- Email: [email protected]
Lymphovascular Invasion and the Presence of More Than Three Tumors Are Associated With Poor Outcomes of Muscle-invasive Bladder Cancer After Bladder-conserving Therapies
Oncology Lymphovascular Invasion and the Presence of More Than Three Tumors Are Associated With Poor Outcomes of Muscle-invasive Bladder Cancer After Bladder-conserving Therapies Minguang Zhang, Ran Tao, Cunming Zhang, and Zhoujun Shen OBJECTIVES
METHODS
RESULTS
CONCLUSIONS
To identify the predictive factors for survival and recurrence of patients with muscle-invasive bladder cancer (MIBC) (urothelial carcinoma) after bladder-conserving therapies and to determine the efficacy of partial cystectomy plus chemotherapy and radiotherapy in the treatment of MIBC. From 2002 through 2007, 100 patients with MIBC (pT2 74%, pT3-4 26%) underwent partial cystectomy (PC). Subjects who had stage pT3-4 disease received adjuvant chemotherapy and radiotherapy. Univariate and multivariate analyses were performed to determine the predictive factors. At median follow-up of 31.5 months (range 6-66 months), 46% patients experienced superficial local recurrence and 14% developed muscle-invasive local recurrence. At the end of follow-up, 24 patients died of bladder cancer, and 71 patients (71%) survived with intact bladders. The 5-year bladder-intact survival rate was 63%. The 5-year cancer-specific survival (CSS) rate was 68%. By multivariate analysis, the presence of more than 3 tumors (P ⫽ .002, RR 2.718, 95% CI 1.455-5.079) and nonpapillary growth patterns (P ⫽ .005, RR 4.537, 95% CI 1.573-13.081) were predictive factors for local cancer recurrence; the presence of more than 3 tumors (P ⫽ .002, RR 4.109, 95% CI 1.676-10.072), lymphovascular invasion (P ⫽ .001, RR 6.098, 95% CI 2.03818.246), and partial cystectomy plus ureteral reimplantation (PC plus UR) (P ⫽ .011, RR 0.129, 95% CI .027-0.627) were significantly associated with 5-year CSS, and PC plus UR promoted survival. PC plus chemotherapy and radiotherapy is a rational alternative to radical cystectomy for the treatment of MIBC. Lymphovascular invasion and the presence of more than 3 tumors predict poor outcomes in MIBC after bladder-sparing therapy. UROLOGY 76: 902–907, 2010. © 2010 Elsevier Inc.
B
ladder cancer is the fifth most common malignancy in developed countries and the fourth most prevalent cancer in men in the United States.1 Although radical cystectomy (RC) is the standard treatment for muscle-invasive bladder cancer (MIBC), multimodality bladder-sparing strategies have recently gradually
From the Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; and Organ Transplant Center and Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Reprint requests: Professor ZJ Shen, M.D., Ph.D., Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine 197# 2nd Ruijin Road, Shanghai, 200025, PR China. E-mail: [email protected] Submitted: April 16, 2010, accepted (with revisions): May 15, 2010
902
© 2010 Elsevier Inc. All Rights Reserved
gained popularity. Generally, this approach comprises the combination of thorough transurethral resection of bladder tumor (TURB) and chemotherapy and radiotherapy. However the efficacy of this therapy is dubious.2-5 Partial cystectomy (PC) is another bladder-sparing option that has several advantages over routine therapy, including complete tumor removal, accurate tumor staging, and resection of occult metastasis by complete lymph node dissection. PC is generally the recommended treatment for nonurothelial bladder carcinomas, such as adenocarcinoma. A common indication for PC in urothelial carcinoma of the bladder is a solitary tumor at the dome that is not associated with carcinoma in situ (CIS). Less than 5% MIBCs fulfill such strict criteria.6 0090-4295/10/$34.00 doi:10.1016/j.urology.2010.05.007
Recently, based on more selective criteria, several studies have reported improved local control and survival rates using PC-based protocols to treat MIBC.7-9 The value of PC for MIBC, however, cannot be evaluated adequately, because patients who meet such criteria will also experience satisfactory long-term survival rates with RC. Also, the indications for and predictive factors of PC have not been analyzed thoroughly. Our institution has relatively few inclusion criteria for PC in the treatment of MIBC (urothelial carcinoma). However, the outcome of expanding the selection criteria has never been fully assessed. We retrospectively reviewed our 5-year single-institution experience of PCbased multimodality regimens. Outcomes and predictive factors for survival and local recurrence were systematically determined.
