OBESITY AND CAPSULAR INCISION AT THE TIME OF OPEN RETROPUBIC RADICAL PROSTATECTOMY

0022-5347/05/1745-1798/0 THE JOURNAL OF UROLOGY® Copyright © 2005 by AMERICAN UROLOGICAL ASSOCIATION

Vol. 174, 1798 –1801, November 2005 Printed in U.S.A.

DOI: 10.1097/01.ju.0000177077.53037.72

OBESITY AND CAPSULAR INCISION AT THE TIME OF OPEN RETROPUBIC RADICAL PROSTATECTOMY STEPHEN J. FREEDLAND,* KELLY A. GRUBB, SINDY K. YIU, MATTHEW E. NIELSEN, LESLIE A. MANGOLD, WILLIAM B. ISAACS, JONATHAN I. EPSTEIN AND ALAN W. PARTIN From The James Buchanan Brady Urological Institute (SJF, KAG, SKY, MEN, LAM, WBI, JIE, AWP) and Department of Pathology (JIE), The Johns Hopkins School of Medicine and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions (WBI), Baltimore, Maryland

ABSTRACT

Purpose: The goal of radical prostatectomy (RP) is complete removal of the intact prostate. Obese men can represent a technical challenge. However, to our knowledge objective data linking obesity with technically inferior surgery are lacking. Therefore, we examined the association between body mass index (BMI) and capsular incision at RP as a surrogate of a poor technical operation in men treated for prostate cancer by several high volume surgeons at a center of excellence. Materials and Methods: The study population consisted of 7,027 men treated with anatomical retropubic RP between 1996 and 2004 by 7 high volume surgeons. We evaluated the association between BMI and capsular incision using logistic regression, adjusting for clinical and pathological variables, and for the surgeon. Results: Overall capsular incision was noted in 4.6% of all RP specimens. After adjustment for preoperative prostate specific antigen, patient race, height, year of surgery, clinical stage, pathological Gleason sum, prostate weight, extraprostatic extension and seminal vesicle invasion increased BMI was associated with increased odds of capsular incision (p trend ⫽ 0.005). After further adjustment for surgeon mild obesity was associated with 30% increased odds of capsular incision (OR 1.30, 95% CI 0.92 to 1.83), while moderate and severe obesity was associated with 57% increased odds of capsular incision (OR 1.57, 95% CI 0.82 to 3.00) relative to normal weight men (p trend ⫽ 0.06). Conclusions: In a study of more than 7,000 men treated by 7 experienced surgeons BMI was positively related to capsular incision. This suggests that open retropubic RP is technically more difficult in obese men, which results in a greater likelihood of a less than technically ideal operation. Although this may be predicted to have a negative impact on disease-free survival outcomes in obese men, it is unlikely to alone explain the worse outcomes in obese men noted in previous RP series. KEY WORDS: prostate, prostatic neoplasms, prostatectomy, obesity, body mass index

Obesity has been associated with increased an risk of prostate cancer death in multiple prospective cohort studies.1, 2 The exact reasons for this increased risk of mortality is unclear, although probably multifactorial. Alterations in the balance of serum hormonal concentrations (estrogen, testosterone, insulin and leptin)3⫺5 as well as dietary and life-style factors6⫺8 may contribute to more aggressive disease in obese men. However, alternate explanations may, exist such as obese men not receiving as effective therapy as nonobese men. For example, during external beam radiation therapy special considerations must be considered in obese men to prevent setup error, thereby, decreasing the amount of radiation delivered to the prostate.9 However, whether technical considerations may affect outcome after other treatment mo-

dalities, specifically retropubic radical prostatectomy (RP), is unclear. Two prior multicenter studies showed that obese men are more likely to have a positive surgical margin in the absence of other signs of advanced disease, eg extraprostatic extension, seminal vesicle invasion, etc.10, 11 These studies suggest that the higher positive surgical margin rate in obese men may be related to iatrogenic positive surgical margins due to technical difficulty during surgical dissection of the prostate in obese men.11 While this intuitively makes sense, a positive surgical margin does not necessarily represent a technically inferior surgical procedure.12 Beyond these 2 reports there are little objective data to support the hypothesis that open RP is technically more difficult in obese men. An objective measure of technically inferior surgery is capsular incision.13 While data linking capsular incision in and of itself to poorer outcomes can be debated,12, 14 capsular incision can be used a marker of a technically less than ideal surgery. Therefore, we assessed the association between capsular incision and body mass index (BMI) in a large group of men who underwent RP, as performed by 7 experienced surgeons at a center of excellence.

