JOURNAL OF ENDOUROLOGY Volume 28, Number 6, June 2014 ª Mary Ann Liebert, Inc. Pp. 699–703 DOI: 10.1089/end.2014.0009
Holmium Laser Enucleation of the Prostate and Perioperative Diagnosis of Prostate Cancer: An Outcomes Analysis Marcelino E. Rivera, MD,1 Igor Frank, MD,1 Boyd R. Viers, MD,1 Laureano J. Rangel,2 and Amy E. Krambeck, MD1
Abstract
Objective: Our objective is to assess the outcomes of patients with prostate cancer (PCa) diagnoses undergoing holmium laser enucleation of the prostate (HoLEP). Methods: From 2009 to 2012, 450 patients underwent HoLEP at our institution. We performed a retrospective review of these patients to identify those with PCa. Results: PCa was diagnosed in 57 (12.7%) HoLEP patients: 11 (19.2%) preoperatively, 43 (75.4%) in the operative specimen, and 3 (5.4%) during follow-up. Mean time to PCa development in the postoperative group was 16 months (9–23). There was no difference in patient characteristics for those diagnosed with PCa at the time of HoLEP or in the postoperative period. There were 5 patients with a Gleason score (GS) > 8 and 52 with GS < 8 PCa. In the operative group, 39 (91%) elected for active surveillance and 4 (9%) elected to have cancer treatment. In subgroup analysis, men diagnosed with GS > 8 intraoperatively or postoperatively had significantly elevated preoperative, postoperative, and percent change prostate-specific antigen (PSA) levels when compared to patients diagnosed GS £ 7 (P = 0.01, 0.02, and 0.01, respectively). There were no complications, all voided spontaneously, and one patient had persistent incontinence. Conclusion: HoLEP for the treatment of lower urinary tract symptoms (LUTS) in selectively chosen men with known PCa can safely improve urination. Furthermore, PCa is diagnosed at the time of or post HoLEP in nearly 12% of patients. Those patients with persistently elevated post HoLEP PSA levels or low percent change PSA levels should raise suspicion for high GS PCa. Finally, HoLEP does not preclude active surveillance or treatment for PCa when appropriate. Introduction
H
olmium laser enucleation of the prostate (HoLEP) has been demonstrated to be an effective and durable transurethral surgery for treatment of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS).1 Incidental prostate cancer (PCa) discovered at the time of HoLEP or standard transurethral resection (TUR) currently remains between 5% and 12%.2,3 Due to the ability of HoLEP to enucleate the vast majority of prostatic tissue, prostate volume and prostate-specific antigen (PSA) levels decrease between 60% and 90% postoperatively.1 Previous investigations have demonstrated that patients diagnosed with incidental PCa at time of HoLEP had significantly higher postoperative PSA levels when compared to the benign groups.4 Additionally, minimal change in PSA after HoLEP has been demonstrated in PCa detected in the postoperative period.5
Patients with preexisting, locally advanced PCa can develop outlet obstruction due to disease progression. While recent data would suggest patients with LUTS and castrateresistant PCa suffer more from detrusor overactivity than bladder outlet obstruction, in patients with outlet obstruction significant relief of symptoms can be obtained through palliative TUR. The reintervention rate is as high as 29%.6,7 When compared to patients with only LUTS related to BPH, patients treated with palliative TUR were not only more likely to require a second procedure, they were also more likely to fail the initial trial of void and require chronic catheterization.7 Concerns regarding TUR and dissemination of localized disease that leads to progression, metastasis, and cancerspecific morality have been evaluated, and mixed conclusions have been drawn regarding whether or not TUR itself plays a role in cancer progression and mortality rates. Several studies have suggested procedure-related disease progression,8,9 while
Departments of 1Urology and 2Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
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Table 1. Preoperative PCa Group Patient Characteristics (N = 11) Mean age (years) Follow-up (months) Mean preoperative PSA (ng/mL) Mean postoperative PSA (ng/mL) Mean prostate volume (mL) Mean GS Enucleation time (min) Morcellation time (min) Resected tissue (g) Peak flow preoperatively (mL/s) Peak flow postoperatively (mL/s) AUA symptom score preoperatively AUA symptom score postoperatively Hospital stay (days) Length of indwelling catheter (days)
74.6 9.6 12.4 5.9 70.6 6.5 40.4 16.1 45.1 9.7 33 21.8 4.5 1.1 1.2
(67–82) (3–31) (0.7–44.2) (0.1–33.1) (34–137) (6–9) (23–63) (2–39) (7.8–110.9) (2–24) (13–49) (9–30) (1–10) (1–2) (1–3)
AUA = American Urological Association; GS = Gleason score; PSA = prostate-specific antigen.
others have concluded no influence of TUR on survival or dissemination of disease.10–12 While TUR has been studied extensively, there is a paucity of information addressing HoLEP in PCa patients who are diagnosed preoperatively, at time of procedure, and postoperatively. Furthermore, few studies have focused on patients with low, intermediate, and high-risk PCa diagnosis after HoLEP. We evaluated all patients treated with HoLEP at our institution who were diagnosed with PCa preoperatively, in the operative specimen, or during follow-up and reviewed their clinical outcomes. Materials and Methods
After obtaining Institutional Review Board approval, we retrospectively analyzed our electronic medical record for all patients between July 2009 and August 2012 with the diagnosis of PCa preoperatively, in the operative pathology specimen, or during follow-up from HoLEP. Clinicopathologic and functional variables were analyzed. All HoLEP procedures were performed by a single surgeon (Amy E. Krambeck). Preoperatively, all patients underwent PSA screening, digital rectal exam, transrectal ultrasound, and standard twelve-core biopsy if indicated based on elevated PSA or abnormal examination.
