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Lymphovascular invasion, ureteral reimplantation and prior history of urothelial carcinoma are associated with poor prognosis after partial cystectomy for muscle-invasive bladder cancer with negative pelvic lymph nodes
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ScienceDirect EJSO 39 (2013) 1150e1156
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Lymphovascular invasion, ureteral reimplantation and prior history of urothelial carcinoma are associated with poor prognosis after partial cystectomy for muscle-invasive bladder cancer with negative pelvic lymph nodes B. Ma a, H. Li b, C. Zhang a, K. Yang b, B. Qiao a, Z. Zhang a, Y. Xu a,* a
Department of Urologic Surgery, Tianjin Medical University Second Hospital, Tianjin, China b Tianjin Urologic Institute, Tianjin, China Accepted 25 April 2013 Available online 27 May 2013
Abstract Purpose: To identify predictive factors underlying recurrence and survival after partial cystectomy for pelvic lymph node-negative muscleinvasive bladder cancer (MIBC) (urothelial carcinoma) and to report the results of partial cystectomy among select patients. Methods: We retrospectively reviewed 101 cases that received partial cystectomy for MIBC (pT2-3N0M0) between 2000 and 2010. The logrank test and a Cox regression analyses were performed to identify factors that were predictive of recurrence and survival. Results: With a median follow-up of 53.0 months (range 9e120), the 5-year overall survival (OS), cancer-specific survival (CSS) and recurrence-free survival (RFS) rates were 58%, 65% and 50%, respectively. A total of 33 patients died of bladder cancer and 52 patients survived with intact bladder. Of the 101 patients included, 55 had no recurrence, 12 had non-muscle-invasive recurrence in the bladder that was treated successfully, and 34 had recurrence with advanced disease. The multivariate analysis showed that prior history of urothelial carcinoma (PH.UC) was associated with both CSS and RFS and weakly associated with OS; lymphovascular invasion (LVI) and ureteral reimplantation (UR) were associated with OS, CSS and RFS. Conclusions: Among patients with pelvic lymph node-negative MIBC, PH.UC and UR should be considered as contraindications for partial cystectomy, and LVI is predictive of poor outcomes after partial cystectomy. Highly selective partial cystectomy is a rational alternative to radical cystectomy for the treatment of MIBC with negative pelvic lymph nodes. Ó 2013 Elsevier Ltd. All rights reserved. Keywords: Muscle-invasive bladder cancer; Partial cystectomy; Lymphovascular invasion; Ureteral reimplantation; Outcome
Introduction Radical cystectomy is a good option for cancer control of muscle-invasive bladder cancer (MIBC), but it may not preserve patient quality of life as well as bladder-sparing procedures.1 Historically, partial cystectomy was criticized as having an unacceptable recurrence rate (partially due to varied patient selection and treatments). However, this criticism did not consider its advantages, namely that it is a bladder-sparing procedure that permits pathological nodal staging by lymphadenectomy, allows complete tumor
* Corresponding author. Department of Urologic Surgery, Tianjin Medical University Second Hospital, 23 Pingjiang Road, Hexi District, Tianjin 300211, China. Tel.: þ86 022 88326723; fax: þ86 022 28273211. E-mail address: [email protected] (Y. Xu). 0748-7983/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejso.2013.04.006
excision with wide surgical margins and preserves sexual function. Recently, partial cystectomy-based multimodality treatment among select patients has resulted in ideal cancer control,2e6 and one of the latest matched case-control analysis showed that partial cystectomy can achieve cancer control comparable to radical cystectomy in properly selected patients with urothelial carcinoma of the urinary bladder.7 Obtaining acceptable cancer control while maintaining good quality of life among select patients is the definitive goal of partial cystectomy for MIBC. Nevertheless, data regarding partial cystectomy remain limited and prognostic factors affecting recurrence and survival have not been properly identified and evaluated in these selected patients. Therefore, this study aimed to fill this gap in knowledge. We retrospectively reviewed our 10-year singleinstitutional experience of partial cystectomy among
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selected patients and identified several factors affecting recurrence and survival after partial cystectomy.
incision, the operating field was soaked with distilled water for 10e15 min to prevent tumor implantation.
Materials and methods
Histopathological evaluation
Patient selection
T stage was determined using the 2002 American Joint Committee on Cancer TNM staging system and histological grade was determined using the WHO staging system. Routine lymphovascular invasion (LVI) evaluations were performed. LVI was considered present only when tumor cells were unequivocally noted within or attached to the wall of a vascular or lymphatic space in hematoxylinand eosin-stained sections. Multiple serial sections were used in equivocal cases and in cases of aggressive tumors. Two independent uropathologists reviewed the hematoxylin- and eosin-stained slides.