MATERIAL AND METHODS
Using a 4-field box technique with individually shaped portals, external beam radiation therapy was administered with a linear accelerator. The treatment field encompassed the entire bladder and the pelvic lymph nodes. The cumulative dose was 45-50 Gy (1.8-2 Gy per fraction, 5 fractions per week for 5 weeks). All patients received a re-evaluation TUR within 3 months after PC. Complete response (CR) was defined as no evidence of residual tumor on re-evaluation TUR. Patients with infiltrating residual disease underwent salvage RC.
Follow-Up The routine follow-up schedule of bladder-sparing treatment included physical and instrumental examinations (cystoscopic re-evaluation, biopsy of the tumor site and all suspected areas, urine cytology, chest X-ray, and abdominal and pelvic CT scans) every 3 months for the first 2 years and every 6 months thereafter. Intravesical chemotherapy (mitomycin or theprubicin) was given weekly for 6 weeks and then monthly for 1 year. Upper urinary tract examinations and bone scans were performed as needed.
Patients and Inclusion Criteria Between 2002 and 2007, 106 patients with biopsy-confirmed urothelial carcinoma of the bladder (cT2-4N0M0) were treated with PC plus chemotherapy and radiation therapy; 6 cases were abandoned because of loss of follow-up. Therefore 100 patients entered the study. The selection criteria for PC included the following: no evidence of CIS at the time of PC; no involvement of the bladder neck or urethra; surgical unsuitability for RC; and the patient’s option for bladder-sparing therapy. Exclusion criteria included invasive tumors in the trigone and MIBC with invasion of the prostate. Tumors that were within 2 cm lateral to the ureteral orifice were not excluded from PC. cT2 and solitary cT3 MIBCs were strong candidates for PC. Patients were fully informed about the advantages and disadvantages of bladder-sparing therapy and RC, and ultimately selected the final procedure. The treatment protocol was approved by the ethics committee of our institution.
Statistical Analysis Survival time (ST) was defined as the interval from the date of surgery to the last follow-up or cancer-specific death. Local recurrence-free interval (RFI) was calculated as the time of surgery to the date of pathologically confirmed local recurrence or the last follow-up. Cancer-specific death was defined death from metastatic disease. Deaths from causes other than bladder cancer were treated as censored data. Actuarial survival curves and survival rates were computed using the Kaplan–Meier method and log-rank test. To determine the predictive and prognostic impact on CSS and RFI, the following variables were analyzed using Cox’s regression model: gender, age, pathologic staging, grading, primary or recurrent bladder cancer, tumor number, size and growth pattern of tumor, presence of hydronephrosis or lymphovascular invasion (LVI), and urine cytology results before the operation. A P value ⬍.05 was considered statistically significant. All statistical analyses were performed using SPSS for Windows, version 16.0 (SPSS, Inc., Chicago, IL).
