Oncologic Outcomes of Laparoscopic Radical Prostatectomy: Intermediate-Term Follow-up

european urology supplements 5 (2006) 934–941

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Oncologic Outcomes of Laparoscopic Radical Prostatectomy: Intermediate-Term Follow-up Fernando P. Secin, Fernando J. Bianco, Nicholas T. Karanikolas, Karim Touijer, Bertrand Guillonneau * Department of Urology, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, NY, United States

Article info

Abstract

Keywords: Laparoscopy Oncology Prostatectomy Prostatic neoplasms Treatment outcome

Objectives: A paucity of literature discusses biochemical recurrence (BCR) after laparoscopic radical prostatectomy (LRP). We report the intermediateterm cancer control and variables associated with BCR based on the 8-yr experience of a single surgeon. Methods: Between January 1998 and March 2006, one surgeon performed LRP on 1071 patients at two institutions. Excluded from analysis are 20 patients who received neoadjuvant therapy, 27 lost to follow-up, and 23 without prostate-specific antigen (PSA) controls due to recent date of surgery. Kaplan-Meier curves were generated to estimate time to BCR, defined as a PSA of 0.2 ng/ml and rising or start of secondary therapy. The log-rank test was used to compare pathologic variables. Positive surgical margin (PSM) was defined as cancer cells at the inked margins. Cox regression analysis estimated variables associated with time to BCR. Results: Of the study population, 1%, 75%, 23%, and 1% had pT0, pT2, pT3, and pT4 disease, respectively; 41%, 1%, and 58% had no nodal involvement, lymph node metastases, and no lymph node dissection, respectively. The cumulative 5-yr BCR-free rate was 75% for the 1001 evaluable patients, with 95 patients fulfilling criteria for BCR. The mean follow-up was 22.3 mo (95%CI, 20,24.6). In multivariable Cox regression analysis, higher serum PSA ( p < 0.001), palpable nodule ( p = 0.009), presence of extracapsular extension (ECE; p = 0.038), seminal vesicle invasion (SVI; p < 0.001), pathologic Gleason 4 + 3 ( p < 0.001), and pathologic Gleason 8–10 ( p < 0.001) when compared to pathologic Gleason < 6 were significantly associated with shorter time to BCR. The concordance index for the model was 0.86. The overall PSM rate was 13%, 9% for capsule-confined disease (pT2) and 24% for extracapsular extension (pT3). Conclusion: LRP seems to offer comparable oncologic outcomes to open surgery; however, more extended follow-up of patients is needed to better assess the oncologic safety of the LRP.

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# 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Memorial Sloan-Kettering Cancer Center, Sidney Kimmel Center for Prostate and Urologic Cancers, Department of Urology, 1275 York Avenue, New York, NY 10021, United States. Tel. +1 646 422 4406; Fax: +1 212 988 0760. E-mail address: [email protected] (B. Guillonneau). 1569-9056/$ – see front matter # 2006 European Association of Urology. Published by Elsevier B.V. All rights reserved.

doi:10.1016/j.eursup.2006.08.001

european urology supplements 5 (2006) 934–941

1.

Introduction

Although radical prostatectomy is the most proven oncologically effective treatment for clinically localised carcinoma of the prostate and the only therapy that has gone through the test of a randomised trials [1,2], only three publications have hitherto reported their prostate-specific antigen (PSA) recurrence rates as a surrogate for cancer control in laparoscopically operated patients, with one of them reporting data from three institutions together [3–5]. Therefore, it is obvious that there is still not enough evidence supporting the oncologic safety of the laparoscopic approach, and although the short-term biochemical recurrence (BCR)-free results may appear similar to those reported in the open radical prostatectomy experience, more outcomes of series with longer follow-up periods are eagerly awaited. This study examines the cancer control presently available and identifies the variables associated with BCR of a laparoscopic surgeon after 8 yr of experience. 2.

Patients and methods

2.1.

