Prostate Cancer and Prostatic Diseases (2010) 13, 328–332 & 2010 Macmillan Publishers Limited All rights reserved 1365-7852/10
www.nature.com/pcan
ORIGINAL ARTICLE
Robot-assisted laparoscopic radical prostatectomy in men with human immunodeficiency virus JL Silberstein1,2,3,4, JK Parsons1,2,3, K Palazzi-Churas2, TM Downs1,2,3,4, K Sakamoto1,3, IH Derweesh1,2,3, J Woldrich1,2,3 and CJ Kane1,2,3 1
Division of Urology, University of California San Diego, San Diego, CA, USA; 2Urologic Cancer Unit, Moores University of California San Diego Cancer Center, La Jolla, CA, USA and 3Section of Urology, VA San Diego Medical Center, La Jolla, CA, USA
The aim of this study is to evaluate the outcomes of robot-assisted laparoscopic prostatectomy (RALP) in prostate cancer (PCa) patients with human immunodeficiency virus (HIV). This is a prospective cohort study of HIV patients undergoing RALP, comparing the demographics, tumor characteristics, complications, and short-term oncological outcomes of HIV-positive men to HIV-negative men using univariate (v2, Mann–Whitney test) and multivariable (logistic regression) analyses. From 2007 to 2010, 298 men underwent RALP, 8 of whom were known to be HIV positive. Preoperatively, all eight were taking highly active antiretroviral therapy (HAART) and had undetectable viral loads (o50); mean CD4 count was 634 cells per mm3. HIV-positive men were younger (54 versus 62 years, P ¼ 0.010) and less likely to be white (P ¼ 0.007). There were no significant differences between groups with respect to clinical staging, pathological and oncological outcomes or most complication rates. However, the prevalence of perioperative transfusions (P ¼ 0.031) and ileus (P ¼ 0.021) were higher in HIV-positive patients. HIV remained significantly associated with risk of transfusion after adjustment for age, race, Gleason sum and clinical T stage (P ¼ 0.002). After a median of 2.6 (range 0.03–19.2) months of follow-up, PSA remained undetectable in all eight HIV patients. These data suggest that RALP is safe for, and demonstrates short-term oncological efficacy in, HIV-positive patients with PCa. Prostate Cancer and Prostatic Diseases (2010) 13, 328–332; doi:10.1038/pcan.2010.35; published online 28 September 2010
Keywords: HIV; AIDS; robot-assisted laparoscopic prostatectomy; HAART; radical prostatectomy
Introduction As of 2007, at least 1.23 million persons in the United States were human immunodeficiency virus (HIV) positive; 75% of these were male and 50% African American.1–2 There are an estimated 56 000 new HIV infections every year in the United States.2 Although the majority of HIV-positive men in the United States are between the ages of 25 and 49 years, more than a quarter—over 300 000—are over the age of 50 years.3–4 The number of older men with HIV will likely continue to increase because of improved survival with the widespread use of highly active antiretroviral therapy (HAART).4 HAART has significantly improved
Correspondence: Dr JL Silberstein, Division of Urology, UC San Diego, 200 West Arbor Drive #8897, San Diego, CA 92103-8897, USA. E-mail:
[email protected] 4 Since the completion of this work, Dr Downs’s affiliation has been changed to Department of Urology, University of Wisconsin, Madison, WI, USA; and Dr Silberstein’s has been changed to Department of Urology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Received 10 June 2010; revised 19 August 2010; accepted 21 August 2010; published online 28 September 2010
the health and prognosis of HIV-positive patients. Mortality rates of HIV-positive patients on HAART now approach those of the general population.5–7 Morbidity in HIV patients now arises primarily from heart disease, diabetes, and non-AIDS-defining cancers rather than conditions related specifically to immunosuppression. HIV is associated with an increased incidence of specific malignancies, including Kaposi sarcoma, nonHodgkin’s lymphoma and cervical cancer.8 Additionally, several genitourinary malignancies have been demonstrated to have an increased incidence in the HIVpositive population, including testicular seminoma and renal cell carcinoma.8–9 This has been postulated to be a result of immunosuppression; however, these interactions have yet to be fully understood. Similarly, associations of HIV with prostate cancer (PCa) remain incompletely defined. Some studies have suggested increased prevalence of PCa in HIV-positive cohorts, whereas others have not.10–11 Regardless, PCa is the most common malignancy in US men and is particularly prevalent among older and AfricanAmerican populations.12–13 Thus, as the HIV population ages, it is likely that the prevalence of HIV among PCa patients will rise substantially, as will the need to assess
RALP in men with HIV JL Silberstein et al
20 12 10 22 21 10 10 20 o50 o50 o50 o50 o50 o50 o48 o48 506 510 597 600 538 600 980 737 African American African American Caucasian Caucasian African American Caucasian African American African American 50 48 45 49 60 66 58 58 1 2 3 4 5 6 7 8
Abbreviations: bx, biopsy; G, Gleason; HIV, human immunodeficiency virus; pre-tx, pretreatment; RALP, robot-assisted laparoscopic prostatectomy; UTI, urinary tract infection.
