9 8.5 ± 5.4

Gleason score (biopsy) ≤6 7 ≥8

Table 3 Relationship between biochemical and pathological variables (univariate). Variable

Biochemical relapse

p

63.2% 36.8% 0%

Gleason score of the RP ≤6 7 ≥8

% 11.8 17.8 44.7

<0.001

Clinical stage T1c T2a-b T2c

68.2% 28.7% 3.1%

Capsular invasion Yes No

% 24.9 15.8

0.001

47.1% 39.6% 13.3%

Surgical margins Positive Negative

% 37.9 16

<0.001

D’Amico Risk Group Low Intermediate High

Perineural invasion Yes No

% 23.6 19.8

0.30

Pathological stage pT2a-b pT2c

% 25.8 19.5

0.13

Statistics: mean, standard deviation and percentage.

(GS) ≥ 8 and 21.7% had PSM. The other pathological variables obtained after PR are shown in Table 2. In 49%, there was concordance between the GS of the specimen and that of the prostatectomy, 47.2% were understaged (52.9% for the GS of 6 and 29.1% for the GS of 7) and 8.1% of GS 7 was understaged. Follow-up of the series was 63.9 ± 35 (8---168) with a median of 57 months. At follow-up, 112 (20.9%) patients had BR. In 9 (8%) patients post-prostatectomy PSA was never below 0.4 ng/ml (biochemical persistence --- BP) and in 103 (92%) cases, PSA increased after a varying period of time, with PSA less than 0.4 ng/ml. 15.1% of the patients were classified as low risk, 19.8% were categorized as intermediate risk and 45.1% of the high risk group (p < 0.001) presented BR. At the end of the trial, 523 (97.6%) patients were alive: 414 (77.2%) without BR, 109 (20.3%) with BR and 13 (2.4%)

Table 2

Post-prostatectomy variables.

Pathological stage pT2a-b pT2c

% 22.4 77.6

Gleason score ≤6 7 ≥8

% 30.3 52 17.7

Capsular invasion If No

% 54.6 45.4

Surgical margins Positive Negative

% 21.7 78.3

Perineural invasion Yes No

% 57.9 42.1

Statistical study: percentage.

Statistical analysis: binary logistic regression.

had died. 3 (0.5%) patients died from prostate cancer and 10 (1.7%) patients from other causes. 59.8% of patients with BR were treated with salvage radiotherapy, 19.7% with hormone therapy and 20.5% did not receive any salvage treatment. The overall median actuarial BRSF of the series was 123.6 months (95% CI: 116.8, 130.4). The BRSF at 5 and 10 years was estimated at 78.1 and 62.4% respectively. Overall survival at 5 and 10 years was estimated at 97.7 and 94.2% respectively and cancer-specific survival at 5 and 10 years was estimated at 99.3 and 97.1% respectively. 37.9% of patients with pathological involvement of surgical resection margins presented BR versus 16% who did not (p < 0.001). In the univariate analysis, we observed an association of BR with the following pathological variables: Gleason score (p < 0.0001), pathologic condition of surgical margins (p < 0.0001) and capsular invasion (p = 0.01). The rest of the data of the univariate analysis is given in Table 3. We introduced the following variables in the multivariate analysis: Gleason score, surgical margins and capsular invasion. Only the surgical margin (p < 0.001) and Gleason score ≥ 8 (p < 0.001) acted as independent factors of biochemical relapse (Table 4). We stratified according to surgical margin status (SM) and the prostatectomy GS in 4 risk groups: 1) (−) SM and GS ≤ 7; 2) (−) SM and GS ≥ 8; 3) (+) SM and GS ≤ 7; 4) (+) SM and GS ≥ 8. The recurrence rate in these groups was 11.7%, 37.5%, 31% and 60.7% respectively (p < 0.001). The probability of recurrence at 5 and 10 years depending on these risk groups is described in Table 5. Patients with (+) SM and GS ≤ 7 had a probability of relapsing at 5 and 10 years of 35% and 50%, compared with 74% and 87% in the group with (+) SM and GS ≥ 8 (p = 0.002) (Fig. 1).