Patients were placed into groups based on time of PCa diagnosis: before HoLEP (group 1), on the intraoperative specimen (group 2), or in post-HoLEP follow-up (group 3). Patients in groups 2 and 3 were then further stratified based on Gleason score (GS), with GS of 6 indicating low-, 7 intermediate-, and 8–10 high-grade disease.13 Assuming non-normal distribution, median maximum flow (QMax), PSA, and American Urological Association Symptom Score were compared before and after surgery using Kruskal-Wallis test to determine statistical difference (P < 0.05) between groups 2 and 3. After diagnosis of PCa, patients were counseled on different treatment options, including active surveillance, radical prostatectomy, and external beam radiation therapy (XRT). Those patients choosing to undergo active surveillance were monitored with PSA and digital rectal examination every 3 months for the first year and transrectal needle biopsy 12 months after PCa diagnosis when indicated. Upon an abnormal examination or three consecutive rises in PSA, a transrectal-guided needle biopsy was performed. Results
There were 11 patients in group 1, 43 in group 2, and 3 in group 3. Clinical characteristics for the preoperative patients (group 1) are listed in Table 1. In group 1 there were 8 patients with low-grade, 2 with intermediate-grade, and 1 with high-grade disease. Patients were hospitalized for a mean of 1.1 days and had an indwelling catheter for 1.2 days. There were no complications. All patients were voiding at most recent follow-up, with one group 1 patient requiring two pads daily for incontinence. Two patients in group 1 had their GS upgraded on the intraoperative specimen: One from GS 6 to 7, and one from GS 6 to 9. Of these two patients, one patient (GS 7) underwent androgen deprivation therapy (ADT), and the other combined ADT and XRT. Neither patient has evidence of disease progression. There were no significant differences in baseline demographic characteristics between groups 2 and 3 (Table 2). There were 4 high-, 6 intermediate-, and 36 low-grade GS PCas in groups 2 and 3. In group 3, 2 patients had GS upgrading on follow-up biopsy: one from 7 to 8 and the other from 7 to 10. In group 2, 39 (91%) elected for active surveillance and 4 (9%) elected for cancer treatment: 2 combined
Table 2. HoLEP Patient Characteristics Based on Timing of PCa Diagnosis Operative (group 1) (N = 43) Age (years) Preoperative number of biopsies Estimated volume (mL) Resected tissue (g) Resection time (min) Morcellation time (min) Length of stay (days) QMax before diagnosis (mL/s) QMax after diagnosis (mL/s) AUASS before diagnosis AUASS after diagnosis Follow-up (mo)
72.0 0.7 82.0 37.8 38.5 8.5 1.0 7.5 25.0 19.4 7.0 12.8
Postoperative (group 2) (N = 3)
(53.0–89.0) (0.0–5.0) (24.6–210.0) (2.6–166.5) (11.0–98.0) (1.0–63.0) (0–3.0) (0.0–20.0) (3.0–53.0) (3.0–28.0) (1.0–31.0) (3–35)
AUASS = American Urological Association Symptom Score; QMax = maximum flow.
70.0 1.0 113.0 35.1 76.0 25.0 1.0 11.5 22.0
(66.0–73.0) (0.0–2.0) (36.5–113.0) (26.0–197) (60.0–79.0) (4.0–60.0) (0.0–1.0) (11.0–12.0) (9.0–33.0)
9.0 (5.0–14.0) 23 (15–35)
P values 0.449 0.270 0.436 0.409 0.017 0.338 0.468 0.169 0.922 0.357 0.08
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Table 3. HoLEP Patient Characteristics Based on Grade High grade (GS 8–10) (N = 4) Age (years) Preoperative number of biopsies Estimated volume (mL) Resected tissue (g) Resection time (min) Morcellation time (min) Length of stay (days) QMax before diagnosis (mL/s) QMax after diagnosis (mL/s) AUASS before diagnosis AUASS after diagnosis Period of diagnosis operative: postoperative (nos)
70.5 1.0 94.4 40.6 44.5 12.0 1.0 3.0 33.0
(65.0–80.0) (0.0–5.0) (36.0–209.0) (10.0–197.0) (18.0–79.0) (2.0–60.0) (1.0–1.0) (1.0–12.0) (10.9–44.0)
3.5 (2.0–5.0) 3:1
Intermediate grade (GS 7) (N = 6) 72.5 0.5 78.5 39.9 35.5 7.0 1.0 10.0 18.0 25.0 14.0
(59.0–80.0) (0.0–2.0) (36.5–113.0) (2.6–60.0) (16.0–76.0) (2.0–25.0) (0.0–3.0) (8.5–17.0) (9.0–26.0) 5:1
Low grade (GS 6) (N = 36) 72.6 0.0 82.0 34.9 40.0 11.0 1.0 7.0 24.0 21.0 7.0
(53.0–89.0) (0.0–5.0) (24.6–210.0) (4.5–166.5) (11.0–98.0) (1.0–63.0) (0.0–3.0) (0.0–20.0) (3.0–53.0) (3.0–28.0) (1.0–31.0) 35:1
P values 0.841 0.162 0.834 0.904 0.903 0.643 0.633 0.356 0.506 0.271 0.183
AUASS = American Urological Association Symptom Score; GS = Gleason score; QMax = maximum flow.