Protocol for Bladder-Sparing Therapy For muscle-invasive tumors, PC and pelvic lymphadenectomy were performed with a 2-cm tumor-free margin. For concomitant non–muscle-invasive tumors, aggressive resections were performed to a depth of the deep muscle layers. The resection margin was evaluated by frozen section analysis. Ureteral reimplantation (UR) was performed if the lesion lay within 2 cm lateral to the ureteral orifice. Patients with pathologic stage T3 or T4 tumors or with positive pelvic lymph nodes received 3 cycles of cisplatin-based adjuvant chemotherapy, followed by radiotherapy. Adjuvant chemotherapy was performed within 2 weeks after the operation, and radiation was started within 1-2 weeks after completion of chemotherapy. Patients with hydronephrosis were not given radiotherapy. Chemotherapy protocols differed because of the evolution of regimens in our institution. Fifteen patients were given methotrexate, vinblastine, adriamycin, and cisplatin (M-VAC), and 9 patients were given gemcitabine and cisplatin, based on a published protocol protocol.10 In patients with hydronephrosis or impaired renal function, cisplatin was replaced with carboplatin. UROLOGY 76 (4), 2010
RESULTS Demographic Characteristics and Survival of Patients We included 72 men and 28 women (age 30-88 years; mean age 65.7 ⫾ 12.7 years; median age 67.0 years). Table 1 lists clinical and pathologic characteristics of the patients. The median follow-up time was 31.5 months (range 6-66 months, mean 32.6 ⫾ 16.9 months). The 5-year CSS rate was 68% and the mean length of CSS was 52.6 ⫾ 2.3 months in all patients who underwent bladder-sparing treatment. The 5-year CSS rates and lengths of CSS, subdivided by stage and grade, are shown in Table 2. At the end of the follow-up period, 24 (24%) patients had died of bladder cancer, and 71 patients (71%) had survived with intact bladders. The 5-year bladder-intact survival rate was 63%. 903
Table 1. Clinical and pathologic characteristics of patients with MIBC Variable
Patients with MIBC N
Gender Male Female Age ⱕ50 y 51-70 y ⬎70 y Pathologic staging T2 T3 T4 Grade Lowa Highb Growth pattern Papillary Nonpapillary Primary Yes No Number 1-3 ⬎3 LVI Yes No Size 3 cm ⱖ3 cm
72 28
72% 28%
10 52 38
10% 52% 38%
74 16 10
74% 16% 10%
36 64
36% 64%
14 86
14% 86%
62 38
62% 38%
84 16
84% 16%
16 84
16% 84%
18 82
18% 82%
LVI, lymphovascular invasion. a Grade 1 or 2. b Grade 3.
Table 2. Five-Year CSS rate and mean survival time according to stage and grade
Pathologic stage T2 T3 T4 Grade Lowa Highb
n 100
5-Year CSS Rate 68.0%
Mean ST (mo) 52.6
74 16 10
68.3% 87.5% 52.5%
53.2 57.8 27.7
.182
36 64
76.3% 63.4%
56.6 49.7
.091
P Value
CSS, cancer-specific survival; ST, survival time. Overall comparisons of 5-year cancer-specific survival rate and mean survival time according to different stages and tumor grades. Difference between stages and tumor grades were analyzed using the Kaplan–Meier method and log-rank test (Mantel– Cox). P ⬍ .05 was considered statistically significant. a Grade 1 or 2. b Grade 3.
Clinical Response and Local Recurrence in PC No positive margin was observed in the pathologic examination, and 5 patients (5%) were positive for pelvic lymph nodes. Two patients (2%) were confirmed to have residual muscle-invasive tumors at the re-evaluation TUR and received salvage RC. In all, 98 patients (98%) achieved CR. Adjuvant chemotherapy was completed in 904
21 of 24 patients (87.5%), and radiation therapy was completed in 18 of 21 patients (85.7%). Local recurrence was defined as a recurrence within the bladder. At the end of the follow-up, 46 patients (46%) had experienced superficial local recurrence and 14 (14%) had developed muscle-invasive local recurrence. The 5-year local recurrence-free survival rate was 29%, and the median RFI was 9.4 months (mean 14.0 ⫾ 13.3 months). In all, 75% (45/60) and 90% (54/60) of local recurrences occurred within 16 and 32 months, respectively. No wound recurrence was detected in our series during follow-up. Eight patients with muscle-invasive relapse underwent RC, for whom the mean interval from partial to salvage radical cystectomy was 20.6 ⫾ 5.6 months (range 4-46 months). In the subsequent 9-33 months of follow-up, 3 patients (3/8) died of bladder cancer metastasis. The mean length of CSS in patients who received salvage radical cystectomy was 42.4 ⫾ 5.9 months. Three patients who experienced muscle-invasive relapse developed concomitant distant metastasis and received palliative TURB, all of whom died within 6 months. The remaining 3 patients with muscle-invasive local recurrence refused RC and were treated with radical TURB, followed by radiochemotherapy (total radiation 60-65 Gy, combined with cisplatin as a radiation sensitizer) with curative intent. The 3 patients survived with intact bladders for at least 17, 13, and 18 months, respectively. Predictive Factors for Local Recurrence In our multivariate analysis, the presence of more than 3 tumors (P ⫽ .002, RR 2.718, 95% CI 1.455-5.079) and tumors that showed nonpapillary growth patterns (P ⫽ .005, RR 4.537, 95% CI 1.573-13.081) were risk factors for local cancer recurrence (Table 3). Predictive Factors for Cancer-Specific Survival In our multivariate analysis, a tumor number greater than 3 (P ⫽ .002, RR 4.109, 95% CI 1.676-10.072), LVI (P ⫽ .001, RR 6.098, 95% CI 2.038-18.246), and PC plus UR (P ⫽ .011, RR 0.129, 95% CI 0.027-0.627) were significant predictive factors for 5-year CSS rate, and PC plus UR was a protective factor for survival (Table 4). The 5-year CSS rate was higher in patients with 3 tumors or less (73.8% vs 37.5%, P ⫽ .000) and in patients who underwent PC plus UR (88.9% vs 60.2%, P ⫽ .032). The 5-year CSS rate was much lower (34.1% vs 72.6%, P ⫽ .000) in patients with lymphovascular invasion.