No Yes Yes No No No No No UTI Acute blood loss anemia Urinary renention None None Anastomotmic leak/ileus None Ileus CJK CJK CJK CJK CJK CJK TMD JKP Negative Negative Negative Negative Negative Negative Negative Negative T2c T2c T2c t2c T2c T2c T2c T2c 3+3 3+4 3+3 3+4 3+4 3+4 3+4 4+3 3+3 3+4 3+3 3+4 3+3 3+4 3+3 4+4 T1c T2b T1c T2a T1c T2a T2a T2a 6 7 10 3 4 6 5 10
Margin status Pathological stage Final G score bx G score Clinical stage Pre-tx PSA Hepatitis C Years with HIV Viral load CD4 count Ethnicity Age (years)
Patient population HIV-positive men had a mean CD4 count of 634 cells per mm3. All had been HIV seropositive for X10 years; all were on HAART; and two (25%) were also seropositive for hepatitis C (Table 1). HIV-positive men were significantly younger (median age 54 versus 62 years, P ¼ 0.01) and more likely to be African American (62.5 versus 17.3%, P ¼ 0.007). There were no significant differences with respect to other preoperative variables, including clinical tumor stage, biopsy Gleason sum and D’Amico risk stratification (Table 2).
Patient number
Results
Table 1 Demographic and clinical characteristics and outcomes of HIV-positive men who underwent RALP for prostate cancer
Between October 2007 and January 2010, four surgeons performed 316 consecutive RALPs for clinically localized PCa. Under an institutional review board-approved protocol, prospective clinicopathological data were collected. Complete data were available for 298 patients, and 8 men with HIV were identified. Eighteen men who underwent RALP were not consented for, and thus not included in our institutional database. Lack of consent was a result of various logistical considerations and no identifiable bias was introduced with the exclusion of these patients. Patients who did not have a prior diagnosis of HIV were not screened for HIV and were presumed to be HIV negative. Patients who were known to be HIV positive underwent counseling with their primary care physician and their HIV specialist. RALP was performed using the DaVinci-S model (Intuitive Surgical). Nerve-sparing surgery was performed in appropriate patients, and pelvic lymph node dissection was performed in select patients based on preoperative risk stratification and published clinical guidelines.15 Patients were discharged when they were able to tolerate a regular diet and when their pain was adequately controlled with oral medication. Perioperative complications were noted using Clavien classification.16 Low-grade complications were designated as those not requiring any surgical, endoscopic or radiological intervention; those requiring intervention or resulting in a life-threatening condition or death were designated high grade. Statistical analysis was performed with SPSS v. 17.0 (SPSS, Chicago, IL, USA). HIV-positive men were compared with the rest of the cohort using the Mann– Whitney U-test for continuous variables, and w2 and Fisher’s exact tests for categorical variables, with Po0.05 considered significant. Multivariable analysis was performed using binary logistic regression to compare HIV status, adjusting for covariates.
Surgeon
Materials and methods
329
No No Yes Yes No No No No
Complication
Blood transfusion
the safety and efficacy of PCa treatments in the HIV population. The most common surgical therapy for PCa in the United States is robot-assisted laparoscopic prostatectomy (RALP) (Intuitive Surgical, Sunnyvale, CA, USA).14 There are no published data on RALP in HIV-positive men. Therefore, we investigated outcomes of HIV-positive men undergoing RALP at our institution.