XRT and ADT, 1 had XRT alone, and 1 had robotic radical prostatectomy followed by ADT and XRT. In group 3, the mean time to cancer diagnosis was 16 months (9–23) with 2 patients electing for treatment: 1 combined ADT with XRT and 1 had ADT alone. All patients were voiding and continent at most recent follow-up. When evaluating groups 2 and 3 based on PCa GS, there was no significant difference between the high-, intermediate-, and low-grade GS groups for multiple baseline characteristics or outcomes (Table 3). In subgroup analysis combining the low- and intermediate-grade PCa patients, men diagnosed with a GS > 8 in either group had significantly elevated postoperative PSA difference and percent change PSA when compared to patients diagnosed with a GS £ 7 (P = 0.01, 0.02, and 0.01, respectively; Table 4). Discussion
HoLEP is an effective and durable transurethral surgery for the treatment of LUTS secondary to BPH.1 To date, patients diagnosed with PCa before HoLEP represent a unique group of patients in whom there is a lack of objective data. The vast majority of PCa patients with LUTS harbor low-grade disease. In patients diagnosed with PCa on active surveillance, with locally advanced disease or those already treated with XRT and ADT, outlet obstruction can occur and cause a significant impact on quality of life. In an effort to improve outlet obstruction, Crain and colleagues7 evaluated palliative TUR in patients with locally
advanced PCa in a retrospective study that compared TUR in patients with BPH and PCa. Patients who underwent TUR had significant improvement in International Prostate Symptom Score from 21 to 11 (P = 0.002); however, urinary flow rates actually decreased from 9.6 to 7.3 mL/s, and 50% of the cohort required either reoperation or long-term catheter drainage.7 This is in significant contrast to our cohort of patients, which had a mean increase in urinary flow from 9.7 to 33 mL/s, and none of whom have required reintervention or catheterization. Also, 67% of the patients in Crain’s study were diagnosed with high-grade GS after TURP, whereas only 18% of our cohort had such diagnosis after HoLEP. In group 1, three patients had a diagnosis of intermediate- or high-grade disease, and the two patients with GS 7 disease both remain on active surveillance protocols. Meanwhile, the patient with high-grade disease preoperatively was treated with cryotherapy, developed a metastatic lesion, and was being treated palliatively for urinary retention due to local tumor overgrowth. Based on our small cohort study, HoLEP appears to treat outlet obstruction in the presence of PCa successfully and safely with a single procedure. While HoLEP can relieve LUTS in patients with preexisting PCa, it is uncertain what effect it has on cancer progression. While there are currently no studies evaluating HoLEP specifically, controversy exists with regards to TURP and its influence on PCa progression. Krupski and colleagues discusses the relationship between palliative TURP and disease progression using data from the Surveillance Epidemiology, and End Results registry.14 The authors evaluated
Table 4. PSA Characteristics Based on Grade High grade (GS 8–10) (N = 4) Age (years) Preoperative PSA (ng/mL) Postoperative PSA (ng/mL) PSA difference (ng/mL) Percent change PSA ( · 100) Estimated volume (mL)
71.5 31.5 31.8 - 0.2 0.0 108.5
(65.0–80.0) (1.0–110.0) (1.1–113.0) ( - 3.0 to 4.1) ( - 0.6 to 0.2) (36.0–209.0)
GS = Gleason score; PSA = prostate-specific antigen.
Combined intermediate and low grades (GS 6–7) (N = 42) 72.4 5.9 1.2 5.0 - 0.7 86.3
(53.0–89.0) (0.5–25.0) (0.1–5.5) ( - 1.1 to 23.2) ( - 1.0 to 0.8) (24.6–210.0)
P values 0.710 0.299 0.010 0.023 0.013 0.626
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men who underwent TURP within 3 months of PCa diagnosis and found in multivariate analysis that patients who underwent TURP had significantly higher risk of mortality hazard ratio (HR) 1.26 (1.17–1.35) when compared to those who did not. While this was an observational, database-driven study able to determine association, not causation, it nonetheless raises the question as to whether palliative TURP increases the risk of PCa-specific mortality. Clearly, further prospective trials are warranted. While our follow-up is limited, there have been no PCa-specific mortalities in our cohort. When evaluating our patients diagnosed with PCa at time of HoLEP and postoperatively, several unique observations can be made. Previous evaluations of TURP and open surgery have demonstrated a significant difference in PSA kinetics between patients with benign disease and PCa tissue in the specimen.4,5 While we did not directly evaluate the nadir of PSA levels in a separate cohort of patients with benign disease, previous literature would suggest that when evaluating HoLEP specifically, in benign cases PSA levels have been found to decrease by more than 80%, with direct correlation between percent change PSA and the amount of tissue removed.15 In our study, in patients with low GS PCa, the percent decrease in PSA was very similar to that of benign cases, with a mean decrease of 70% after HoLEP. Intermediate GS had a mean decrease of 50%, and in our group of high GS patients there was a mean 0% change in PSA postoperatively. Absolute PSA value after HoLEP appears to also be predictive of high-grade disease, with low- and intermediategrade groups having a significantly lower PSA postoperative value. In the oncology literature PSA nadir after definitive and adjuvant therapy for PCa is used routinely to determine the likelihood of cancer progression and cancer-specific mortality.16 Unfortunately the use of PSA nadir after other transurethral surgeries is variable, which has made surveillance of individuals diagnosed with low-grade incidental PCa at time of TUR difficult, as there is no way to predict those with and without high-risk disease.3,4 HoLEP has proven to be a durable therapy and PSA reduction remains consistent in follow-up, thus making surveillance more reliable in patients who are candidates for an active surveillance protocol.5,17 Tissue quality after resection has also been investigated and compared with standard TURP by Naspro and associates.18 They performed a prospective histologic evaluation of 80 consecutive patients undergoing TURP or HoLEP, in which HoLEP cases demonstrated a significantly larger amount of resected tissue with preservation of prostatic tissue morphology in the majority of the specimen. Tissue damage was induced in a similar fashion as TURP, via coagulation necrosis, and even though the tissue was altered the authors concluded that HoLEP specimens could be adequately evaluated by pathologists and the diagnoses of incidental PCa detected. Patients diagnosed with PCa at the time of HoLEP are candidates for curative therapy, including open and robotic prostatectomy or XRT. Suardi and colleagues19 evaluated outcomes in patients undergoing nerve-sparing radical retropubic prostatectomy after HoLEP. Cases were matched 1 to 1 in a retrospective fashion to patients who had undergone TUR or simple prostatectomy. Functional outcomes were evaluated among the three groups and no statistically sig-