Upon cystoscopy, patients meeting the criteria of limited tumors (3 or less) within the bladder that were unlikely to be non-muscle invasive and amenable to trans-urethral resection (TUR); no involvement of the trigone, bladder neck or urethra and with no concomitant carcinoma in situ on random biopsy were considered preliminary candidates for partial cystectomy. Computed tomography (CT) of the pelvis and chest X-ray were performed, and patients with involvement of adjacent organs (T4), obvious pelvic lymph node involvement or distant metastasis were excluded. Clinical staging was based on the growth pattern of the tumor, CT and chest x-ray findings and TUR of the index tumors, if necessary. Tumors located near the ureteral orifice that require ureteral reimplantation (UR) were not excluded from PC, whereas solitary cT2 or cT3 tumors were strong candidates for partial cystectomy. Patients with clinical MIBC who fulfilled the inclusion criteria abovementioned were presented with the options of radical cystectomy and partial cystectomy and were fully informed of the advantages and disadvantages of both modalities; written informed consent was obtained from each patient. The treatment protocol was approved by the ethics committee of our institution. From 2000 to 2010, 144 selected patients who preferred partial cystectomy over radical cystectomy or who were surgically unsuitable for radical cystectomy underwent partial cystectomy for MIBC. Of these patients, 43 were excluded from this study cohort: 10 were lost to follow up, 11 had non-urothelial carcinoma, 15 had clinically “muscle-invasive” but pathologically non-muscle-invasive bladder cancer, and 7 had positive lymph node pathology (explained in the Supplementary materials). Thus 101 patients with MIBC (urothelial carcinoma) without pelvic lymph node involvement were available for analysis. Surgical technique A lower abdominal incision was made and lymphadenectomy was performed in a standard fashion, the surrounding organs and wound were well packed before incision into the bladder. The body of the tumor was held by a spoon-shaped clamp upon opening of the bladder and partial cystectomy was performed with a 2-cm tumor-free margin. UR was performed if the lesion was within 2 cm lateral to the ureteral orifice. For concomitant non-muscle-invasive tumors, aggressive resections were performed to reach the deep muscle layers at the time of partial cystectomy, and the base of the resection was evaluated histologically by frozen section. Before closing the
Adjuvant therapy For patients with pT3N0M0, systemic chemotherapy employing methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) or gemcitabine and cisplatin (GC) was initiated within 2 weeks after partial cystectomy based on published protocols.8 Sixteen patients received the MVAC regimen, 13 patients received the GC regimen and 3 patients could not receive chemotherapy due to severe renal insufficiency. Cisplatin was replaced by carboplatin for patients with impaired renal function. All patients underwent intravesical therapy after partial cystectomy. Intravesical therapy consisted of 6 weekly doses followed by 12 monthly doses of therarubicin or mitomycin C, starting within 2 weeks after partial cystectomy. Follow-up protocol Surveillance cystoscopy and urinary cytology were conducted at 3-month intervals within the first 2 years, at 6month intervals within the next 3 years and annually thereafter. Generally, pelvic computed tomography and chest radiography were conducted at 6- to 12-month intervals. Intravenous urography (IVU) was performed if necessary. Patient clinical and pathological data were retrieved from their charts, and follow-up information was collected at outpatient visits or via phone interviews. The endpoints were overall survival (OS), cancer-specific survival (CSS) and recurrence-free survival (RFS). Recurrence was defined as non-muscle invasive (CIS, Ta or T1 tumors) or advanced (recurrence of muscle-invasive urothelial carcinoma, or development of pelvic or distant metastasis). The recurrence-free interval (RFI) was defined as the time from surgery to pathologically confirmed recurrence. Statistical analysis The log-rank test was used to compare OS, CSS and RFS between groups. A KaplaneMeier analysis was
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performed to assess OS and CSS, which were calculated from the date of partial cystectomy to the date of death or last known follow-up, and RFS, which was calculated from the date of partial cystectomy to the date of first detectable recurrence or last follow-up. For the analysis of OS, death was counted as event. For the analysis of CSS, only cancer-specific death was counted as event. For the analysis of RFS, death and the earliest recurrence, whether non-muscle-invasive or advanced, were counted as events. Cox’s proportional hazards regression model was then used to test the statistical significance of several potential prognostic factors for OS, CSS and RFS. All potential prognostic factors with p < 0.10 from the log-rank test were then included in a saturated model and backward elimination was used to remove factors from the model based on the likelihood ratio test in the multiple regression analysis. P < 0.05 was considered significant, and all p values reported are two sided. All statistical analyses were performed using SPSS for Windows, version 17.0 (SPSS, Inc., Chicago, IL). Results The study population consisted of 83 men and 18 women with a median age of 69.0 years (mean 65.8 12.2, range 24e84). Table 1 lists the clinical and pathological characteristics of the patients.
No positive margin was reported in the final pathologic examination, no wound recurrence occurred and no patient suffered from insufficient bladder capacity. Several male patients underwent transurethral resection of the prostate (TURP) for bladder outlet obstruction caused by benign prostatic hyperplasia (BPH) during follow-up. A total of 25 patients completed chemotherapy, 4 patients withdrew due to an inability to tolerate the side effects of chemotherapy, and 3 patients did not receive chemotherapy due to severe renal insufficiency. Survival after partial cystectomy With a median follow-up of 53.0 months (range 9e120), the 5-year overall survival (OS), cancer-specific survival (CSS) and recurrence-free survival (RFS) rates were 58%, 65% and 50%, respectively (Fig. 1). The log-rank test results of differences in 5-year survival rates between subgroups stratified by the evaluated variables are shown in Table 2. KaplaneMeier curves for OS, CSS and RFS stratified by LVI and UR are shown in Fig. 2. At the end of the follow-up period, 33 patients died of bladder cancer with a median survival time of 23.0 months (range 9e73), 52 patients had survived with intact bladder with a median follow-up time of 79.0 months (range 24e120). Recurrences after partial cystectomy