Procedure

Between January 1998 and March 2006, 1071 patients were treated with transperitoneal laparoscopic radical prostatectomy (LRP) by a single surgeon at two institutions, the first 502 at the Institut Mutualiste Montsouris (Paris, France), and the second 569 at Memorial Sloan Kettering Cancer Center (MSKCC; New York, NY). We excluded from this analysis 20 patients who received neoadjuvant therapy (19 androgen-deprivation therapy and 1 external-beam radiation therapy), 27 patients operated in France and lost to follow-up, and 23 without PSA controls at the time of study closure due to recent date of surgery, leaving 1001 patients in the study population. The study was designed to evaluate the oncologic outcome of men after LRP and received institutional board approval. Endorectal coil magnetic resonance imaging (MRI) was performed on 93% of patients who had surgery at MSKCC, but none of those treated in France. The criteria for lymphadenectomy (LND) in the first 502 patients included clinical stage T2b, PSA > 10 ng/mL, predominant biopsy Gleason grade  4, or more than three of six positive biopsies. From patient number 503 through 938 (July 2005), a ‘‘limited’’ LND was performed in patients with a preoperative probability of lymph node metastases (LNM) > 1.5% as per Partin tables. ‘‘Limited’’ LND involved only the lymph node packets around the obturator nerve. As of July 2005, an ‘‘extended’’ LND has been systematically performed in all patients, which included not only the obturator chains but also part of the external iliacs and hypogastric packets.

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Prostatectomy specimen evaluation followed the protocol of each institution and included formalin fixation, external surface inking, and perpendicular sectioning. The apical prostate was truncated perpendicular to the prostatic urethra and subsequently sectioned in parallel slices. The remaining prostate was completely transected at 2–4-mm intervals in a plane perpendicular to the urethra. The whole-mount technique was used in the patients operated at MSKCC. The 2002 TNM classification was used. Positive surgical margin (PSM) was defined in all cases as tumour cells in contact with ink and tumour invasion of the seminal vesicles (SVI) was recorded when malignant cells invaded into the muscular layer of the wall of the SV. Extracapsular extension (ECE) was noted when neoplastic glands were located immediately outside the capsule in contact with the periprostatic fat. The Gleason system was used for histologic characterisation and scored by the sum of the primary and secondary patterns. The standard follow-up protocol for the first 498 patients involved serum PSA measurements at 1.5 mo and 6 mo postoperatively and yearly in the absence of increasing PSA. In the rest of the patients, the follow-up was mostly based on serum PSA measured at 6 wk, 3 mo, 6 mo, and every 6 mo during the first 2 yr, and annually thereafter. For all patients, BCR was defined by two consecutive PSA values > 0.2 ng/mL or initiation of therapy for a PSA rise after surgery. The rationale for choosing this definition of BCR was based on consideration of clinical practice and on prior findings that patients with a postoperative PSA value > 0.2 ng/ml are at very high risk of developing an additional rise in PSA [6]. Adjuvant hormone therapy or adjuvant external-beam radiation was never indicated. Prostate cancer-specific mortality was determined from death certificates and medical records. All the information was treated according to the US Health Insurance Portability and Accountability Act (HIPAA) and de-identified prior to analysis.

2.2.

Statistical methods

Univariate analysis of factors predicting time to BCR incorporated preoperative serum PSA (log PSA was entered as a continuous variable), and the specimen characteristics (pathologic Gleason score, presence of ECE, surgical margin status, lymph node invasion [LNI]). The log-rank test was used to compare Kaplan-Meier curves between pathologic variables. Cox proportional hazard regression analysis was performed to identify independent risk factors that predicted BCR. We prespecified a single multivariable analysis that included preoperative serum PSA levels (entered as a continuous variable), clinical stage (palpable vs. nonpalpable nodule), biopsy Gleason grade (6 vs. 3 + 4 vs. 4 + 3 vs. 8–10), and presence of PSM, ECE and SVI. Due to differences in criteria for LND and no performance of LRP among patients with LNM on frozen section, LNM was not included in the multivariable model. All tests were two-sided, with p  0.05 considered statistically significant. Statistical analyses were conducted using S-PLUS software (Insightful Technologies, Seattle, WA) and Stata 8.2 (Stata, College Station, TX).