Submitted for publication February 21, 2005. Study received Institutional Review Board approval. Supported by National Institute of Health/National Cancer Institute SPORE Grant P50CA58236, Department of Defense, Prostate Cancer Research Program PC030666 (SJF), American Foundation for Urological Disease/American Urological Association Education and a Research Scholarship Award. Views and opinions of, and endorsements by the author(s) do not reflect those of the United States Army or Department of Defense. * Correspondence and requests for reprints: The James Buchanan MATERIALS AND METHODS Brady Urological Institute, Johns Hopkins School of Medicine, 600 Study population, and assessment of BMI and other cliniNorth Wolfe St., Baltimore, Maryland 21287-2101 (telephone: 410copathological variables. After obtaining Institutional Re955-2520; FAX: 410-502-9336; e-mail: [email protected]). 1798

OBESITY AND CAPSULAR INCISION AT PROSTATECTOMY

view Board approval and informed consent when appropriate 7,704 consecutive patients treated with anatomical RP for prostate adenocarcinoma from 1996 to 2004 at The Johns Hopkins Hospital were identified. Prior to 1996 capsular incision was not consistently commented on in the pathological report at our institution and, therefore, only patients treated from 1996 and later were examined. Prior studies show that greater surgical volume correlates with better outcomes, eg a lower incidence of positive surgical margins, suggesting better technical skills in more experienced surgeons.15 Therefore, we limited our analysis to patients treated by 7 high volume surgeons, defined as a surgeon who performed 50 or greater RPs annually during the study period (433 patients were excluded). Men known to have been treated with preoperative hormonal therapy (luteinizing hormone releasing hormone agonist, antiandrogen or 5␣reductase type II inhibitor) (57), chemotherapy (2) or radiation therapy (2) were excluded. In addition, 29 men diagnosed from a transurethral resection specimen (clinical stage T1a/T1b) were excluded because this can affect the prostate specific antigen (PSA) concentration and prostate size. Men with missing data on clinical stage (12), preoperative PSA (29), biopsy Gleason sum (6) or race (2) were excluded. Of the remaining 7,168 patients preoperative BMI (weight in kg divided by height in m2), which was abstracted from the medical records, was available in 7,027 (98%), who represent the study population. Prostatectomy specimens were sectioned, as previously described.16 A single pathologist reviewed all pathological reports for capsular incision, defined as where “the surgeon inadvertently develops the plane of resection within the prostate rather than exterior to the prostate.”13 In areas of capsular incision, if tumor was organ confined elsewhere with negative margins, we denoted pathological stage as pT2x, since extraprostatic extension status in the area of capsular incision was unknown. In the area of the apex, where histological boundaries are vague, we “restrict the term positive margin due to capsular incision for cases where benign prostate glands, as well as tumor, are cut across.”13 Prostate weight was determined by measuring gross RP specimen weight, including the seminal vesicles and vasal tips. Statistical analysis. Differences in the distribution of clinicopathological characteristics between men with and without capsular incision were compared using the Wilcoxon rank sum test for continuous variables and the chi-square test for categorical variables. Preoperative PSA, age at RP, year of RP and prostate weight were examined as continuous variables. Race (nonwhite vs white), height (tertiles, that is 69 inches or less, 69.1 to 71.9 and 72 or greater), clinical stage (T1c, T2a, T2b and T2c/T3a) and Gleason sum (2 to 6, 3 ⫹ 4 and 4 or greater ⫹ 3) were examined as categorical variables. Because data on preoperative PSA and prostate weight were not normally distributed, we examined the data after logarithmic transformation. The OR of capsular incision was estimated for the BMI categories of normal weight—less than 25 kg/m2, overweight—25 to 29.9, obese—30 to 34.9, and moderately and severely obese—35 or greater using logistic regression. Multivariate analysis was performed, adjusting for preoperative PSA, age at RP, race, height, year of surgery, clinical stage, pathological Gleason sum, prostate weight, extraprostatic extension and seminal vesicle invasion. BMI was entered into all models as a series of indicator variables for each BMI category. We tested for trend by entering the median BMI of each BMI category as a continuous term into the model and evaluating the coefficient by the Wald test. When capsular incision was present, there was usually a concomitant positive surgical margin and, therefore, the 2 variables correlated highly and were not independent. Thus, we did not adjust for positive surgical margins in our analysis. Because the case mix and possibly technical skill level varied among