Table 1 Clinical and pathologic characteristics of 101 patients with MIBC. Variables Gender Male Female Age <65 y 65 y Prior history of urothelial carcinoma (PH.UC) Yes No Multicentricity Single Multiple Tumor size <3 cm 3 cm Grade High (Grade 3) Low (Grade 1 or 2) Pathological stage pT2 pT3 Lymphovascular invasion (LVI) Yes No Ureteral reimplantation (UR) Yes No
No. Pts 83 18 37 64 11 90 81 20 35 66 78 23 69 32 25 76 21 80
With a median follow-up time of 53.0 months (range 9e120), 46 patients had recurrence with a median recurrence free interval (RFI) of 14.0 months (range 2e99). Twelve patients had non-muscle-invasive recurrence with a median RFI of 27.0 months (range 5e99). Of the 12 patients who had non-muscle-invasive recurrence, 8 were treated successfully with transurethral resection of the bladder tumor (TURBT) and demonstrated a high survival rate within a median follow-up time of 87.5 months (range 29e103) after partial cystectomy; the remaining 4 had late recurrence of MIBC, and 3 of them died of bladder cancer within a median follow-up time of 13.0 months (range 11e16) after late muscle-invasive recurrence. Thirty-four patients had advanced recurrence with a median RFI of 10.5 months (range 2e40). Of these 34 patients, 27 had muscle-invasive recurrence only, 3 had muscle-invasive recurrence with concomitant lymph node metastasis, 2 had muscle-invasive recurrence with concomitant distant metastasis and 2 had distant metastasis only. The 4 patients with distant metastases underwent palliative chemotherapy, but all died of bladder cancer within 6 months after advanced recurrence. Twenty-three patients with local muscle-invasive recurrence, including the 3 patients with concomitant pelvic lymph node recurrence, underwent TURBT and/or chemoradiotherapy, and 22 of them died of bladder cancer with a median follow-up
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Potential prognostic factors underlying recurrence and survival Eleven patients with PH.UC were included in this cohort and 9 of these patients developed recurrences with a median RFI of 10.0 months (range 5e40). PH.UC was associated with both CSS (HR 3.235, CI 1.211e8.644, p ¼ 0.019) and RFS (HR 2.713, CI 1.231e5.978, p ¼ 0.013), and was weakly associated with OS ( p ¼ 0.064). LVI was identified in 25 cases, and LVI was more prevalent among cancers with higher pathological stage (19% of pT2 vs 38% of pT3, p ¼ 0.043, chi-square test). Seventeen of the 25 patients with LVI experienced recurrences with a median RFI of 12.0 months (range 5e40). LVI was associated with OS (HR 2.902, CI 1.515e5.559, p ¼ 0.001), CSS (HR 3.010, CI 1.386e6.538, p ¼ 0.005) and RFS (HR 2.055, CI 1.121e3.765, p ¼ 0.020). UR was performed in 21 cases, and 15 of these patients experienced recurrences with a median RFI of 14 months (range 2e35). UR was associated with OS (HR 3.465, CI 1.813e6.625, p < 0.001), CSS (HR 3.756, CI 1.768e7.976, p ¼ 0.001) and RFS (HR 3.044, CI 1.680e5.517, p < 0.001) (Table 3). Age was associated with OS (HR 2.189, CI 1.080e4.438, p ¼ 0.030) but was not associated with CSS or RFS. Although multiple tumors and tumors with higher pathological stage (pT3) showed a trend toward decreased survival compared to single and lower staged tumors (pT2), respectively (Table 2), the difference was not as significant as expected. Tumor multicentricity and pathological stage were not associated with survival. Grade was also not associated with survival (Table 3). Discussion
Figure 1. KaplaneMeier curves of OS, CSS and RFS in 101 patients after partial cystectomy. OS, overall survival; CSS, cancer-specific survival; RFS, recurrence-free survival.
Partial cystectomy is typically performed as a definitive treatment with curative intent. It is occasionally performed as either a therapeutic intervention for tumors that are not amenable to complete TUR or even as a palliative procedure for patients who are not suitable candidates for radical cystectomy.9 The advantages of partial cystectomy compared to radical cystectomy include preservation of a functioning urinary reservoir and improved potency in male patients. In addition, with partial cystectomy perioperative morbidity and postoperative complications are minimal compared with radical cystectomy plus urinary diversion or bladder reconstruction.10 Thus, partial cystectomy is an attractive option for select patients with MIBC. Risk factors associated with recurrence and survival
time of 6.0 months (range 3e33) after muscle-invasive recurrence. Ten patients underwent delayed cystectomy and 7 of them died of bladder cancer with a median survival time of 16.0 months (range9e47) after cystectomy.
The ideal indications for partial cystectomy were limited to solitary, primary tumors located at the dome of the bladder without concomitant CIS.11 Tumors located near or at the ureteral orifice that require UR have been excluded from partial cystectomy by some urologists.3 However, prior to this
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Table 2 Log-rank test of variables affecting OS, CSS and RFS. OS
Gender (male vs female) Age (<65 vs 65) PH.UC (yes vs no) Multicentricity (Single vs multiple) Tumor size: (<3 cm vs 3 cm) Tumor grade (Grade 3 vs 1or 2) Pathological stage (pT2 vs pT3) LVI (yes vs no) UR (yes vs no)
CSS
RFS
5-Year OS (%)
p Value
5-Year CSS (%)
p Value
5-Year RFS (%)
p Value
61 67 32 61 67 56 63 29 33
0.373 0.059 0.124 0.480 0.224 0.445 0.053 <0.001 0.001
67 77 40 69 74 59 68 37 37
0.711 0.199 0.069 0.325 0.569 0.091 0.184 0.001 0.001
52 50 18 56 54 44 55 31 22
0.508 0.330 0.024 0.045 0.267 0.883 0.231 0.011 <0.001
vs 48 vs 53 vs 61 vs48 vs 53 vs 63 vs 46 vs 68 vs 65
vs 58 vs 57 vs 67 vs52 vs 59 vs 82 vs 58 vs 73 vs 72
vs vs vs vs vs vs vs vs vs
43 50 54 28 48 52 40 56 57
PH.UC, prior history of urothelial carcinoma; LVI, lymphovascular invasion; UR, ureteral reimplantation; OS, overall survival; CSS, cancer-specific survival; RFS, recurrence-free survival.