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nificant differences were found with regard to postoperative complications, rate of incontinence, or erectile dysfunction. Patients who underwent HoLEP did have significantly lower positive margin rates. While there is a lack of literature on XRT after HoLEP, XRT after TUR did appear to increase the risk of grade 3, toxicity including severe LUTS requiring intervention.20 In our series, all patients did functionally well and the incidental diagnosis of PCa did not alter clinical outcomes. Such clinical results have been replicated by other series as well as the rate of incidentally diagnosed PCa after transurethral surgery, between 5% and12%.2,5,9 Even those patients going on to receive XRT, radical prostatectomy, or ADT did not develop urinary incontinence, stricture, bladder neck contracture, or retention. Outcomes did not appear to differ based on when the PCa was diagnosed. Those diagnosed post HoLEP reported similar outcomes to those diagnosed at time of HoLEP. Limitations of this study are its retrospective nature, relatively small numbers of patients with high-grade disease, and a large variation in PSA among patients. While our values were significant between preoperative and postoperative PSA, a larger number of patients would add significant power to the data, particularly with regard to patients with high GS. Our classification of PCa based solely on GS and not using other well-known risk stratification systems was twofold: All patients had clinical T1a or T1b disease, and several of these patients had elevated PSA levels due to BPH but would have been stratified into intermediate- or high-risk groups as prostatic volume is not considered. Follow-up was limited to date and thus warrants further prospective evaluation regarding clinical and oncologic outcomes. Conclusion
PCa is common and can be diagnosed before, during, and after surgical intervention for LUTS. We found that HoLEP in selectively chosen men with known PCa can improve urination without an increase in complications. Furthermore, diagnosis of PCa at time of surgery or in the postoperative period occurs in 12% of patients. A finding of persistently elevated post-HoLEP PSA or low percent change PSA should raise suspicion for high GS PCa. We propose that if the reduction of PSA after HoLEP is negligible, these patients should be evaluated for malignancy and high-grade disease should be suspected. Additionally, HoLEP does not preclude active surveillance or definitive therapy when appropriate in PCa patients. Disclosure Statement
Igor Frank is a consultant for Rochester Medical, and Amy Krambeck is a consultant for Histosonics, a data safety monitoring board. No competing financial interests exist for the other authors. References
1. Krambeck AE, Handa SE, Lingeman JE. Experience with more than 1,000 holmium laser prostate enucleations for benign prostatic hyperplasia. J Urol 2010;183:1105. 2. Nunez R, Hurd KJ, Noble BN, et al. Incidental prostate cancer revisited: Early outcomes after holmium laser enucleation of the prostate. Int J Urol 2011;18:543.
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3. Melchior S, Hadaschik B, Thuroff S, et al. Outcome of radical prostatectomy for incidental carcinoma of the prostate. BJU Int 2009;103:1478. 4. Helfand BT, Anderson CB, Fought A, et al. Postoperative PSA and PSA velocity identify presence of prostate cancer after various surgical interventions for benign prostatic hyperplasia. Urology 2009;74:177. 5. Elmansy HM, Elzayat EA, Sampalis JS, et al. Prostaticspecific antigen velocity after holmium laser enucleation of the prostate: Possible predictor for the assessment of treatment effect durability for benign prostatic hyperplasia and detection of malignancy. Urology 2009;74:1105. 6. Rom M, Waldert M, Schatzl G, et al. Bladder outlet obstruction in men with castration-resistant prostate cancer. BJU Int 2013 [epub ahead of print] 7. Crain DS, Amling CL, Kane CJ. Palliative transurethral prostate resection for bladder outlet obstruction in patients with locally advanced prostate cancer. J Urol 2004;171:668. 8. Hanks GE, Leibel S, Kramer S. The dissemination of cancer by transurethral resection of locally advanced prostate cancer. J Urol 1983;129:309. 9. Forman JD, Order SE, Zinreich ES, et al. The correlation of pretreatment transurethral resection of prostatic cancer with tumor dissemination and disease-free survival. A univariate and multivariate analysis. Cancer 1986;58:1770. 10. Kuban DA, el-Mahdi AM, Schellhammer PF, et al. The effect of transurethral prostatic resection on the incidence of osseous prostatic metastasis. Cancer 1985;56:961. 11. Pansadoro V, Sternberg CN, DePaula F, et al. Transurethral resection of the prostate and metastatic prostate cancer. Cancer 1991;68:1895. 12. Anscher MS, Prosnitz LR. Transurethral resection of prostate prior to definitive irradiation for prostate cancer. Lack of correlation with treatment outcome. Urology 1991;38:206. 13. Mohler JL, Armstrong AJ, Bahnson RR, et al. Prostate cancer, featured updates to the NCCN guidelines. Version 3.2012. J Natl Compr Cancer Net 2012;10:1081. 14. Krupski TL, Stukenborg GJ, Moon K, et al. The relationship of palliative transurethral resection of the prostate with disease progression in patients with prostate cancer. BJU Int 2010;106:1477. 15. Tinmouth WW, Habib E, Kim SC, et al. Change in serum prostate specific antigen concentration after holmium laser
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17. 18. 19.
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enucleation of the prostate: a marker for completeness of adenoma resection? J Endourol 2005;19:550. D’Amico AV, McLeod DG, Carroll PR, et al. Time to an undetectable prostate-specific antigen (PSA) after androgen suppression therapy for postoperative or postradiation PSA recurrence and prostate cancer-specific mortality. Cancer 2007;109:1290. Humphreys MR, Miller NL, Handa SE, et al. Holmium laser enucleation of the prostate—outcomes independent of prostate size? J Urol 2008;180:2431. Naspro R, Freschi M, Salonia A, et al. Holmium laser enucleation versus transurethral resection of the prostate. Are histological findings comparable? J Urol 2004;171:1203. Suardi N, Scattoni V, Briganti A, et al. Nerve-sparing radical retropubic prostatectomy in patients previously submitted to holmium laser enucleation of the prostate for bladder outlet obstruction due to benign prostatic enlargement. Eur Urol 2008;53:1180. Devisetty K, Zorn KC, Katz MH, et al. External beam radiation therapy after transurethral resection of the prostate: a report on acute and late genitourinary toxicity. Int J Radiat Oncol Biol Phys 2010;77:1060.