COMMENT PC is usually the definitive treatment for MIBC with very strict inclusion criteria. In our institution, we expanded the inclusion criteria of PC. Tumors that are near the ureteral orifice are considered unsuitable for TURB and are excluded from PC by some urologists.8 In our series, UROLOGY 76 (4), 2010
Table 3. Univariate and multivariate analysis of potential prognostic factors affecting RFI
Variable Grade Lowa Highb Treatment PC/PC plus UR Primary cancer Yes/no Number 1-3/⬎3 Growth pattern Papillary/nonpapillary LVI Yes/no
5-Year RF Rate (%/%)
Mean RFI (mo)
49.4% 10.6%
38.8 25.8
Univariate P Value
RR
Multivariate (Cox model) 95% CI P Value
.013
.069
12.9%/63.6%
26.6/45.1
0.005
.075
36.2%/22.6%
36.7/19.9
.016
.723
33.4%/0.0%
34.7/9.4
.000
2.718
1.455-5.079
.002*
66.7%/14.3%
54.7/26.6
.001
4.537
1.573-13.081
.005*
20.0%/31.3%
15/2/2033.3
.046
.138
Predictive factors for RFI of patients in partial cystectomy (PC) group. Univariate analyses were performed using Kaplan–Meier Method and log-rank test. Only those factors that were significant in univariate analysis were entered into the multivariate analysis using Cox regression model (forward stepwise), P ⬍ .05 was considered statistically significant. RFI was defined as the interval from the time of surgery to the date of pathologically confirmed recurrence or the last follow-up. LVI, lymphovascular invasion; RF rate, recurrence-free rate; RFI: recurrence-free interval. * P ⬍ .05. a Grade 1 or 2. b Grade 3.
Table 4. Univariate and multivariate analysis of potential prognostic factors affecting CSS
Variable Gender Male/female Age ⬍50 y 50-70 y ⬎70 y Pathologic stage pT2 pT3 pT4 Grade Low/ahighb Treatment PC/PC plus UR Primary cancer Yes/no Number 1-3/⬎3 Sizec ⬍3 cm/ⱖ3 cm Growth patternc Papillary/nonpapillary LVI Yes/no Cytology With or without Hydronephrosis Yes/no
Univariate P Value
5-Year CSS (%/%)
Mean ST (mo)
74.2%/50.9%
53.9/49.0
50.0% 67.8% 70.7%
43.3 53.5 51.0
68.3% 87.5% 52.5%
53.2 57.8 27.7
75.3%/63.4%
56.6/49.7
.091
60.2%/88.9%
49.6/60.8
.032
80.4%/41.4%
57.2/38.7
.007
75.2%/24.3%
55.4/30.7
.001
RR
Multivariate (Cox model) 95% CI P Value
.466 .890
.182
100%/59.9%
.007
100%/60.9%
.014
32.3%/72.2%
27.7/54.6
.014
78.6%/81.8%
49.5/56.8
.319
66.1%/80.0%
38.3/52.3
.739
0.129
0.027-0.627
.011* .137
4.109
1.676-10.072
.002*
6.098
2.038-18.246
.001*
Predictive factors for cancer-specific survival (CSS) of patients in partial cystectomy (PC) group. Univariate analyses were performed using Kaplan–Meier Method and log-rank test. Only those factors that were significant in univariate analysis were entered into the multivariate analysis using Cox regression model (forward-stepwise), P ⬍ .05 was considered statistically significant. LVI, lymphovascular invasion; ST, survival time. a Grade 1 or 2. b Grade 3. c Size and growth pattern were not included in Cox regression analysis model because none of patients with tumor size ⬍3 cm or papillary tumors reached end point, with a censored rate of 100%. * P ⬍ .05.