report, there was no indication that UR would compromise the oncological outcome after partial cystectomy. On the contrary, Zhang et al.5 reported that UR was protective in partial cystectomy. In our series partial cystectomy plus UR was performed in 20% of patients with MIBC, but UR was associated with poor prognosis after partial cystectomy (Table 3). We attribute this to the fact that it is difficult to maintain a sufficiently wide surgical margin around a tumor that is located near the ureteral orifice while avoiding injury to the contralateral ureteral orifice. Furthermore, in cases where muscle-invasive recurrence occurred and delayed radical cystectomy was needed, prior dissection around the ureteral orifice made this procedure much more difficult, increasing the risk of positive surgical margin. The major limitation of partial cystectomy is the risk of recurrence. The reported local recurrence rates following partial cystectomy ranged between 38% and 78%,11 varying significantly among published series due to varied patient selection. It is not surprising that patients with a prior history of urothelial carcinoma (PH.UC) would be much more likely to develop another recurrence after bladder-sparing therapy. In the present study, PH.UC was associated with both CSS and RFS .This result was somewhat consistent with the results of a study from the M.D. Anderson Cancer Center in which patients with PH.UC had higher recurrence rates and lower survival rates compared with those with primary bladder cancer.3 Most patients with non-muscle-invasive recurrence survived, whereas most patients with advanced recurrence died of bladder cancer even after cystectomy. This finding is consistent with most recent reports on partial cystectomy, but the absolute survival rate after delayed cystectomy varied among studies due to patient selection, patient compliance, adjuvant treatment, and the length of follow-up after cystectomy.2e5,12 Notably, 4 of the 12 patients who experienced non-muscle-invasive recurrence developed late muscleinvasive recurrence emphasizing the importance of lifetime surveillance after partial cystectomy. LVI has been reported to be associated with poor prognosis after TURBT or radical cystectomy for
urothelial carcinoma of the bladder, but fewer reports have shown the prognostic value of LVI after partial cystectomy.13,14 In the present series, LVI was associated with OS, CSS and RFS. Moreover, LVI was more prevalent among cancers with a higher pathological stage (p ¼ 0.043). The role of LVI in this cohort was fully consistent with the results of another multicenter retrospective study of radical cystectomy. In that study, LVI was an independent predictor of survival after radical cystectomy in node-negative patients but not in node-positive patients, and the prevalence of LVI increased with increasing pathologic stage.15 In a multicenter study, patient age was shown to be associated with overall and cancer-specific mortality after radical cystectomy.16 In that study, higher age was associated with higher pathological stage, higher tumor grade, the prevalence of LVI and positive soft-tissue surgical margin status. In the present series, age was associated with OS ( p ¼ 0.030) but not with CSS or RFS (Table 2). This result was reasonable because elderly patients had higher rates of non-cancer-specific death and a higher rate of LVI (28% vs 19%), which are both associated with poor prognosis. Thus, our findings are somewhat consistent with those of the multicenter study. Comparison with radical cystectomy The 5-year OS, CSS and RFS were 58%, 65% and 50%, respectively. Considering that all the cases included in this series were pelvic lymph node-negative, this survival rate was lower than those of the RC series. However, we tend to believe that it was the result of patient selection as well as the cost of bladder sparing. In the present series, 11 patients with PH.UC and 21 patients who required UR were included, and both PH.UC and UR were associated with poor prognosis. Therefore a relatively low survival rate could be expected. Interestingly, when patients with PH.UC and UR were considered as contraindications for partial cystectomy and excluded from this cohort, the 5-
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Figure 2. KaplaneMeier curves of OS, CSS and RFS in 101 patients after partial cystectomy, stratified by LVI and UR status. LVI, lymphovascular invasion; UR, ureteral reimplantation; OS, overall survival; CSS, cancer-specific survival; RFS, recurrence-free survival.
year OS, CSS and RFS increased to 70%, 77% and 63%, respectively, achieving results comparable to those of larger scale radical cystectomy series.17,18 In other words, one cannot expect better oncological results with partial cystectomy than radical cystectomy, but for properly selected cases, partial cystectomy can achieve comparable oncological results with radical cystectomy.
Limitations of this study Although we achieved acceptable results, this study still has some limitations. This study was retrospective in nature, the partial cystectomy surgeries were performed by different surgeons, and several different adjuvant chemotherapy regimens were used (although a randomized
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Table 3 Cox regression analysis of variables that predict OS, CSS and RFS. Variables
OS HR(95% CI)
Age PH.UC Multicentricity Grade pStage LVI UR
2.189(1.080e4.438) 2.311(0.953e5.607) Not significant Not significant Not significant 2.902(1.515e5.559) 3.465(1.813e6.625)
CSS p Value 0.030 0.064
0.001 <0.001
RFS
HR(95% CI)
p Value
Not significant 3.235(1.211e8.644) Not significant Not significant Not significant 3.010(1.386e6.538) 3.756(1.768e7.976)
0.019
0.005 0.001
HR(95% CI) Not significant 2.713(1.231e5.978) Not significant Not significant Not significant 2.055(1.121e3.765) 3.044(1.680e5.517)
p Value 0.013
0.020 <0.001
PH.UC, prior history of urothelial carcinoma; LVI, lymphovascular invasion; UR, ureteral reimplantation; OS, overall survival; CSS, cancer-specific survival; RFS, recurrence-free survival.
control trial has shown similar long-term results for MVAC and GC regimens in an adjuvant setting in the treatment of locally advanced MIBC19).
7.
Conclusions Among patients with pelvic lymph node-negative MIBC, PH.UC and UR should be considered contraindications for partial cystectomy, and LVI predicts poor outcomes after partial cystectomy. Highly selective partial cystectomy is a rational alternative to radical cystectomy for pelvic lymph node-negative MIBC.
8.
9.
Appendix A. Supplementary data
10.
Supplementary data related to this article can be found online at http://dx.doi.org/10.1016/j.ejso.2013.04.006.
11. 12.
Conflict of interest 13.
The authors declare that they have no conflict of interest.