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Table 2 Demographic and clinical characteristics
Table 3 Operative and pathological outcomes
Non-HIV (n ¼ 290)
HIV (n ¼ 8)
61.6±6.5 62 (41–78)
54.5±7.2 54 (46–66)
0.01* — —
Race Caucasian African-American/other
239 (82.7%) 50 (17.3%)
3 (37.5%) 5 (62.5%)
0.007* — —
PSA (ng ml–1) Mean±s.d. Median (range)
7.2±5.5 5.6 (0.5-45.1)
Age (years) Mean±s.d. Median (range)
6±2.4 5.6 (2.5–10)
0.79 — —
25.4±3.2 26.3 (19–29)
0.14 — —
–2
BMI (kg m ) Mean±s.d. Median (range)
27.6±3.8 27.3 (14–40)
Hypertension Hypercholesterolemia Diabetes Coronary artery disease
106 103 23 14
(36.6%) (35.5%) (7.9%) (4.8%)
1 1 1 1
(12.5%) (12.5%) (12.5%) (12.5%)
0.27 0.27 0.49 0.34
Clinical T stage T1b-c T2a-c T3a-b
179 (65.1%) 89 (32.4%) 7 (2.5%)
3 (37.5%) 5 (62.5%) 0
0.20 — — —
Biopsy gleason score p6 7 X8
153 (53.7%) 87 (30.5%) 45 (15.8%)
4 (50%) 3 (37.5%) 1 (12.5%)
0.91 — — —
D’Amico risk group Low risk Intermediate risk High risk
136 (46.9%) 98 (33.8%) 49 (16.9%)
4 (50%) 3 (37.5%) 1 (12.5%)
0.95 — — —
Abbreviations: BMI, body mass index; HIV, human immunodeficiency virus. *Significant using two-tailed, ao0.05, w2-test, Fisher’s exact test, Mann– Whitney U-test.
Outcomes Perioperative transfusions—defined as blood transfusions within 30 days of surgical intervention—occurred more frequently in HIV-positive patients (P ¼ 0.03). This difference persisted in multivariable logistic regression modeling adjusting for age, race, clinical Gleason sum and tumor stage (P ¼ 0.002). Although Gleason 7 tumors were more common in the HIV-positive group, Gleason X8 tumors were more common in the HIV-negative group, and there was no significant difference between the groups with respect to Gleason sum X6 (Table 3). There were no significant differences with respect to other operative outcomes, including operative time (measured from the initial skin incision to the placement of the sterile dressings), estimated blood loss (as measured by volume in suction canister as well as estimated by surgeon and anesthesiologist) and pathological T stage (Table 3). Immediate postoperative PSA was undetectable in all eight patients (median follow-up 2.6 months, range 0.03–19.2). There were no significant differences in the prevalence of overall, low-grade, or high-grade complications between HIV-positive and HIV-negative patients (Table 4). HIV-positive patients were significantly more likely to develop postoperative ileus (P ¼ 0.02) and (marginally) significantly more likely to have an anastomotic leak (P ¼ 0.08) (Table 4). Prostate Cancer and Prostatic Diseases
Non-HIV (n ¼ 290)
HIV (n ¼ 8)
Operative time (min) Mean±s.d. Median (range)
207.9±63.1 195 (100–525)
190.6±27.8 190 (160–235)
0.71 — —
Estimated blood loss (ml) Mean±s.d. Median (range)
164.2±98.6 150 (25–700)
132.1±71.8 100 (50–250)
0.40 — —
9 (3.1%)
2 (25%)
0.03*
1.4±0.8 1 (1–8)
2.3±1.9 1 (1–6)
0.11 — —
4 (50%)
0.73
14.8±9.5 10.5 (9–29)
0.50 — —
P-value
Blood transfusions (o30 days) Hospital stay (days) Mean±s.d. Median (range) Lymph node dissection
126 (43.4%)
Lymph nodes retrieved Mean±s.d. Median (range)
17.1±10.7 16 (0–82)
Patients with nodal metastasis
9 (7.1%)
0
P-value
1.000
Pathological Gleason score p6 83 (28.9%) 7 150 (52.3%) X8 54 (18.8%)
2 (25%) 6 (75%) 0
0.32 — — —
Pathological T stage T2a-c T3a-b T4
233 (80.3%) 51 (17.6%) 6 (2.1%)
8 (100%) 0 0
0.38 — — —
68 (23.5%)
0
0.21
Positive margins –1
PSA at 6 weeks (ng ml ) Mean±s.d. 0.1±0.5 0.03±0.01 Median (range) 0.03 (0.01–7.45) 0.03 (0.01–0.05)
0.67 — —
Length of follow-up (months) Mean±s.d. 6.9±6.4 Median (range) 4.6 (0–31.5) Disease persistence/ 21 (7.6%) recurrence
0.46 — — 1.000
5.6±6.5 2.6 (0–19.2) 0
Abbreviation: HIV, human immunodeficiency virus. *Significant using two-tailed, ao0.05, w2-test, Mann–Whitney U-test.