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the 7 surgeons, we also examined the data after including a categorical term for the surgeon. Point estimates for the crude and age adjusted models for predicting capsular incision were similar and, therefore, only results for the age adjusted models are shown. All statistical analyses were performed using STATA 8.0 (Stata Corp., College Station, Texas). RESULTS

Overall capsular incision was noted in 325 of the 7,027 RP specimens (4.6%). The incidence of capsular incision among the 7 surgeons was 2.9% to 7.9%. Men with a capsular incision in the RP specimen were younger (p ⫽ 0.02), and had lower biopsy (p ⫽ 0.01) and lower pathological Gleason sum (p ⫽ 0.003) cancers, a smaller prostate (p ⫽ 0.002), and a greater prevalence of positive surgical margins (p ⬍0.001) and extraprostatic disease (p ⫽ 0.01, table 1). After adjustment for age at RP increased BMI was associated with significantly increased odds of capsular incision (p trend ⫽ 0.007). After further adjustment for preoperative PSA, race, height, year of surgery, clinical stage, pathological Gleason sum, prostate weight, extraprostatic extension and seminal vesicle invasion increased BMI remained significantly associated with increased odds of capsular incision (p trend ⫽ 0.005, table 2). Because patients were treated by multiple surgeons, it is possible that differential distribution of BMI among surgeons with varying degrees of technical skill may have accounted for our results, eg the best surgeons only treated men with a low BMI. To address this we included a categorical term for surgeon in the multivariate analysis predicting capsular incision. After further adjusting for surgeon the association between increased BMI and capsular incision was somewhat attenuated (p trend ⫽ 0.06, table 2). DISCUSSION

Obese patients can represent a technical challenge when performing RP due to excess adiposity, making access to the pelvic organs difficult. To our knowledge whether this translates into a technically inferior operation has not been studied. Using capsular incision as a surrogate of a technically inferior operation in a group of more than 7,000 men treated by 7 experienced surgeons at a center of excellence increased BMI was significantly and positively related to increased odds of capsular incision. The degree to which technical difficulty in performing RP in obese men contributes to the increased risk of progression after RP in obese men, as observed in multiple prior studies,10, 11, 17, 18 remains to be determined. Obesity is a growing problem in the United States. Currently more than 30% of the adult population is obese.19 Given that in 2004 it was estimated that there would be 230,100 new cases of prostate cancer diagnosed, this means that almost 70,000 obese men were diagnosed with prostate cancer, assuming that there is no association between obesity and the risk of being diagnosed with prostate cancer, which is a matter of debate.20 In men with prostate cancer the goal of any primary therapy is complete tumor eradication. Therefore, any technical challenge has the potential of decreasing the likelihood of rendering the patient tumor-free. Prior studies show that surgical skill can have a significant impact on the risk of a positive surgical margin, which is a known poor prognostic factor.15 Therefore, if obesity in and of itself results in a technical challenge sufficient to interfere with the surgeon ability to perform a high quality operation, this could have major repercussions for the thousands of obese men who are newly diagnosed with prostate cancer annually. Indeed, prior studies show that obese men are at greater risk for positive surgical margins in the absence of other signs of