References 1. Gontero PFF, Kocjancic E, Frea B, Tizzani A. Male and female sexual dysfunction (SD) after radical pelvic urological surgery. ScientificWorldJournal 2006;6:2302–14. 2. Holzbeierlein JM, Lopez-Corona E, Bochner BH, et al. Partial cystectomy: a contemporary review of the Memorial Sloan-Kettering Cancer Center experience and recommendations for patient selection. The Journal of Urology 2004;172:878–81. 3. Kassouf W, Swanson D, Kamat AM, et al. Partial cystectomy for muscle invasive urothelial carcinoma of the bladder: a contemporary review of the M. D. Anderson Cancer Center experience. The Journal of Urology 2006;175:2058–62. 4. Smaldone MC, Jacobs BL, Smaldone AM, Hrebinko Jr RL. Long-term results of selective partial cystectomy for invasive urothelial bladder carcinoma. Urology 2008;72:613–6. 5. Zhang M, Tao R, Zhang C, Shen Z. Lymphovascular invasion and the presence of more than three tumors are associated with poor outcomes of muscle-invasive bladder cancer after bladder-conserving therapies. Urology 2010;76:902–7. 6. Koga FKK, Yoshida S, Yokoyama M, et al. Selective bladder-sparing protocol consisting of induction low-dose chemoradiotherapy plus
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partial cystectomy with pelvic lymph node dissection against muscle-invasive bladder cancer: oncological outcomes of the initial 46 patients. BJU International 2012;109:860–6. Knoedler JJ, Boorjian SA, Kim SP, et al. Does partial cystectomy compromise oncologic outcomes for patients with bladder cancer compared to radical cystectomy? A matched case-control analysis. The Journal of Urology 2012;188:1115–9. von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. Journal of Clinical Oncology 2000;18:3068–77. Solsona E, Iborra I, Ricos JV, Monros JL, Casanova J, Calabuig C. Feasibility of transurethral resection for muscle infiltrating carcinoma of the bladder: long-term followup of a prospective study. The Journal of Urology 1998;159:95–9. Laufer. Transurethral resection and partial cystectomy for invasive bladder cancer. Seminars in Urologic Oncology 2000;18:296–9. Sweeney PKE, Resnik MI. Partial cystectomy. Urologic Clinics of North America 1992;19:701–11. Bruins HM, Wopat R, Mitra AP, et al. Long-term outcomes of salvage radical cystectomy for recurrent urothelial carcinoma of the bladder following partial cystectomy. BJU International 2013;111:E37–42. Cho KSSH, Joung JY, Park WS, et al. Lymphovascular invasion in transurethral resection specimens as predictor of progression and metastasis in patients with newly diagnosed T1 bladder urothelial cancer. Journal of Urology 2009;182:2625–30. Bolenz C, Herrmann E, Bastian PJ, et al. Lymphovascular invasion is an independent predictor of oncological outcomes in patients with lymph node-negative urothelial bladder cancer treated by radical cystectomy: a multicentre validation trial. BJU International 2010;106:493–9. Lotan YGA, Shariat SF, Palapattu GS, et al. Lymphovascular invasion is independently associated with overall survival, cause-specific survival, and local and distant recurrence in patients with negative lymph nodes at radical cystectomy. Journal of Clinical Oncology 2005;23: 6533–9. Chromecki T, Mauermann J, Cha EK, et al. Multicenter validation of the prognostic value of patient age in patients treated with radical cystectomy. World Journal of Urology 2012;30:753–9. Stein JPLG, Cote R, Groshen S, et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. Journal of Clinical Oncology 2001;19:666–75. Madersbacher S, Hochreiter W, Burkhard F, et al. Radical cystectomy for bladder cancer todayda homogeneous series without neoadjuvant therapy. Journal of Clinical Oncology 2003;21:690–6. von der Maase H, Sengelov L, Roberts JT, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. Journal of Clinical Oncology 2005;23: 4602–8.
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Lymphovascular invasion, ureteral reimplantation and prior history of urothelial carcinoma are associated with poor prognosis after partial cystectomy for muscle-invasive bladder cancer with negative pelvic lymph nodes B. Ma a, H. Li b, C. Zhang a, K. Yang b, B. Qiao a, Z. Zhang a, Y. Xu a,* a
Department of Urologic Surgery, Tianjin Medical University Second Hospital, Tianjin, China b Tianjin Urologic Institute, Tianjin, China Accepted 25 April 2013 Available online 27 May 2013
Abstract Purpose: To identify predictive factors underlying recurrence and survival after partial cystectomy for pelvic lymph node-negative muscleinvasive bladder cancer (MIBC) (urothelial carcinoma) and to report the results of partial cystectomy among select patients. Methods: We retrospectively reviewed 101 cases that received partial cystectomy for MIBC (pT2-3N0M0) between 2000 and 2010. The logrank test and a Cox regression analyses were performed to identify factors that were predictive of recurrence and survival. Results: With a median follow-up of 53.0 months (range 9e120), the 5-year overall survival (OS), cancer-specific survival (CSS) and recurrence-free survival (RFS) rates were 58%, 65% and 50%, respectively. A total of 33 patients died of bladder cancer and 52 patients survived with intact bladder. Of the 101 patients included, 55 had no recurrence, 12 had non-muscle-invasive recurrence in the bladder that was treated successfully, and 34 had recurrence with advanced disease. The multivariate analysis showed that prior history of urothelial carcinoma (PH.UC) was associated with both CSS and RFS and weakly associated with OS; lymphovascular invasion (LVI) and ureteral reimplantation (UR) were associated with OS, CSS and RFS. Conclusions: Among patients with pelvic lymph node-negative MIBC, PH.UC and UR should be considered as contraindications for partial cystectomy, and LVI is predictive of poor outcomes after partial cystectomy. Highly selective partial cystectomy is a rational alternative to radical cystectomy for the treatment of MIBC with negative pelvic lymph nodes. Ó 2013 Elsevier Ltd. All rights reserved. Keywords: Muscle-invasive bladder cancer; Partial cystectomy; Lymphovascular invasion; Ureteral reimplantation; Outcome
Introduction Radical cystectomy is a good option for cancer control of muscle-invasive bladder cancer (MIBC), but it may not preserve patient quality of life as well as bladder-sparing procedures.1 Historically, partial cystectomy was criticized as having an unacceptable recurrence rate (partially due to varied patient selection and treatments). However, this criticism did not consider its advantages, namely that it is a bladder-sparing procedure that permits pathological nodal staging by lymphadenectomy, allows complete tumor
* Corresponding author. Department of Urologic Surgery, Tianjin Medical University Second Hospital, 23 Pingjiang Road, Hexi District, Tianjin 300211, China. Tel.: þ86 022 88326723; fax: þ86 022 28273211. E-mail address: [email protected] (Y. Xu). 0748-7983/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejso.2013.04.006
excision with wide surgical margins and preserves sexual function. Recently, partial cystectomy-based multimodality treatment among select patients has resulted in ideal cancer control,2e6 and one of the latest matched case-control analysis showed that partial cystectomy can achieve cancer control comparable to radical cystectomy in properly selected patients with urothelial carcinoma of the urinary bladder.7 Obtaining acceptable cancer control while maintaining good quality of life among select patients is the definitive goal of partial cystectomy for MIBC. Nevertheless, data regarding partial cystectomy remain limited and prognostic factors affecting recurrence and survival have not been properly identified and evaluated in these selected patients. Therefore, this study aimed to fill this gap in knowledge. We retrospectively reviewed our 10-year singleinstitutional experience of partial cystectomy among
B. Ma et al. / EJSO 39 (2013) 1150e1156
1151
selected patients and identified several factors affecting recurrence and survival after partial cystectomy.
incision, the operating field was soaked with distilled water for 10e15 min to prevent tumor implantation.