UROLOGY 76 (4), 2010
905
PC plus UR was performed in 22% of patients with MIBC. Notably, our study revealed that UR was not associated with poor prognosis, effecting a higher 5-year CSS rate compared with the PC-only cohort (88.9% vs 60.2%, P ⫽ .032). By multivariate analysis, UR was a protective factor for 5-year CSS (P ⫽ .011, RR 0.129, 95% CI 0.027-0.627). This “unreasonable” result might be attributed to satisfactory surgical margins and more frequent follow-ups. Yet, the numbers of such patients were relatively low, suggesting that we should consider this conclusion cautiously. By multivariate analysis, the presence of more than 3 tumors was the only predictive factor for both local recurrence and 5-year CSS survival; LVI was another predictive factor for 5-year CSS survival in patients with MIBC after bladder-sparing treatment. Therefore, a tumor count of more than 3 should be considered an exclusion criterion for bladder-preservation protocols. LVI is indicative of bladder cancer that has the potential to metastasize; therefore, it should be treated more aggressively. Compared with RC, PC is advantageous in the treatment of MIBC because of its preservation of potency, preservation of a functional urinary reservoir and urinary continence in male patients, and minimal perioperative morbidity and complications.11 With regard to survival rate, our results suggest that the efficacy of PC plus multimodality therapy is comparable with RC. A major goal of PC is to achieve satisfactory long-term patient survival. The outcomes in our study are comparable to results from other large series. A study by the Memorial SloanKettering Cancer Center7 reported on 58 patients who were treated with PC, which represents the largest clinical study of this kind. With nearly the same mean follow-up period as in our series (33 vs 32.6 months), the percentage of patients who were alive with intact bladders at the last follow-up was 74% (vs 71% in our series), and the 5-year CSS survival rate was 69% vs 68% in our series. The M.D. Anderson Cancer Center also reported on 37 patients with MIBC who underwent PC; their 5-year CSS rate was higher than in our study (87% vs 68%), and the 5-year bladder-intact CSS rates were similar (65% vs 63%).8 These data suggest that PC-based multimodality therapy is undoubtedly an attractive option for the treatment of MIBC, even with our expanded inclusion criteria, and warrants a prospective randomized trial to evaluate the rationale of expanding the inclusion criteria of this bladder preservation treatment further. The inherent drawbacks of TURB, another bladdersparing therapy, include tumor understaging,2 high residual rates,12 and inaccurate staging because of the lack of pelvic lymph node dissection. In our series, the PC-based bladder-sparing protocol resulted in satisfactory local control, with a 2% residual rate and 0% positive margin 906
rate. Furthermore, positive pelvic lymph nodes were detected in 5 patients (5%) in whom lymphadenopathy was not detected by preoperative CT scan. With radical dissection of the pelvic lymph nodes, PC provides complete resection of local tumors within the bladder as well as occult metastases of regional lymph nodes. Robotic partial cystectomy is a new technique, and its feasibility recently has been demonstrated by Allaparthi et al.13 However the lack of tactile feedback, which affects the margins, and the cost of this technique render it unlikely replace open PC. The major limitation of PC is the associated high risk of local tumor recurrence. Local recurrence rates after PC range between 40% and 78%.9 In recent studies of PCbased multimodality treatment, despite strict inclusion criteria, the total local recurrence rate has ranged between 28% and 49% (superficial local recurrence rate 8%-24%, muscle-invasive local recurrence rate 20%28%).7-9,14 Because of the expanded inclusion criteria in our series, we observed a higher total local recurrence rate was (60%) compared with published data. However we must consider that, in contrast to other reports, the majority (77%) of local recurrences in our study comprised cases of superficial recurrence, which are amenable to TURB. The muscle-invasive recurrence rate (14%) in our series was lower than in other reports. Another limitation of PC is the risk of wound recurrence. In our series, there was no instance of wound recurrence, which could be attributed largely to the improved surgical technique, wherein the surrounding organs and wound were well packed before incision into the bladder. Our series is the largest clinical study on MIBC treatment with PC and multimodality adjuvant therapy. Our 5-year CSS rate (68%) and 5-year bladder-intact survival rate (63%) were comparable with those in published reports on partial or radical cystectomy therapy.7,8,15,16 Despite these encouraging results, we should not ignore the caveats of our study. The follow-up period (median 31.5 months) was relatively short. However, because 75% and 90% of local bladder cancer recurrence was observed within 16 and 32 months, respectively, we nevertheless obtained a reasonable assessment of outcomes after PC. Also, our series was a retrospective study with an apparent selection bias. As shown in Table 1, the majority (74%) of patients had stage pT2 disease. Therefore our conclusions should be considered carefully before any prospective randomized study on this treatment is performed.