Value of positive resection margins in patients with pT2 prostate cancer

275

1.0

0.8

MQ_SG MQ(-) + SG <=7 MQ(-) + SG >=8 MQ(+) + SG <=7 MQ(+) + SG >=8 MQ(-) + SG <=7censored MQ(-) + SG >=8censored MQ(+) + SG <=7censurado MQ(+) + SG >=8censored

Percentage

0.6

0.4

MQ(-) + SG<=7 vs. MQ(-) + SG>=8 − p<0,001 MQ(-) + SG>=8 vs. MQ(+) + SG<=7 − p=0,98 MQ(+) + SG<=7 vs. MQ(+) + SG>=8 − p=0,002

0.2

0.0 0

50

100

150

200

Supervivencia libre de recidiva bioquímica

Fig. 1 tomy.

Actuarial biochemical relapse-free survival according to the surgical margin and Gleason score variables of the prostatec-

Discussion Radical prostate surgery currently offers excellent control for localized disease, however, one-third of the surgical specimens have PSMs, seminal vesicle invasion and/ or extracapsular extension, which increases the risk of recurrence.10 In our trial, 21.7% of patients had PSMs, out of which only 37.9% presented BR, which was significant, since only 16% of patients that did not have PSMs suffered BR. The presence of positive margins increases the risk of biochemical and local recurrence after RP.11 Moreover, Stephenson et al. found that patients with PSMs, GS 8---10

Table 4 Relationship between biochemical relapse and clinical and pathological variables (multivariate). Variable

p

Gleason score of the RP ≤6 7 ≥8

<0.001 Reference 0.13 <0.001

Capsular invasion Surgical margins

0.28 <0.001

Statistical analysis: binary logistic regression.

and PSA doubling the time less than 10 months, entail a higher risk of developing metastasis.12,13 The recurrence of prostate cancer following potentially curative surgery continues to be a dilemma, because patients feel that they have lost their first chance to be cured and express the urgency to initiate another treatment in order to be cured. However, it is still difficult for physicians to decide on which treatment is more appropriate, whether to initiate adjuvant therapy, or to wait until PSA increases.3 In patients with PSMs or pT3, radiation therapy immediately after RP increases biochemical progression-free survival, local control and the risk of progression.14---16 On the other hand, it has recently been confirmed that there is a 10% overall increase in survival in patients that Table 5 Probability of recurrence at 5 and 10 years depending on risk groups (SM + GS). Risk group SM SM SM SM

(−) + GS ≤ 7 (−) + GS ≥ 8 (+) + GS ≤ 7 (+) + GS ≥ 8

Probability of relapse at 5 years 12% 30% 35% 74%

Probability of relapse at 10 years 26% 50% 50% 87%

Statistical study: survival analysis using the Kaplan---Meier method.

276 receive adjuvant radiotherapy (ART), and an 8% increase in metastasis-free survival.17 Katz et al. reported that patients with PSMs have the least probability of biochemical control with salvage radiation therapy.18 ART is generally well tolerated and secondary toxic reactions are generally low grade.19---21 It has been noted that the quality of life is greater in patients that receive ART, as after 2 years, patients who did not initially receive it, begin with different salvage therapies that have more adverse effects, and thus a greater impact on quality of life.17 ART is indicated in pT2 patients with PSMs, however each case must be individualized according to its risk factors.22 Leibovich et al. observed that there was an 88% BR-free rate in patients with pT2 and positive margins who were treated with ART compared to those that were only monitored, in which the BR-free rate was 59% (p < 0.05).23 A GS ≥ 8 in patients with organ-confined PCa (pT2) and PSMs significantly increases the likelihood of BR. These patients would be those who would most benefit from ART, while in 50% of patients with PSMs and a GS ≤ 7, ART could be considered as overtreatment; moreover, they can also be salvaged with radiation therapy in the event they suffer BR.

Conflict of interest The authors declare that they have no conflict of interest.

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