Address correspondence to: Amy E. Krambeck, MD Department of Urology Mayo Clinic 200 1st Southwest Rochester, MN 55905 E-mail: [email protected]
Abbreviations Used ADT ¼ androgen deprivation therapy BPH ¼ benign prostatic hyperplasia GS ¼ Gleason score HoLEP ¼ holmium laser enucleation of the prostate LUTS ¼ lower urinary tract symptoms PCa ¼ prostate cancer PSA ¼ prostate-specific antigen TUR ¼ transurethral resection XRT ¼ external beam radiation therapy
Holmium Laser Enucleation of the Prostate and Perioperative Diagnosis of Prostate Cancer: An Outcomes Analysis Marcelino E. Rivera, MD,1 Igor Frank, MD,1 Boyd R. Viers, MD,1 Laureano J. Rangel,2 and Amy E. Krambeck, MD1
Abstract
Objective: Our objective is to assess the outcomes of patients with prostate cancer (PCa) diagnoses undergoing holmium laser enucleation of the prostate (HoLEP). Methods: From 2009 to 2012, 450 patients underwent HoLEP at our institution. We performed a retrospective review of these patients to identify those with PCa. Results: PCa was diagnosed in 57 (12.7%) HoLEP patients: 11 (19.2%) preoperatively, 43 (75.4%) in the operative specimen, and 3 (5.4%) during follow-up. Mean time to PCa development in the postoperative group was 16 months (9–23). There was no difference in patient characteristics for those diagnosed with PCa at the time of HoLEP or in the postoperative period. There were 5 patients with a Gleason score (GS) > 8 and 52 with GS < 8 PCa. In the operative group, 39 (91%) elected for active surveillance and 4 (9%) elected to have cancer treatment. In subgroup analysis, men diagnosed with GS > 8 intraoperatively or postoperatively had significantly elevated preoperative, postoperative, and percent change prostate-specific antigen (PSA) levels when compared to patients diagnosed GS £ 7 (P = 0.01, 0.02, and 0.01, respectively). There were no complications, all voided spontaneously, and one patient had persistent incontinence. Conclusion: HoLEP for the treatment of lower urinary tract symptoms (LUTS) in selectively chosen men with known PCa can safely improve urination. Furthermore, PCa is diagnosed at the time of or post HoLEP in nearly 12% of patients. Those patients with persistently elevated post HoLEP PSA levels or low percent change PSA levels should raise suspicion for high GS PCa. Finally, HoLEP does not preclude active surveillance or treatment for PCa when appropriate. Introduction
H
olmium laser enucleation of the prostate (HoLEP) has been demonstrated to be an effective and durable transurethral surgery for treatment of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS).1 Incidental prostate cancer (PCa) discovered at the time of HoLEP or standard transurethral resection (TUR) currently remains between 5% and 12%.2,3 Due to the ability of HoLEP to enucleate the vast majority of prostatic tissue, prostate volume and prostate-specific antigen (PSA) levels decrease between 60% and 90% postoperatively.1 Previous investigations have demonstrated that patients diagnosed with incidental PCa at time of HoLEP had significantly higher postoperative PSA levels when compared to the benign groups.4 Additionally, minimal change in PSA after HoLEP has been demonstrated in PCa detected in the postoperative period.5
Patients with preexisting, locally advanced PCa can develop outlet obstruction due to disease progression. While recent data would suggest patients with LUTS and castrateresistant PCa suffer more from detrusor overactivity than bladder outlet obstruction, in patients with outlet obstruction significant relief of symptoms can be obtained through palliative TUR. The reintervention rate is as high as 29%.6,7 When compared to patients with only LUTS related to BPH, patients treated with palliative TUR were not only more likely to require a second procedure, they were also more likely to fail the initial trial of void and require chronic catheterization.7 Concerns regarding TUR and dissemination of localized disease that leads to progression, metastasis, and cancerspecific morality have been evaluated, and mixed conclusions have been drawn regarding whether or not TUR itself plays a role in cancer progression and mortality rates. Several studies have suggested procedure-related disease progression,8,9 while
Departments of 1Urology and 2Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
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Table 1. Preoperative PCa Group Patient Characteristics (N = 11) Mean age (years) Follow-up (months) Mean preoperative PSA (ng/mL) Mean postoperative PSA (ng/mL) Mean prostate volume (mL) Mean GS Enucleation time (min) Morcellation time (min) Resected tissue (g) Peak flow preoperatively (mL/s) Peak flow postoperatively (mL/s) AUA symptom score preoperatively AUA symptom score postoperatively Hospital stay (days) Length of indwelling catheter (days)
74.6 9.6 12.4 5.9 70.6 6.5 40.4 16.1 45.1 9.7 33 21.8 4.5 1.1 1.2
(67–82) (3–31) (0.7–44.2) (0.1–33.1) (34–137) (6–9) (23–63) (2–39) (7.8–110.9) (2–24) (13–49) (9–30) (1–10) (1–2) (1–3)
AUA = American Urological Association; GS = Gleason score; PSA = prostate-specific antigen.
others have concluded no influence of TUR on survival or dissemination of disease.10–12 While TUR has been studied extensively, there is a paucity of information addressing HoLEP in PCa patients who are diagnosed preoperatively, at time of procedure, and postoperatively. Furthermore, few studies have focused on patients with low, intermediate, and high-risk PCa diagnosis after HoLEP. We evaluated all patients treated with HoLEP at our institution who were diagnosed with PCa preoperatively, in the operative specimen, or during follow-up and reviewed their clinical outcomes. Materials and Methods
After obtaining Institutional Review Board approval, we retrospectively analyzed our electronic medical record for all patients between July 2009 and August 2012 with the diagnosis of PCa preoperatively, in the operative pathology specimen, or during follow-up from HoLEP. Clinicopathologic and functional variables were analyzed. All HoLEP procedures were performed by a single surgeon (Amy E. Krambeck). Preoperatively, all patients underwent PSA screening, digital rectal exam, transrectal ultrasound, and standard twelve-core biopsy if indicated based on elevated PSA or abnormal examination.