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TABLE 1. Clinical and pathological features in men undergoing RP from 1996 to 2004 by presence or absence of capsular incision Capsular Incision No No. pts (%) No. race (%): White Nonwhite Age: Mean ⫾ SD Median PSA (ng/ml): Mean ⫾ SD Median No. 2002 TNM clinical T stage (%): T1 T2a T2b T2c/T3 No. biopsy Gleason sum (%): 2–6 7 (3⫹4) 7 (4⫹3) ⫹ 8–10 Prostate wt (gm): Mean ⫾ SD Median No. pathological Gleason sum (%): 2–6 7 (3⫹4) 7 (4⫹3) ⫹ 8–10 No. pos margins (%) No. extraprostatic extension (%) No. seminal vesicle invasion (%) No. lymph node metastasis (%)

p Value

Yes

6,702 (95)

325 (5)

5,946 (89) 756 (11)

296 (91) 29 (9)

0.19 (chi-square test)

57.4 ⫾ 6.4 58

56.7 ⫾ 5.8 57

6.9 ⫾ 5.1 5.8

6.7 ⫾ 4.0 5.8

0.02 (rank sum test) 0.71 (rank sum test) 0.37 (chi-square test)

4,912 (73) 1,208 (18) 497 (7) 85 (1)

241 (74) 63 (19) 16 (5) 5 (2)

5,356 (80) 870 (13) 476 (7)

280 (86) 33 (10) 12 (4)

0.01 (chi-square test)

56.3 ⫾ 20.8 52.0

52.2 ⫾ 16.3 50.0

0.002 (rank sum test) 0.003 (chi-square test)

4,481 (67) 1,467 (22) 729 (11) 526 (8) 1,860 (28) 286 (4) 94 (1)

220 (68) 87 (27) 18 (6) 196 (60) 111 (34) 10 (3) 5 (2)

⬍0.001 (chi-square test) 0.01 (chi-square test) 0.30 (chi-square test) 0.84 (chi-square test)

TABLE 2. OR of capsular incision by BMI relative to normal weight in men undergoing RP between 1996 and 2004 OR

95% CI

p Value

Age adjusted: 0.007 Overwt 0.99 0.75–1.29 Mild obesity 1.42 1.02–1.98 Moderate ⫹ severe obesity 1.97 1.05–3.71 Multivariable adjusted:* 0.005 Overwt 1.00 0.76–1.31 Mild obesity 1.44 1.03–2.02 Moderate ⫹ severe obesity 2.03 1.07–3.84 Multivariable ⫹ surgeon adjusted:† 0.06 Overwt 0.97 0.74–1.27 Mild obesity 1.30 0.92–1.83 Moderate ⫹ severe obesity 1.57 0.82–3.00 Normal weight—BMI less than 25 kg/m2, overweight—BMI 25 to 29.9, mild obesity—BMI 30 to 34.9, and moderate and severe obesity—BMI 35 or greater. * Age, race, clinical stage, height, preoperative PSA, year of surgery, pathological Gleason sum, pathological prostate weight, extraprostatic extension and seminal vesicle invasion. † Age, race, clinical stage, height, preoperative PSA, year of surgery, pathological Gleason sum, pathological prostate weight, extraprostatic extension, seminal vesicle invasion and surgeon.

advanced disease, suggesting the possibility of iatrogenic positive margins due to technical difficulties.10, 11 To examine whether obesity is associated with a technically inferior operation we studied men undergoing RP, as performed by 7 experienced surgeons at a center of excellence. Because surgical inexperience (low volume) can be associated with inferior outcomes,15 we limited our analyses to men who underwent RP done by surgeons who performed 50 or greater RPs annually. After adjustment for clinical and pathological characteristics as well as surgeon obesity was associated with 30% increased odds of capsular incision, and moderate and severe obesity was associated with 57% increased odds of capsular incision. Given that the overall prevalence of capsular incision in this group of men was only 4.6%, a 30% increase would amount to less than a 1.5% absolute increase in the incidence of capsular incision in obese men. Moreover, whether capsular incision alone impacts biochemical progression is debatable.12, 14 However, it is likely that a less technically well performed surgery would negatively impact disease-free survival. Therefore, using