CONCLUSIONS Collectively, our results confirm that in combination with adjuvant chemotherapy and radiation therapy, PC is an effective alternative treatment for certain patients with MIBC who are unwilling to undergo total cystectomy. The rationale for this regimen includes less tumor residue and lower muscle-invasive local recurrence rates, UROLOGY 76 (4), 2010
as well as comparable survival and bladder preservation rates. Our study also indicates that despite the traditionally strict inclusion criteria, PC can be used more widely as the primary component of multimodality bladder-sparing treatment for MIBC with curative intent. For tumors that are adjacent to the ureteral orifice, UR should be performed, because the long-term prognosis is comparable to, if not better than, that for patients who do not undergo ureteral reimplantation. LVI and a tumor number greater than 3 are risk factors that are associated with poor prognosis in patients with MIBC. Patients with more than 3 tumors should be excluded from bladdersparing treatment modalities.
References 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;76:71-96. 2. Herr HW, Bajorin DF, Scher HI. Neoadjuvant chemotherapy and bladder-sparing surgery for invasive bladder cancer: ten-year outcome. J Clin Oncol. 1998;16:1298-1301. 3. Splinter T, Denis L. Restaging procedures, criteria of response, and relationship between pathological response and survival. Semin Oncol. 1990;17:606-612. 4. Herr HW. Transurethral resection of muscle-invasive bladder cancer: 10-year outcome. J Clin Oncol. 2001;19:89-93. 5. Zapatero A, Martin de Vidales C, Arellano R, et al. Updated results of bladder-sparing trimodality approach for invasive bladder cancer. Urol Oncol. 2009;27:1-7. 6. Sweeney P, Kursh ED, Resnik MI. Partial cystectomy. Urol Clin North Am. 1992;19:701-711.
UROLOGY 76 (4), 2010
7. 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. J Urol. 2004;172:878-881. 8. Kassouf W, Swanson D, Ashish M, Kamat, et al. Partial cystectomy for muscle invasive urothelial carcinoma of the bladder: a contemporary review of the M. D. Anderson Cancer Center experience. J Urol. 2006;175:2058-2062. 9. Smaldone MC, Jacobs BL, Smaldone AM, et al. Long-term results of selective partial cystectomy for invasive urothelial bladder carcinoma. Urology. 2008;72:613-616. 10. Moore MJ, Winquist EW, Murray N, et al. Gemcitabine plus cisplatin, an active regimen in advanced urothelial cancer: a phase II trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1999;17:2876-2881. 11. Laufer M. Transurethral resection and partial cystectomy for invasive bladder cancer. Semin Urol Oncol. 2000;18:296-299. 12. Sternberg CN, Parmar MK. Neoadjuvant chemotherapy is not (yet) standard treatment for muscle-invasive bladder cancer. J Clin Oncol. 2001;19(Suppl):21S-26S. 13. Allaparthi S, Ramanathan R, Balaji KC. Robotic partial cystectomy for bladder cancer: a single-institutional pilot study. J Endourol. 2010;24:223-227. 14. Sternberg CN, Pansadoro V, Fabio Calabro, et al. Can patient selection for bladder preservation be based on response to chemotherapy? Cancer. 2003;97:1644-1652. 15. Solsona E, Climent MA, Iborra I, et al. Bladder preservation in selected patients with muscle-invasive bladder cancer by complete transurethral resection of the bladder plus systemic chemotherapy: long-term follow-up of a phase 2 nonrandomized comparative trial with radical cystectomy. Eur Urol. 2009;55:911-921. 16. Shipley WU, Kaufman DS, Zehr E, et al. Selective bladder preservation by combined modality protocol treatment: long-term outcomes of 190 patients with invasive bladder cancer. Urology. 2002; 60:62-68.