Discussion These data—the largest surgical cohort of HIV-positive men with PCa to date, and the first for RALP— demonstrate that RALP provides robust and safe shorter-term outcomes for HIV-positive men. Although HIV-positive patients had a higher prevalence of perioperative transfusion and ileus/small bowel obstruction, other perioperative and initial oncological outcomes were comparable with HIV-negative patients. In our study, HIV-positive men were significantly younger than the overall cohort: 54 versus 62 years (P ¼ 0.01) (Table 2). This is consistent with most published data.17 Although a definitive explanation for the youthfulness of HIV-positive PCa patients cannot be reached in this study, it is likely a result of sampling bias related to the relatively young HIV-positive population overall.3 Additionally, older HIV-positive men may be screened less aggressively for PCa than age-matched HIV-negative men because of a perceived shorter life expectancy. Alternatively it is possible that there is a
RALP in men with HIV JL Silberstein et al Table 4 Complications after RALP Non-HIV (n ¼ 290)
HIV (n ¼ 8)
P-value
Low-grade complications (I/II) Urinary retention Urinary tract infection Ileus/small bowel obstruction Lymphocele, no surgery Anastomotic leak, no surgery Pulmonary embolus Pneumonia Acute blood loss anemia SV tachycardia Low blood pressure Urosepsis Wound infection Deep vein thrombosis Other
20 12 7 6 5 2 2 1 1 1 1 1 1 18
(6.9%) (4.1%) (2.4%) (2.1%) (1.7%) (0.7%) (0.7%) (0.3%) (0.3%) (0.3%) (0.3%) (0.3%) (0.3%) (6.2%)
1 (12.5%) 1 (12.5%) 2 (25%) 0 0 0 0 1 (12.5%) 0 0 0 0 0 0
0.37 0.45 0.30 0.02* 1.000 1.000 1.000 1.000 0.05 1.000 1.000 1.000 1.000 1.000 1.000
High-grade complications (III–V)a Bladder neck contracture Lymphocele/fluid collection Anastomotic leak Rectal laceration Other Death
5 5 2 1 3 1
(1.7%) (1.7%) (0.7%) (0.3%) (1%) (0.3%)
0 0 1 (12.5%) 0 0 0
0.360 1.000 1.000 0.08 1.000 1.000 1.000
Abbreviations: HIV, human immunodeficiency virus; RALP, robot-assisted laparoscopic prostatectomy; SV, superventricular. a High grade requiring reoperation. * Significant using two-tailed a o0.05; Fisher’s exact test.
biological link between HIV infection and PCa, and such an association is particularly plausible given known associations of inflammation with PCa. All HIV-positive men in this series had been seropositive for at least 10 years prior to their diagnosis of PCa. Although a definitive cause for this finding cannot be reached in this study, it is possible that these findings are a result of the youthfulness of the HIV population overlapping with the older PCa population during the natural history of the disease. Alternatively it is possible that chronic HIV infection may be associated with PCa risk, as suggested by other authors.10,18 Similarly, the high proportion of African-American men with HIV and PCa (62.5%) in our series likely reflects the high proportion of HIV-positive individuals who are African American, but again a biological link between race, HIV and PCa cannot be excluded.2 It is important to note that the HIV-positive men in this study were a select group in that they all had high CD4 counts, low viral loads, were on HAART and had elected to undergo RALP as primary therapy for their PCa. No HIV-positive patients with low CD4 counts (o500) or detectable viral loads were seen by these surgeons, and thus the results of this study cannot be generalized to all HIV-positive patients. As PCa is often a slow-growing malignancy that does not require urgent intervention, the authors recommend consultation with an HIV specialist to optimize immunologic status prior to surgery. Professional groups provide no specific guidance on treatment of HIV-positive men with PCa but broadly suggest that when a man’s life expectancy is relatively long (that is, 410 years), definitive treatment should be considered.19–20 Radical retropubic prostatectomy,21 laparoscopic radical prostatectomy,22 cryosurgery,22 external beam radiation therapy,23 brachytherapy24
and active surveillance22 have been reported for HIVpositive men with localized PCa and found to be generally safe and efficacious in the short term.17 The oncological risk posed by PCa in the HIV-positive cohort did not differ significantly from the non-HIVpositive cohort, based on a variety of prognostic data including PSA value, clinical tumor stage, biopsy Gleason sum, D’Amico risk stratification and pathological tumor grade or stage. Some authors have suggested that PCa may be more aggressive in patients with HIV; although this study has a limited number of HIV-positive patients with high CD4 counts and low viral loads, it does not support these assertions.25 The findings of Huang et al.21 were similar to ours (although with a smaller series, different surgical approach and longer follow-up): negative surgical margins in five patients with known HIV who underwent