capsular incision as a surrogate of a technically inferior operation obese men are at increased risk for a technically inferior operation, which would be predicted to have a negative impact on disease-free survival. However, to what degree is unknown to our knowledge. Multiple prior studies, in which data on almost 10,000 men were collectively analyzed, consistently show that men with increased BMI are at increased risk for biochemical progression after RP.10, 11, 17, 18 In light of the current data one must wonder whether this increased risk of biochemical progression is only technical in nature. While the current data cannot specifically answer that question, based on several lines of reasoning we would suggest that technical difficulty alone cannot explain the disparate outcomes noted in prior series. There are many men with early stage, organ confined disease in whom poor technique does not negatively impact outcome. Likewise, there are men with advanced disease, possibly metastatic, in whom RP is not curative regardless of surgical technique. Therefore, the population of men in whom poor technique negatively impacts outcome is a subset of all men, although to our knowledge the

OBESITY AND CAPSULAR INCISION AT PROSTATECTOMY

exact size of this subset is unknown. Thus, 30% increased odds of an inferior operation in obese men would translate into a modestly increased but less than 30% increased risk of progression due to technical issues alone. Hence, technical issues alone cannot fully explain the 51% to 55% increased risk of progression relative to normal weight men in men in the current study with a BMI of between 30 and 35 kg/m2 who had followup information available, as reported in our prior studies.17, 18 Finally, a previous study of only men with organ confined, margin negative disease, in whom technical issues should not have a major impact on outcome, has indicated that men with a BMI of 35 kg/m2 or greater were at 4-fold increased risk for progression. Collectively these findings suggest that, while technical issues are important and likely contribute to poorer outcomes after RP in men with higher BMI, they alone are unlikely to fully explain the disparate outcomes observed in prior studies.10, 11, 17, 18 There are several limitations to the current study. We did not have data and, therefore, could not adjust for other factors that may have affected the technical difficulty of open RP, including pelvic anatomy (narrow vs wide and deep vs shallow) and the degree of desmoplastic response around the prostate. In addition, we did not evaluate the extent or location of capsular incision. We limited our analysis to experienced high volume surgeons. It is possible that among less experienced surgeons the association between BMI and capsular incision may be even stronger. Future studies are needed to address whether a similar association between BMI and technical difficulty is found for alternative surgical approaches, eg perineal, laparoscopic, etc. Finally, although our pathologists have been diligent about reporting capsular incision into tumor, we suspect that our data reflect under reporting of capsular incision into benign glands. However, there is no reason to suspect that this under reporting would be differential by BMI. Therefore, although the overall incidence of capsular incision may be higher than we reported, this under reporting would not have affected the OR for capsular incision by BMI.

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CONCLUSIONS

In a study of more than 7,000 men treated by 7 experienced surgeons at a center of excellence BMI was significantly and positively related to capsular incision. This suggests that open retropubic RP is technically more difficult in obese men, which results in a greater likelihood of a less than ideal operation. This may be predicted to have a negative impact on disease-free survival outcomes in obese men but it is unlikely to alone explain the disparate outcomes noted in previous RP series.10, 11, 17, 18 REFERENCES

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Pelvic surgery in general and RP specifically are undoubtedly more technically challenging in obese patients. In this large series the incidence of capsular incision at RP was significantly related to increasing obesity. The reasons for this finding remain speculative but they include suboptimal visualization due to body habitus and/or increased blood loss. In addition, noting the location of the capsular incision may be important in future attempts aimed at decreasing capsular incision. For example, if the majority of capsular incisions were found to be posterolateral, this may imply iatragenic capsular incision with attempted nerve sparing vs the apex, where better visualization through decreased blood loss may be of benefit. What is not resolved in this study is whether capsular incision was independently associated with a higher rate of biochemical relapse. Thus, the clinical significance of capsular incision and whether it is likely to add independently to the potentially worse outcome in obese patients requires additional followup. Finally, whether the rates of capsular incision and margin positivity will be decreased through laparoscopic approaches, which afford improved visualization and decreased blood loss, will be of significant interest. Michael S. Cookson Department of Urologic Surgery Vanderbilt University Medical Center Nashville, Tennessee