Materials and methods
Histopathological evaluation
Patient selection
T stage was determined using the 2002 American Joint Committee on Cancer TNM staging system and histological grade was determined using the WHO staging system. Routine lymphovascular invasion (LVI) evaluations were performed. LVI was considered present only when tumor cells were unequivocally noted within or attached to the wall of a vascular or lymphatic space in hematoxylinand eosin-stained sections. Multiple serial sections were used in equivocal cases and in cases of aggressive tumors. Two independent uropathologists reviewed the hematoxylin- and eosin-stained slides.
Upon cystoscopy, patients meeting the criteria of limited tumors (3 or less) within the bladder that were unlikely to be non-muscle invasive and amenable to trans-urethral resection (TUR); no involvement of the trigone, bladder neck or urethra and with no concomitant carcinoma in situ on random biopsy were considered preliminary candidates for partial cystectomy. Computed tomography (CT) of the pelvis and chest X-ray were performed, and patients with involvement of adjacent organs (T4), obvious pelvic lymph node involvement or distant metastasis were excluded. Clinical staging was based on the growth pattern of the tumor, CT and chest x-ray findings and TUR of the index tumors, if necessary. Tumors located near the ureteral orifice that require ureteral reimplantation (UR) were not excluded from PC, whereas solitary cT2 or cT3 tumors were strong candidates for partial cystectomy. Patients with clinical MIBC who fulfilled the inclusion criteria abovementioned were presented with the options of radical cystectomy and partial cystectomy and were fully informed of the advantages and disadvantages of both modalities; written informed consent was obtained from each patient. The treatment protocol was approved by the ethics committee of our institution. From 2000 to 2010, 144 selected patients who preferred partial cystectomy over radical cystectomy or who were surgically unsuitable for radical cystectomy underwent partial cystectomy for MIBC. Of these patients, 43 were excluded from this study cohort: 10 were lost to follow up, 11 had non-urothelial carcinoma, 15 had clinically “muscle-invasive” but pathologically non-muscle-invasive bladder cancer, and 7 had positive lymph node pathology (explained in the Supplementary materials). Thus 101 patients with MIBC (urothelial carcinoma) without pelvic lymph node involvement were available for analysis. Surgical technique A lower abdominal incision was made and lymphadenectomy was performed in a standard fashion, the surrounding organs and wound were well packed before incision into the bladder. The body of the tumor was held by a spoon-shaped clamp upon opening of the bladder and partial cystectomy was performed with a 2-cm tumor-free margin. UR was performed if the lesion was within 2 cm lateral to the ureteral orifice. For concomitant non-muscle-invasive tumors, aggressive resections were performed to reach the deep muscle layers at the time of partial cystectomy, and the base of the resection was evaluated histologically by frozen section. Before closing the
Adjuvant therapy For patients with pT3N0M0, systemic chemotherapy employing methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) or gemcitabine and cisplatin (GC) was initiated within 2 weeks after partial cystectomy based on published protocols.8 Sixteen patients received the MVAC regimen, 13 patients received the GC regimen and 3 patients could not receive chemotherapy due to severe renal insufficiency. Cisplatin was replaced by carboplatin for patients with impaired renal function. All patients underwent intravesical therapy after partial cystectomy. Intravesical therapy consisted of 6 weekly doses followed by 12 monthly doses of therarubicin or mitomycin C, starting within 2 weeks after partial cystectomy. Follow-up protocol Surveillance cystoscopy and urinary cytology were conducted at 3-month intervals within the first 2 years, at 6month intervals within the next 3 years and annually thereafter. Generally, pelvic computed tomography and chest radiography were conducted at 6- to 12-month intervals. Intravenous urography (IVU) was performed if necessary. Patient clinical and pathological data were retrieved from their charts, and follow-up information was collected at outpatient visits or via phone interviews. The endpoints were overall survival (OS), cancer-specific survival (CSS) and recurrence-free survival (RFS). Recurrence was defined as non-muscle invasive (CIS, Ta or T1 tumors) or advanced (recurrence of muscle-invasive urothelial carcinoma, or development of pelvic or distant metastasis). The recurrence-free interval (RFI) was defined as the time from surgery to pathologically confirmed recurrence. Statistical analysis The log-rank test was used to compare OS, CSS and RFS between groups. A KaplaneMeier analysis was
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performed to assess OS and CSS, which were calculated from the date of partial cystectomy to the date of death or last known follow-up, and RFS, which was calculated from the date of partial cystectomy to the date of first detectable recurrence or last follow-up. For the analysis of OS, death was counted as event. For the analysis of CSS, only cancer-specific death was counted as event. For the analysis of RFS, death and the earliest recurrence, whether non-muscle-invasive or advanced, were counted as events. Cox’s proportional hazards regression model was then used to test the statistical significance of several potential prognostic factors for OS, CSS and RFS. All potential prognostic factors with p < 0.10 from the log-rank test were then included in a saturated model and backward elimination was used to remove factors from the model based on the likelihood ratio test in the multiple regression analysis. P < 0.05 was considered significant, and all p values reported are two sided. All statistical analyses were performed using SPSS for Windows, version 17.0 (SPSS, Inc., Chicago, IL). Results The study population consisted of 83 men and 18 women with a median age of 69.0 years (mean 65.8 12.2, range 24e84). Table 1 lists the clinical and pathological characteristics of the patients.