907
METHODS
RESULTS
CONCLUSIONS
To identify the predictive factors for survival and recurrence of patients with muscle-invasive bladder cancer (MIBC) (urothelial carcinoma) after bladder-conserving therapies and to determine the efficacy of partial cystectomy plus chemotherapy and radiotherapy in the treatment of MIBC. From 2002 through 2007, 100 patients with MIBC (pT2 74%, pT3-4 26%) underwent partial cystectomy (PC). Subjects who had stage pT3-4 disease received adjuvant chemotherapy and radiotherapy. Univariate and multivariate analyses were performed to determine the predictive factors. At median follow-up of 31.5 months (range 6-66 months), 46% patients experienced superficial local recurrence and 14% developed muscle-invasive local recurrence. At the end of follow-up, 24 patients died of bladder cancer, and 71 patients (71%) survived with intact bladders. The 5-year bladder-intact survival rate was 63%. The 5-year cancer-specific survival (CSS) rate was 68%. By multivariate analysis, the presence of more than 3 tumors (P ⫽ .002, RR 2.718, 95% CI 1.455-5.079) and nonpapillary growth patterns (P ⫽ .005, RR 4.537, 95% CI 1.573-13.081) were predictive factors for local cancer recurrence; the presence of more than 3 tumors (P ⫽ .002, RR 4.109, 95% CI 1.676-10.072), lymphovascular invasion (P ⫽ .001, RR 6.098, 95% CI 2.03818.246), and partial cystectomy plus ureteral reimplantation (PC plus UR) (P ⫽ .011, RR 0.129, 95% CI .027-0.627) were significantly associated with 5-year CSS, and PC plus UR promoted survival. PC plus chemotherapy and radiotherapy is a rational alternative to radical cystectomy for the treatment of MIBC. Lymphovascular invasion and the presence of more than 3 tumors predict poor outcomes in MIBC after bladder-sparing therapy. UROLOGY 76: 902–907, 2010. © 2010 Elsevier Inc.
B
ladder cancer is the fifth most common malignancy in developed countries and the fourth most prevalent cancer in men in the United States.1 Although radical cystectomy (RC) is the standard treatment for muscle-invasive bladder cancer (MIBC), multimodality bladder-sparing strategies have recently gradually
From the Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; and Organ Transplant Center and Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Reprint requests: Professor ZJ Shen, M.D., Ph.D., Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine 197# 2nd Ruijin Road, Shanghai, 200025, PR China. E-mail: [email protected] Submitted: April 16, 2010, accepted (with revisions): May 15, 2010
902
© 2010 Elsevier Inc. All Rights Reserved
gained popularity. Generally, this approach comprises the combination of thorough transurethral resection of bladder tumor (TURB) and chemotherapy and radiotherapy. However the efficacy of this therapy is dubious.2-5 Partial cystectomy (PC) is another bladder-sparing option that has several advantages over routine therapy, including complete tumor removal, accurate tumor staging, and resection of occult metastasis by complete lymph node dissection. PC is generally the recommended treatment for nonurothelial bladder carcinomas, such as adenocarcinoma. A common indication for PC in urothelial carcinoma of the bladder is a solitary tumor at the dome that is not associated with carcinoma in situ (CIS). Less than 5% MIBCs fulfill such strict criteria.6 0090-4295/10/$34.00 doi:10.1016/j.urology.2010.05.007
Recently, based on more selective criteria, several studies have reported improved local control and survival rates using PC-based protocols to treat MIBC.7-9 The value of PC for MIBC, however, cannot be evaluated adequately, because patients who meet such criteria will also experience satisfactory long-term survival rates with RC. Also, the indications for and predictive factors of PC have not been analyzed thoroughly. Our institution has relatively few inclusion criteria for PC in the treatment of MIBC (urothelial carcinoma). However, the outcome of expanding the selection criteria has never been fully assessed. We retrospectively reviewed our 5-year single-institution experience of PCbased multimodality regimens. Outcomes and predictive factors for survival and local recurrence were systematically determined.