Patients were placed into groups based on time of PCa diagnosis: before HoLEP (group 1), on the intraoperative specimen (group 2), or in post-HoLEP follow-up (group 3). Patients in groups 2 and 3 were then further stratified based on Gleason score (GS), with GS of 6 indicating low-, 7 intermediate-, and 8–10 high-grade disease.13 Assuming non-normal distribution, median maximum flow (QMax), PSA, and American Urological Association Symptom Score were compared before and after surgery using Kruskal-Wallis test to determine statistical difference (P < 0.05) between groups 2 and 3. After diagnosis of PCa, patients were counseled on different treatment options, including active surveillance, radical prostatectomy, and external beam radiation therapy (XRT). Those patients choosing to undergo active surveillance were monitored with PSA and digital rectal examination every 3 months for the first year and transrectal needle biopsy 12 months after PCa diagnosis when indicated. Upon an abnormal examination or three consecutive rises in PSA, a transrectal-guided needle biopsy was performed. Results
There were 11 patients in group 1, 43 in group 2, and 3 in group 3. Clinical characteristics for the preoperative patients (group 1) are listed in Table 1. In group 1 there were 8 patients with low-grade, 2 with intermediate-grade, and 1 with high-grade disease. Patients were hospitalized for a mean of 1.1 days and had an indwelling catheter for 1.2 days. There were no complications. All patients were voiding at most recent follow-up, with one group 1 patient requiring two pads daily for incontinence. Two patients in group 1 had their GS upgraded on the intraoperative specimen: One from GS 6 to 7, and one from GS 6 to 9. Of these two patients, one patient (GS 7) underwent androgen deprivation therapy (ADT), and the other combined ADT and XRT. Neither patient has evidence of disease progression. There were no significant differences in baseline demographic characteristics between groups 2 and 3 (Table 2). There were 4 high-, 6 intermediate-, and 36 low-grade GS PCas in groups 2 and 3. In group 3, 2 patients had GS upgrading on follow-up biopsy: one from 7 to 8 and the other from 7 to 10. In group 2, 39 (91%) elected for active surveillance and 4 (9%) elected for cancer treatment: 2 combined
Table 2. HoLEP Patient Characteristics Based on Timing of PCa Diagnosis Operative (group 1) (N = 43) Age (years) Preoperative number of biopsies Estimated volume (mL) Resected tissue (g) Resection time (min) Morcellation time (min) Length of stay (days) QMax before diagnosis (mL/s) QMax after diagnosis (mL/s) AUASS before diagnosis AUASS after diagnosis Follow-up (mo)
72.0 0.7 82.0 37.8 38.5 8.5 1.0 7.5 25.0 19.4 7.0 12.8
Postoperative (group 2) (N = 3)
(53.0–89.0) (0.0–5.0) (24.6–210.0) (2.6–166.5) (11.0–98.0) (1.0–63.0) (0–3.0) (0.0–20.0) (3.0–53.0) (3.0–28.0) (1.0–31.0) (3–35)
AUASS = American Urological Association Symptom Score; QMax = maximum flow.
70.0 1.0 113.0 35.1 76.0 25.0 1.0 11.5 22.0
(66.0–73.0) (0.0–2.0) (36.5–113.0) (26.0–197) (60.0–79.0) (4.0–60.0) (0.0–1.0) (11.0–12.0) (9.0–33.0)
9.0 (5.0–14.0) 23 (15–35)
P values 0.449 0.270 0.436 0.409 0.017 0.338 0.468 0.169 0.922 0.357 0.08
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Table 3. HoLEP Patient Characteristics Based on Grade High grade (GS 8–10) (N = 4) Age (years) Preoperative number of biopsies Estimated volume (mL) Resected tissue (g) Resection time (min) Morcellation time (min) Length of stay (days) QMax before diagnosis (mL/s) QMax after diagnosis (mL/s) AUASS before diagnosis AUASS after diagnosis Period of diagnosis operative: postoperative (nos)
70.5 1.0 94.4 40.6 44.5 12.0 1.0 3.0 33.0
(65.0–80.0) (0.0–5.0) (36.0–209.0) (10.0–197.0) (18.0–79.0) (2.0–60.0) (1.0–1.0) (1.0–12.0) (10.9–44.0)
3.5 (2.0–5.0) 3:1
Intermediate grade (GS 7) (N = 6) 72.5 0.5 78.5 39.9 35.5 7.0 1.0 10.0 18.0 25.0 14.0
(59.0–80.0) (0.0–2.0) (36.5–113.0) (2.6–60.0) (16.0–76.0) (2.0–25.0) (0.0–3.0) (8.5–17.0) (9.0–26.0) 5:1
Low grade (GS 6) (N = 36) 72.6 0.0 82.0 34.9 40.0 11.0 1.0 7.0 24.0 21.0 7.0
(53.0–89.0) (0.0–5.0) (24.6–210.0) (4.5–166.5) (11.0–98.0) (1.0–63.0) (0.0–3.0) (0.0–20.0) (3.0–53.0) (3.0–28.0) (1.0–31.0) 35:1
P values 0.841 0.162 0.834 0.904 0.903 0.643 0.633 0.356 0.506 0.271 0.183
AUASS = American Urological Association Symptom Score; GS = Gleason score; QMax = maximum flow.