No positive margin was reported in the final pathologic examination, no wound recurrence occurred and no patient suffered from insufficient bladder capacity. Several male patients underwent transurethral resection of the prostate (TURP) for bladder outlet obstruction caused by benign prostatic hyperplasia (BPH) during follow-up. A total of 25 patients completed chemotherapy, 4 patients withdrew due to an inability to tolerate the side effects of chemotherapy, and 3 patients did not receive chemotherapy due to severe renal insufficiency. Survival after partial cystectomy With a median follow-up of 53.0 months (range 9e120), the 5-year overall survival (OS), cancer-specific survival (CSS) and recurrence-free survival (RFS) rates were 58%, 65% and 50%, respectively (Fig. 1). The log-rank test results of differences in 5-year survival rates between subgroups stratified by the evaluated variables are shown in Table 2. KaplaneMeier curves for OS, CSS and RFS stratified by LVI and UR are shown in Fig. 2. At the end of the follow-up period, 33 patients died of bladder cancer with a median survival time of 23.0 months (range 9e73), 52 patients had survived with intact bladder with a median follow-up time of 79.0 months (range 24e120). Recurrences after partial cystectomy
Table 1 Clinical and pathologic characteristics of 101 patients with MIBC. Variables Gender Male Female Age <65 y 65 y Prior history of urothelial carcinoma (PH.UC) Yes No Multicentricity Single Multiple Tumor size <3 cm 3 cm Grade High (Grade 3) Low (Grade 1 or 2) Pathological stage pT2 pT3 Lymphovascular invasion (LVI) Yes No Ureteral reimplantation (UR) Yes No
No. Pts 83 18 37 64 11 90 81 20 35 66 78 23 69 32 25 76 21 80
With a median follow-up time of 53.0 months (range 9e120), 46 patients had recurrence with a median recurrence free interval (RFI) of 14.0 months (range 2e99). Twelve patients had non-muscle-invasive recurrence with a median RFI of 27.0 months (range 5e99). Of the 12 patients who had non-muscle-invasive recurrence, 8 were treated successfully with transurethral resection of the bladder tumor (TURBT) and demonstrated a high survival rate within a median follow-up time of 87.5 months (range 29e103) after partial cystectomy; the remaining 4 had late recurrence of MIBC, and 3 of them died of bladder cancer within a median follow-up time of 13.0 months (range 11e16) after late muscle-invasive recurrence. Thirty-four patients had advanced recurrence with a median RFI of 10.5 months (range 2e40). Of these 34 patients, 27 had muscle-invasive recurrence only, 3 had muscle-invasive recurrence with concomitant lymph node metastasis, 2 had muscle-invasive recurrence with concomitant distant metastasis and 2 had distant metastasis only. The 4 patients with distant metastases underwent palliative chemotherapy, but all died of bladder cancer within 6 months after advanced recurrence. Twenty-three patients with local muscle-invasive recurrence, including the 3 patients with concomitant pelvic lymph node recurrence, underwent TURBT and/or chemoradiotherapy, and 22 of them died of bladder cancer with a median follow-up
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Potential prognostic factors underlying recurrence and survival Eleven patients with PH.UC were included in this cohort and 9 of these patients developed recurrences with a median RFI of 10.0 months (range 5e40). PH.UC was associated with both CSS (HR 3.235, CI 1.211e8.644, p ¼ 0.019) and RFS (HR 2.713, CI 1.231e5.978, p ¼ 0.013), and was weakly associated with OS ( p ¼ 0.064). LVI was identified in 25 cases, and LVI was more prevalent among cancers with higher pathological stage (19% of pT2 vs 38% of pT3, p ¼ 0.043, chi-square test). Seventeen of the 25 patients with LVI experienced recurrences with a median RFI of 12.0 months (range 5e40). LVI was associated with OS (HR 2.902, CI 1.515e5.559, p ¼ 0.001), CSS (HR 3.010, CI 1.386e6.538, p ¼ 0.005) and RFS (HR 2.055, CI 1.121e3.765, p ¼ 0.020). UR was performed in 21 cases, and 15 of these patients experienced recurrences with a median RFI of 14 months (range 2e35). UR was associated with OS (HR 3.465, CI 1.813e6.625, p < 0.001), CSS (HR 3.756, CI 1.768e7.976, p ¼ 0.001) and RFS (HR 3.044, CI 1.680e5.517, p < 0.001) (Table 3). Age was associated with OS (HR 2.189, CI 1.080e4.438, p ¼ 0.030) but was not associated with CSS or RFS. Although multiple tumors and tumors with higher pathological stage (pT3) showed a trend toward decreased survival compared to single and lower staged tumors (pT2), respectively (Table 2), the difference was not as significant as expected. Tumor multicentricity and pathological stage were not associated with survival. Grade was also not associated with survival (Table 3). Discussion
Figure 1. KaplaneMeier curves of OS, CSS and RFS in 101 patients after partial cystectomy. OS, overall survival; CSS, cancer-specific survival; RFS, recurrence-free survival.
Partial cystectomy is typically performed as a definitive treatment with curative intent. It is occasionally performed as either a therapeutic intervention for tumors that are not amenable to complete TUR or even as a palliative procedure for patients who are not suitable candidates for radical cystectomy.9 The advantages of partial cystectomy compared to radical cystectomy include preservation of a functioning urinary reservoir and improved potency in male patients. In addition, with partial cystectomy perioperative morbidity and postoperative complications are minimal compared with radical cystectomy plus urinary diversion or bladder reconstruction.10 Thus, partial cystectomy is an attractive option for select patients with MIBC. Risk factors associated with recurrence and survival
time of 6.0 months (range 3e33) after muscle-invasive recurrence. Ten patients underwent delayed cystectomy and 7 of them died of bladder cancer with a median survival time of 16.0 months (range9e47) after cystectomy.
The ideal indications for partial cystectomy were limited to solitary, primary tumors located at the dome of the bladder without concomitant CIS.11 Tumors located near or at the ureteral orifice that require UR have been excluded from partial cystectomy by some urologists.3 However, prior to this
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Table 2 Log-rank test of variables affecting OS, CSS and RFS. OS
Gender (male vs female) Age (<65 vs 65) PH.UC (yes vs no) Multicentricity (Single vs multiple) Tumor size: (<3 cm vs 3 cm) Tumor grade (Grade 3 vs 1or 2) Pathological stage (pT2 vs pT3) LVI (yes vs no) UR (yes vs no)
CSS
RFS
5-Year OS (%)
p Value
5-Year CSS (%)
p Value
5-Year RFS (%)
p Value
61 67 32 61 67 56 63 29 33
0.373 0.059 0.124 0.480 0.224 0.445 0.053 <0.001 0.001
67 77 40 69 74 59 68 37 37
0.711 0.199 0.069 0.325 0.569 0.091 0.184 0.001 0.001
52 50 18 56 54 44 55 31 22
0.508 0.330 0.024 0.045 0.267 0.883 0.231 0.011 <0.001
vs 48 vs 53 vs 61 vs48 vs 53 vs 63 vs 46 vs 68 vs 65
vs 58 vs 57 vs 67 vs52 vs 59 vs 82 vs 58 vs 73 vs 72
vs vs vs vs vs vs vs vs vs
43 50 54 28 48 52 40 56 57
PH.UC, prior history of urothelial carcinoma; LVI, lymphovascular invasion; UR, ureteral reimplantation; OS, overall survival; CSS, cancer-specific survival; RFS, recurrence-free survival.