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3.

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Results

Pathologic characteristics of patients with and without BCR are depicted in Table 1. The mean age of the population was 61 yr (95%CI, 60, 61), with a mean preoperative serum PSA of 7.8 (7.4, 8.1). Only 42% of patients had pelvic lymph node dissection (PLND) and 1% of the total had LNM. Six percent of the cohort had a Gleason sum 8–10 and 24% had pathologic stage pT3 or greater. The cumulative 5-yr BCR-free rate was 75% for the 1001 evaluable patients (Fig. 1). The mean follow-up was 22.3 mo (95%CI, 20, 24.6) and the number of patients with BCR was 95. As demonstrated by a scatter plot of preoperative [7] (Fig. 2A) and postoperative nomogram [8] over time (Fig. 2B), there has not been a clear stage migration or selection of patients over time. This can also be observed in the percentages of patients with pT3 or pT4 disease in comparison to pT2 over time (Fig. 3). Fig. 4A–F shows the univariate association between the different clinical and pathologic Table 1 – Pathologic characteristics of patients with and without biochemical recurrence Variable

No BCR, n (%)

BCR, n (%)

61 (60, 61)

64 (62, 65)

61 (60, 61)

7.3 (7.1, 7.7)

11.3 (9.5, 13.1)

7.8 (7.4, 8.1)

237 (83) 98 (78)

49 (17) 27 (22)

286 (29) 125 (12.5)

727 (94) 179 (80) 32 (58)

50 (6) 45 (20) 23 (42)

777 (78) 224 (22) 55 (5)

369 (91) 9 (60) 528 (91)

38 (9) 6 (40) 51 (9)

407 (41) 15 (1) 579 (58)

Pathologic Gleason score 6 417 (97) 3+4 343 (93) 4+3 112 (77) 8–10 34 (61)

15 25 33 22

(3) (7) (23) (39)

427 (43) 368 (37) 145 (15) 56 (6)

Pathologic stage pT0 pT2a pTb/c pT3a pT3b pT4

5 (100) 177 (95) 532 (94) 154 (85) 31 (60) 6 (67)

0 (0) 10 (5) 33 (6) 28 (15) 21 (40) 3 (33)

5 (1) 187 (19) 565 (57) 182 (18) 52 (5) 9 (1)

Total

906 (91)

95 (9)

1001

Age, yr, mean (95%CI) PSA, ng/ml, mean (95%CI) Palpable nodule Positive surgical margins No ECE ECE SVI Node status N0 N+ Nx

Total, n (%)

BCR = biochemical recurrence; PSA = prostate-specific antigen; ECE = extracapsular extension; SVI = seminal vesicle invasion.

Fig. 1 – The cumulative 5-yr biochemical recurrence-free rate for 1001 patients.

features and time to BCR. As expected, worse pathologic characteristics are able to predict shorter time to BCR; however, note that patients with Nx disease have better outcomes than those with N0 disease, which clearly reflects the result of the patient selection performed during the initial experience (Fig. 4E). The overall PSM rate was 13%, with the PSM rate breakdown by different degrees of tumour extent and pathologic features described in Table 2. In multivariable Cox regression analysis, higher PSA ( p < 0.001), palpable nodule ( p = 0.009), presence of ECE ( p = 0.038), SVI ( p < 0.001), pathologic Gleason score of 7 with predominant Gleason 4 (4 + 3) and 8–10, compared to < 6, ( p < 0.001, for both) were significantly associated with shorter time to BCR. The concordance index for the model was 0.86 (Table 3). Fig. 5A compares the BCR free Kaplan-Meier curves between N0 and Nx disease among patients with low-risk disease, defined as PSA < 10 ng/ml and clinical stage T1c/T2a and biopsy Gleason score < 7 [9]. Fig. 5B compares the same features for patients with intermediate risk, defined by the presence of PSA 10–20 ng/ml or clinical stage T2b or biopsy Gleason score 7 [9]. Of the 544 (54%) patients with low-risk disease, only 2 patients had LNM. Of the 373 (37%) patients with intermediate-risk features, 8 patients had LNM.