XRT and ADT, 1 had XRT alone, and 1 had robotic radical prostatectomy followed by ADT and XRT. In group 3, the mean time to cancer diagnosis was 16 months (9–23) with 2 patients electing for treatment: 1 combined ADT with XRT and 1 had ADT alone. All patients were voiding and continent at most recent follow-up. When evaluating groups 2 and 3 based on PCa GS, there was no significant difference between the high-, intermediate-, and low-grade GS groups for multiple baseline characteristics or outcomes (Table 3). In subgroup analysis combining the low- and intermediate-grade PCa patients, men diagnosed with a GS > 8 in either group had significantly elevated postoperative PSA difference and percent change PSA when compared to patients diagnosed with a GS £ 7 (P = 0.01, 0.02, and 0.01, respectively; Table 4). Discussion
HoLEP is an effective and durable transurethral surgery for the treatment of LUTS secondary to BPH.1 To date, patients diagnosed with PCa before HoLEP represent a unique group of patients in whom there is a lack of objective data. The vast majority of PCa patients with LUTS harbor low-grade disease. In patients diagnosed with PCa on active surveillance, with locally advanced disease or those already treated with XRT and ADT, outlet obstruction can occur and cause a significant impact on quality of life. In an effort to improve outlet obstruction, Crain and colleagues7 evaluated palliative TUR in patients with locally
advanced PCa in a retrospective study that compared TUR in patients with BPH and PCa. Patients who underwent TUR had significant improvement in International Prostate Symptom Score from 21 to 11 (P = 0.002); however, urinary flow rates actually decreased from 9.6 to 7.3 mL/s, and 50% of the cohort required either reoperation or long-term catheter drainage.7 This is in significant contrast to our cohort of patients, which had a mean increase in urinary flow from 9.7 to 33 mL/s, and none of whom have required reintervention or catheterization. Also, 67% of the patients in Crain’s study were diagnosed with high-grade GS after TURP, whereas only 18% of our cohort had such diagnosis after HoLEP. In group 1, three patients had a diagnosis of intermediate- or high-grade disease, and the two patients with GS 7 disease both remain on active surveillance protocols. Meanwhile, the patient with high-grade disease preoperatively was treated with cryotherapy, developed a metastatic lesion, and was being treated palliatively for urinary retention due to local tumor overgrowth. Based on our small cohort study, HoLEP appears to treat outlet obstruction in the presence of PCa successfully and safely with a single procedure. While HoLEP can relieve LUTS in patients with preexisting PCa, it is uncertain what effect it has on cancer progression. While there are currently no studies evaluating HoLEP specifically, controversy exists with regards to TURP and its influence on PCa progression. Krupski and colleagues discusses the relationship between palliative TURP and disease progression using data from the Surveillance Epidemiology, and End Results registry.14 The authors evaluated
Table 4. PSA Characteristics Based on Grade High grade (GS 8–10) (N = 4) Age (years) Preoperative PSA (ng/mL) Postoperative PSA (ng/mL) PSA difference (ng/mL) Percent change PSA ( · 100) Estimated volume (mL)
71.5 31.5 31.8 - 0.2 0.0 108.5
(65.0–80.0) (1.0–110.0) (1.1–113.0) ( - 3.0 to 4.1) ( - 0.6 to 0.2) (36.0–209.0)
GS = Gleason score; PSA = prostate-specific antigen.
Combined intermediate and low grades (GS 6–7) (N = 42) 72.4 5.9 1.2 5.0 - 0.7 86.3
(53.0–89.0) (0.5–25.0) (0.1–5.5) ( - 1.1 to 23.2) ( - 1.0 to 0.8) (24.6–210.0)
P values 0.710 0.299 0.010 0.023 0.013 0.626
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men who underwent TURP within 3 months of PCa diagnosis and found in multivariate analysis that patients who underwent TURP had significantly higher risk of mortality hazard ratio (HR) 1.26 (1.17–1.35) when compared to those who did not. While this was an observational, database-driven study able to determine association, not causation, it nonetheless raises the question as to whether palliative TURP increases the risk of PCa-specific mortality. Clearly, further prospective trials are warranted. While our follow-up is limited, there have been no PCa-specific mortalities in our cohort. When evaluating our patients diagnosed with PCa at time of HoLEP and postoperatively, several unique observations can be made. Previous evaluations of TURP and open surgery have demonstrated a significant difference in PSA kinetics between patients with benign disease and PCa tissue in the specimen.4,5 While we did not directly evaluate the nadir of PSA levels in a separate cohort of patients with benign disease, previous literature would suggest that when evaluating HoLEP specifically, in benign cases PSA levels have been found to decrease by more than 80%, with direct correlation between percent change PSA and the amount of tissue removed.15 In our study, in patients with low GS PCa, the percent decrease in PSA was very similar to that of benign cases, with a mean decrease of 70% after HoLEP. Intermediate GS had a mean decrease of 50%, and in our group of high GS patients there was a mean 0% change in PSA postoperatively. Absolute PSA value after HoLEP appears to also be predictive of high-grade disease, with low- and intermediategrade groups having a significantly lower PSA postoperative value. In the oncology literature PSA nadir after definitive and adjuvant therapy for PCa is used routinely to determine the likelihood of cancer progression and cancer-specific mortality.16 Unfortunately the use of PSA nadir after other transurethral surgeries is variable, which has made surveillance of individuals diagnosed with low-grade incidental PCa at time of TUR difficult, as there is no way to predict those with and without high-risk disease.3,4 HoLEP has proven to be a durable therapy and PSA reduction remains consistent in follow-up, thus making surveillance more reliable in patients who are candidates for an active surveillance protocol.5,17 Tissue quality after resection has also been investigated and compared with standard TURP by Naspro and associates.18 They performed a prospective histologic evaluation of 80 consecutive patients undergoing TURP or HoLEP, in which HoLEP cases demonstrated a significantly larger amount of resected tissue with preservation of prostatic tissue morphology in the majority of the specimen. Tissue damage was induced in a similar fashion as TURP, via coagulation necrosis, and even though the tissue was altered the authors concluded that HoLEP specimens could be adequately evaluated by pathologists and the diagnoses of incidental PCa detected. Patients diagnosed with PCa at the time of HoLEP are candidates for curative therapy, including open and robotic prostatectomy or XRT. Suardi and colleagues19 evaluated outcomes in patients undergoing nerve-sparing radical retropubic prostatectomy after HoLEP. Cases were matched 1 to 1 in a retrospective fashion to patients who had undergone TUR or simple prostatectomy. Functional outcomes were evaluated among the three groups and no statistically sig-