report, there was no indication that UR would compromise the oncological outcome after partial cystectomy. On the contrary, Zhang et al.5 reported that UR was protective in partial cystectomy. In our series partial cystectomy plus UR was performed in 20% of patients with MIBC, but UR was associated with poor prognosis after partial cystectomy (Table 3). We attribute this to the fact that it is difficult to maintain a sufficiently wide surgical margin around a tumor that is located near the ureteral orifice while avoiding injury to the contralateral ureteral orifice. Furthermore, in cases where muscle-invasive recurrence occurred and delayed radical cystectomy was needed, prior dissection around the ureteral orifice made this procedure much more difficult, increasing the risk of positive surgical margin. The major limitation of partial cystectomy is the risk of recurrence. The reported local recurrence rates following partial cystectomy ranged between 38% and 78%,11 varying significantly among published series due to varied patient selection. It is not surprising that patients with a prior history of urothelial carcinoma (PH.UC) would be much more likely to develop another recurrence after bladder-sparing therapy. In the present study, PH.UC was associated with both CSS and RFS .This result was somewhat consistent with the results of a study from the M.D. Anderson Cancer Center in which patients with PH.UC had higher recurrence rates and lower survival rates compared with those with primary bladder cancer.3 Most patients with non-muscle-invasive recurrence survived, whereas most patients with advanced recurrence died of bladder cancer even after cystectomy. This finding is consistent with most recent reports on partial cystectomy, but the absolute survival rate after delayed cystectomy varied among studies due to patient selection, patient compliance, adjuvant treatment, and the length of follow-up after cystectomy.2e5,12 Notably, 4 of the 12 patients who experienced non-muscle-invasive recurrence developed late muscleinvasive recurrence emphasizing the importance of lifetime surveillance after partial cystectomy. LVI has been reported to be associated with poor prognosis after TURBT or radical cystectomy for
urothelial carcinoma of the bladder, but fewer reports have shown the prognostic value of LVI after partial cystectomy.13,14 In the present series, LVI was associated with OS, CSS and RFS. Moreover, LVI was more prevalent among cancers with a higher pathological stage (p ¼ 0.043). The role of LVI in this cohort was fully consistent with the results of another multicenter retrospective study of radical cystectomy. In that study, LVI was an independent predictor of survival after radical cystectomy in node-negative patients but not in node-positive patients, and the prevalence of LVI increased with increasing pathologic stage.15 In a multicenter study, patient age was shown to be associated with overall and cancer-specific mortality after radical cystectomy.16 In that study, higher age was associated with higher pathological stage, higher tumor grade, the prevalence of LVI and positive soft-tissue surgical margin status. In the present series, age was associated with OS ( p ¼ 0.030) but not with CSS or RFS (Table 2). This result was reasonable because elderly patients had higher rates of non-cancer-specific death and a higher rate of LVI (28% vs 19%), which are both associated with poor prognosis. Thus, our findings are somewhat consistent with those of the multicenter study. Comparison with radical cystectomy The 5-year OS, CSS and RFS were 58%, 65% and 50%, respectively. Considering that all the cases included in this series were pelvic lymph node-negative, this survival rate was lower than those of the RC series. However, we tend to believe that it was the result of patient selection as well as the cost of bladder sparing. In the present series, 11 patients with PH.UC and 21 patients who required UR were included, and both PH.UC and UR were associated with poor prognosis. Therefore a relatively low survival rate could be expected. Interestingly, when patients with PH.UC and UR were considered as contraindications for partial cystectomy and excluded from this cohort, the 5-
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Figure 2. KaplaneMeier curves of OS, CSS and RFS in 101 patients after partial cystectomy, stratified by LVI and UR status. LVI, lymphovascular invasion; UR, ureteral reimplantation; OS, overall survival; CSS, cancer-specific survival; RFS, recurrence-free survival.
year OS, CSS and RFS increased to 70%, 77% and 63%, respectively, achieving results comparable to those of larger scale radical cystectomy series.17,18 In other words, one cannot expect better oncological results with partial cystectomy than radical cystectomy, but for properly selected cases, partial cystectomy can achieve comparable oncological results with radical cystectomy.
Limitations of this study Although we achieved acceptable results, this study still has some limitations. This study was retrospective in nature, the partial cystectomy surgeries were performed by different surgeons, and several different adjuvant chemotherapy regimens were used (although a randomized
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Table 3 Cox regression analysis of variables that predict OS, CSS and RFS. Variables
OS HR(95% CI)
Age PH.UC Multicentricity Grade pStage LVI UR
2.189(1.080e4.438) 2.311(0.953e5.607) Not significant Not significant Not significant 2.902(1.515e5.559) 3.465(1.813e6.625)
CSS p Value 0.030 0.064
0.001 <0.001
RFS
HR(95% CI)
p Value
Not significant 3.235(1.211e8.644) Not significant Not significant Not significant 3.010(1.386e6.538) 3.756(1.768e7.976)
0.019
0.005 0.001
HR(95% CI) Not significant 2.713(1.231e5.978) Not significant Not significant Not significant 2.055(1.121e3.765) 3.044(1.680e5.517)
p Value 0.013
0.020 <0.001
PH.UC, prior history of urothelial carcinoma; LVI, lymphovascular invasion; UR, ureteral reimplantation; OS, overall survival; CSS, cancer-specific survival; RFS, recurrence-free survival.
control trial has shown similar long-term results for MVAC and GC regimens in an adjuvant setting in the treatment of locally advanced MIBC19).
7.
Conclusions Among patients with pelvic lymph node-negative MIBC, PH.UC and UR should be considered contraindications for partial cystectomy, and LVI predicts poor outcomes after partial cystectomy. Highly selective partial cystectomy is a rational alternative to radical cystectomy for pelvic lymph node-negative MIBC.
8.
9.
Appendix A. Supplementary data
10.
Supplementary data related to this article can be found online at http://dx.doi.org/10.1016/j.ejso.2013.04.006.
11. 12.
Conflict of interest 13.
The authors declare that they have no conflict of interest.
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