open radical retropubic prostatectomy. No patients had biochemical recurrence after a median follow-up of 26 months. Unlike the present series, however, the prevalence of wound infection was higher (40%) among HIV-positive patients in this cohort. The cause of this observation is unclear. Although it is possible that smaller incisions associated with RALP may decrease the risk of wound infections, caution must be taken in drawing conclusions from small series. Recent prospective studies in HIV-positive cohorts have demonstrated no increased risk of wound infections for various abdominal, gynecologic, breast, orthopedic or cardiothoracic surgery when compared with well-matched non-HIV-positive men.26 Overall perioperative complication rates both in quantity and severity, as defined by the Clavien grading system, were similar between groups. These finding cannot be generalized to all HIV-positive men with PCa because the HIV-positive men in this cohort were all on HAART, with reasonable CD4 counts and undetectable viral loads. We did observe a higher prevalence of perioperative blood transfusions in the HIV-positive men, which persisted in multivariate logistic regression analysis. Despite the higher rate of transfusions in the HIV-positive men, there were no differences with respect to operative blood loss. The reason for this discrepancy is unclear; one possible explanation is that the precision of the estimated blood loss during an RALP is poor. All patients were deemed by the surgeons and anesthesiologists preoperatively to have acceptable preoperative blood counts. HIV and HAART are typically not associated with bleeding diathesis, and although hepatitis C is common in patients with HIV, none of the patients in this cohort with hepatitis C demonstrated evidence of active hepatitis or hepatic dysfunction. Decision to perform a blood transfusion was based on the discretion of the individual surgeon and it is possible that HIV-positive status prompted a lower clinical threshold for transfusion. Alternatively, given the relatively small analytic cohort and relatively low precision of the effect estimates, this difference may be attributable to chance. Ileus, the etiology of which cannot be ascertained in this study, occurred more frequently among HIV-positive men. It is possible that reinitiation of HAART, which is known to cause gastrointestinal malaise, may lead to the ileus, but further data are needed. One (12.5%) of eight HIV patients also had an anastomotic leak, which may cause ileus as well.
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Four surgeons (CJK, JKP, IHD, TMD) were included in order to capture as many HIV-positive cases as possible. The 298 RALPs in this series were not divided equally among them, but because each has specific training in oncology, and expertise in robotics, the potential for significant error is low. Although controversy remains about the relative advantages of RALP compared with open surgery, it has reproducibly been demonstrated that RALP results in decreased blood loss and transfusion when compared with the open technique.27 In HIV patients, decreased hemorrhage may be advantageous because it reduces the exposure of the surgical team to HIV, which may be transmitted even with undetectable viral titers. Furthermore, the use of the robotic system to perform ligation of the dorsal venous complex and the urethral-vesico anastomosis may potentially decrease the potential for needle stick injury. This study has several limitations. In addition to its retrospective nature and the small number of patients known to be HIV positive, the patients who were believed to be HIV negative were never tested for HIV status. It is possible that some of these patients were in fact HIV positive. In summary, these data suggest that RALP is safe for, and demonstrates short-term oncological efficacy in, select HIV-positive patients with PCa. This study gives further insight into the natural history of PCa in men with known HIV, a poorly characterized group. Future studies should include larger cohorts with longer followup, explore potential biological and epidemiological interactions of HIV with PCa, and determine whether immunosuppression and HAART may predispose HIVpositive patients to greater risk of perioperative complications.
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12 13 14 15
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Conflict of interest Dr Kane receives compensation as a consultant for Intuitive Surgical and is on the Scientific Advisory Board for Soar Biodynamics. Dr Derweesh receives compensation as a consultant for Ethicon and as a consultant and Advisory Board member of GTX. Dr Parsons receives compensation as a lecturer for AMS and has financial holdings in Urigen. The remaining authors declare no conflict of interest.
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