4.

Discussion

Only three publications have reported BCR-free rates after LRP [3–5]. In 2003, Guillonneau et al. reported a cumulative BCR-free rate of 90.5% at 3 yr

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Fig. 3 – Bar chart shows the proportion of patients with pT3 or pT4 disease in comparison to pT2 grouped in 100s of cases.

Fig. 2 – Scatter plots of preoperative (A) and postoperative nomograms over time (B), showing that there has not been a clear stage migration or selection of patients over time.

in 1000 consecutive patients, with BCR defined as a PSA level > 0.1 ng/ml and rising [3]. Last year, Rassweiller et al. reported an overall freedom from BCR of 73.1% at 5 yr for the first 500 of 1078 patients with a minimal observation period of 23 mo. Here, BCR was defined as two PSA values > 0.2 ng/ml [4]. More recently, a joint publication of three institutions from Europe (Heilbronn, Basel, Zurich) reported a 5-yr BCR rates of 8.6% (4–15.3%) for pT2 and 17.5% (15–20.6%) for pT3a stages (no definition of BCR was provided).

Since the introduction of the modern anatomic open retropubic radical prostatectomy (RRP) in 1982 by Walsh and Donker [10], BCR free rates after open RRP varied between 69–84% and 47–74% at 5 and 10 years, respectively [11–13]. Notwithstanding, the question remains whether comparisons between retrospective series of open and LRP coming from different institutions are fair enough to make any decisive conclusions about the oncologic safety of LRP. Differences in case selection, pathologic evaluation, length of follow-up, data collection, retrospective analysis, definitions of BCR, extent of LND, and degree of neurovascular bundle preservation are a few of the multiple biases that should be considered before jumping to conclusions. Unlike what happens with most anticancer drug therapies, LRP, with or without robotic assistance, is one of the many surgical techniques that have been incorporated into the realm of the surgical armamentarium without going through the test of randomisation or at least without the performance of prospective comparative studies with the open technique. The widespread dissemination of LRP has resulted from the efforts of a few pioneers who published retrospective analyses of their personal experiences back in the late 1990s [14]. What did not seem to be a good therapeutic approach for some, became gold standard at others centres, and the first systematic description of the technique was published 3 yr after its first description in the literature [15]. Consistent with other open radical prostatectomy series [12,13,16,17], our data demonstrate that advancing Gleason score results in an adverse

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Fig. 4 – Univariate association between (A) pathologic Gleason, (B) serum prostate-specific antigen level, (C) positive surgical margin status, (D) seminal vesicle invasion, (E) lymph node status, and (F) pathologic stage and time to biochemical recurrence. The log-rank test is used to compare the Kaplan-Meier curves.

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Table 2 – Positive surgical margin rate breakdown by different degrees of tumour extent and pathologic features Variable

NSM*, n (%)

PSMy, n (%)

Capsule confined ECE No SVI SVI

687 165 830 38

(91) (76) (88) (69)

65 53 108 17

(9) (24) (12) (31)

Pathologic Gleason score 6 3+4 4+3 8–10

395 314 119 42

(93) (86) (82) (75)

32 53 26 15

(7) (14) (18) (25)

Pathologic stage pT0 pT2a pTb/c pT3a pT3b pT4

5 175 513 145 37 1

(100) (94) (91) (80) (71) (11)

0 12 52 37 15 8

(0) (6) (9) (20) (29) (89)

Total

870 (87)

125 (13)

NSM = negative surgical margin; PSM = Positive surgical margin; ECE = extracapsular extension; SVI = seminal vesicle invasion.

outcome following surgery. The cumulative progression-free survival rates were not significantly different between men with Gleason score  6 and Gleason score of 7 (3 + 4). Those with predominant Gleason pattern 4 (4 + 3 and 4+4 or higher) had statistically significant worse BCR-free rates than those with Gleason  6. Similar to has been observed in the open literature, ECE with or without PSM or SVI does not invariably signal BCR in patients treated with RP [8,17,18] (Fig. 6A and B). Therefore, a substantial proportion of patients with ECE or SVI could be rendered disease free with surgery alone [18]. Although a question might be raised about the potential selection of patients with more benign disease or stage migration over time founded on a slight increase in the BCR-free time probability