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nificant differences were found with regard to postoperative complications, rate of incontinence, or erectile dysfunction. Patients who underwent HoLEP did have significantly lower positive margin rates. While there is a lack of literature on XRT after HoLEP, XRT after TUR did appear to increase the risk of grade 3, toxicity including severe LUTS requiring intervention.20 In our series, all patients did functionally well and the incidental diagnosis of PCa did not alter clinical outcomes. Such clinical results have been replicated by other series as well as the rate of incidentally diagnosed PCa after transurethral surgery, between 5% and12%.2,5,9 Even those patients going on to receive XRT, radical prostatectomy, or ADT did not develop urinary incontinence, stricture, bladder neck contracture, or retention. Outcomes did not appear to differ based on when the PCa was diagnosed. Those diagnosed post HoLEP reported similar outcomes to those diagnosed at time of HoLEP. Limitations of this study are its retrospective nature, relatively small numbers of patients with high-grade disease, and a large variation in PSA among patients. While our values were significant between preoperative and postoperative PSA, a larger number of patients would add significant power to the data, particularly with regard to patients with high GS. Our classification of PCa based solely on GS and not using other well-known risk stratification systems was twofold: All patients had clinical T1a or T1b disease, and several of these patients had elevated PSA levels due to BPH but would have been stratified into intermediate- or high-risk groups as prostatic volume is not considered. Follow-up was limited to date and thus warrants further prospective evaluation regarding clinical and oncologic outcomes. Conclusion
PCa is common and can be diagnosed before, during, and after surgical intervention for LUTS. We found that HoLEP in selectively chosen men with known PCa can improve urination without an increase in complications. Furthermore, diagnosis of PCa at time of surgery or in the postoperative period occurs in 12% of patients. A finding of persistently elevated post-HoLEP PSA or low percent change PSA should raise suspicion for high GS PCa. We propose that if the reduction of PSA after HoLEP is negligible, these patients should be evaluated for malignancy and high-grade disease should be suspected. Additionally, HoLEP does not preclude active surveillance or definitive therapy when appropriate in PCa patients. Disclosure Statement
Igor Frank is a consultant for Rochester Medical, and Amy Krambeck is a consultant for Histosonics, a data safety monitoring board. No competing financial interests exist for the other authors. References
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3. Melchior S, Hadaschik B, Thuroff S, et al. Outcome of radical prostatectomy for incidental carcinoma of the prostate. BJU Int 2009;103:1478. 4. Helfand BT, Anderson CB, Fought A, et al. Postoperative PSA and PSA velocity identify presence of prostate cancer after various surgical interventions for benign prostatic hyperplasia. Urology 2009;74:177. 5. Elmansy HM, Elzayat EA, Sampalis JS, et al. Prostaticspecific antigen velocity after holmium laser enucleation of the prostate: Possible predictor for the assessment of treatment effect durability for benign prostatic hyperplasia and detection of malignancy. Urology 2009;74:1105. 6. Rom M, Waldert M, Schatzl G, et al. Bladder outlet obstruction in men with castration-resistant prostate cancer. BJU Int 2013 [epub ahead of print] 7. Crain DS, Amling CL, Kane CJ. Palliative transurethral prostate resection for bladder outlet obstruction in patients with locally advanced prostate cancer. J Urol 2004;171:668. 8. Hanks GE, Leibel S, Kramer S. The dissemination of cancer by transurethral resection of locally advanced prostate cancer. J Urol 1983;129:309. 9. Forman JD, Order SE, Zinreich ES, et al. The correlation of pretreatment transurethral resection of prostatic cancer with tumor dissemination and disease-free survival. A univariate and multivariate analysis. Cancer 1986;58:1770. 10. Kuban DA, el-Mahdi AM, Schellhammer PF, et al. The effect of transurethral prostatic resection on the incidence of osseous prostatic metastasis. Cancer 1985;56:961. 11. Pansadoro V, Sternberg CN, DePaula F, et al. Transurethral resection of the prostate and metastatic prostate cancer. Cancer 1991;68:1895. 12. Anscher MS, Prosnitz LR. Transurethral resection of prostate prior to definitive irradiation for prostate cancer. Lack of correlation with treatment outcome. Urology 1991;38:206. 13. Mohler JL, Armstrong AJ, Bahnson RR, et al. Prostate cancer, featured updates to the NCCN guidelines. Version 3.2012. J Natl Compr Cancer Net 2012;10:1081. 14. Krupski TL, Stukenborg GJ, Moon K, et al. The relationship of palliative transurethral resection of the prostate with disease progression in patients with prostate cancer. BJU Int 2010;106:1477. 15. Tinmouth WW, Habib E, Kim SC, et al. Change in serum prostate specific antigen concentration after holmium laser
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Address correspondence to: Amy E. Krambeck, MD Department of Urology Mayo Clinic 200 1st Southwest Rochester, MN 55905 E-mail: [email protected]
Abbreviations Used ADT ¼ androgen deprivation therapy BPH ¼ benign prostatic hyperplasia GS ¼ Gleason score HoLEP ¼ holmium laser enucleation of the prostate LUTS ¼ lower urinary tract symptoms PCa ¼ prostate cancer PSA ¼ prostate-specific antigen TUR ¼ transurethral resection XRT ¼ external beam radiation therapy