Fig. 5 – (A) Comparison of biochemical recurrence-free Kaplan-Meier curves between N0 and Nx disease among patients with low-risk disease, defined as prostatespecific antigen (PSA) level < 10 ng/ml and clinical stage T1c/T2a and biopsy Gleason score < 7. (B) Comparison of the same features for patients with intermediate risk, defined by the presence of PSA level of 10–20 ng/ml or clinical stage T2b or biopsy Gleason score 7.

Table 3 – Multivariable Cox regression analysis of variables predicting shorter time to biochemical recurrence Variable Age Serum PSA Palpable nodule Positive Surgical Margins Extracapsular extension SVI Pathologic Gleason  6 Pathologic Gleason 3+4 Pathologic Gleason 4+3 Pathologic Gleason 8–10 CI: 0.86.

HR 1.0 1.04 1.8 1.6 1.7 3.2 Reference 1.6 3.4 6.0

p value

95% CI

0.4 <0.001 0.009 0.07 0.038 <0.001

0.97 1.02 1.1 0.96 1.02 1.9

0.16 <0.001 <0.001

0.8 1.7 2.9

1.03 1.08 2.7 2.5 2.7 5.4 3.1 6.5 12.2

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among patients who had PLND. These data favor forgoing PLND in patients with low-risk disease. Limitations of the analysis include the fact that this is the experience of a single surgeon with a procedure performed at two different institutions and types of populations, with possible differences in preoperative staging (93% of the patients operated at MSKCC had preoperative endorectal coil MRI), mechanisms of follow-up, and specimen pathology reading. Whole-mount section technique may be able to detect PSM that would be otherwise missed with the conventional prostate histologic evaluation [20]. In addition, the LRP technique evolved substantially over time [21], with some authors also recommending systematic intraoperative frozen sections of the apical margins [22], introducing another bias into the analysis of outcomes. The limited number of events in combination with missing data for other variables did not allow us to include other potentially relevant risk factors for BCR in the multivariable analysis, including but not limited to tumour volume, PSM location, gland weight, and pelvimetry. Long-term oncologic results still need maturation, but reports of PSM rates and freedom from BCR rates after LRP are encouraging. However, the challenge for surgeons performing LRP still demands a change towards an evaluation of outcomes in a prospective controlled and randomised manner.

5. Fig. 6 – Cumulative biochemical recurrence free rates of patients with extracapsular extension [ECE] (A) and/or seminal vesicle invasion [SVI] (B) with or without positive surgical margins [PSM].

observed on preoperative nomograms (Fig. 2A), it did not seem to have an impact on the predicted probability of BCR-free time after surgery (Fig. 2B), which clearly argues against the likelihood of stage migration. Contrary to what has been observed by some authors [19], only 2 (0.4%) of the 544 patients with low-risk disease (PSA < 10 ng/ml and clinical stage T1c/T2a and biopsy Gleason score < 7) [9] had LNM. Even if the differences in proportions with the cited series may be accounted by the extent of PLND, we found no statistically significant differences in BCRfree rates between N0 and Nx patients (Fig. 5A). Something similar was observed for the 373 patients with intermediate-risk disease (PSA 10–20 ng/ml or clinical stage T2b or biopsy Gleason score 7); however, the incidence on LNM increased to 2% (8 patients) with an overall LNM incidence of 4%

Conclusions

The follow-up herein reported is not long enough to draw any decisive conclusions about the oncologic safety of LRP. LRP seems to offer comparable oncologic outcomes to open surgery; however, more extended follow-up of patients is needed to better assess the oncologic safety of the LRP.

Acknowledgments We wish to thank Janet Novack and Barbara Kristaponis for their editorial review and Kinjal Vora and Jason Stasi for their help with data search.

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