MATERIAL AND METHODS
Using a 4-field box technique with individually shaped portals, external beam radiation therapy was administered with a linear accelerator. The treatment field encompassed the entire bladder and the pelvic lymph nodes. The cumulative dose was 45-50 Gy (1.8-2 Gy per fraction, 5 fractions per week for 5 weeks). All patients received a re-evaluation TUR within 3 months after PC. Complete response (CR) was defined as no evidence of residual tumor on re-evaluation TUR. Patients with infiltrating residual disease underwent salvage RC.
Follow-Up The routine follow-up schedule of bladder-sparing treatment included physical and instrumental examinations (cystoscopic re-evaluation, biopsy of the tumor site and all suspected areas, urine cytology, chest X-ray, and abdominal and pelvic CT scans) every 3 months for the first 2 years and every 6 months thereafter. Intravesical chemotherapy (mitomycin or theprubicin) was given weekly for 6 weeks and then monthly for 1 year. Upper urinary tract examinations and bone scans were performed as needed.
Patients and Inclusion Criteria Between 2002 and 2007, 106 patients with biopsy-confirmed urothelial carcinoma of the bladder (cT2-4N0M0) were treated with PC plus chemotherapy and radiation therapy; 6 cases were abandoned because of loss of follow-up. Therefore 100 patients entered the study. The selection criteria for PC included the following: no evidence of CIS at the time of PC; no involvement of the bladder neck or urethra; surgical unsuitability for RC; and the patient’s option for bladder-sparing therapy. Exclusion criteria included invasive tumors in the trigone and MIBC with invasion of the prostate. Tumors that were within 2 cm lateral to the ureteral orifice were not excluded from PC. cT2 and solitary cT3 MIBCs were strong candidates for PC. Patients were fully informed about the advantages and disadvantages of bladder-sparing therapy and RC, and ultimately selected the final procedure. The treatment protocol was approved by the ethics committee of our institution.
Statistical Analysis Survival time (ST) was defined as the interval from the date of surgery to the last follow-up or cancer-specific death. Local recurrence-free interval (RFI) was calculated as the time of surgery to the date of pathologically confirmed local recurrence or the last follow-up. Cancer-specific death was defined death from metastatic disease. Deaths from causes other than bladder cancer were treated as censored data. Actuarial survival curves and survival rates were computed using the Kaplan–Meier method and log-rank test. To determine the predictive and prognostic impact on CSS and RFI, the following variables were analyzed using Cox’s regression model: gender, age, pathologic staging, grading, primary or recurrent bladder cancer, tumor number, size and growth pattern of tumor, presence of hydronephrosis or lymphovascular invasion (LVI), and urine cytology results before the operation. A P value ⬍.05 was considered statistically significant. All statistical analyses were performed using SPSS for Windows, version 16.0 (SPSS, Inc., Chicago, IL).
Protocol for Bladder-Sparing Therapy For muscle-invasive tumors, PC and pelvic lymphadenectomy were performed with a 2-cm tumor-free margin. For concomitant non–muscle-invasive tumors, aggressive resections were performed to a depth of the deep muscle layers. The resection margin was evaluated by frozen section analysis. Ureteral reimplantation (UR) was performed if the lesion lay within 2 cm lateral to the ureteral orifice. Patients with pathologic stage T3 or T4 tumors or with positive pelvic lymph nodes received 3 cycles of cisplatin-based adjuvant chemotherapy, followed by radiotherapy. Adjuvant chemotherapy was performed within 2 weeks after the operation, and radiation was started within 1-2 weeks after completion of chemotherapy. Patients with hydronephrosis were not given radiotherapy. Chemotherapy protocols differed because of the evolution of regimens in our institution. Fifteen patients were given methotrexate, vinblastine, adriamycin, and cisplatin (M-VAC), and 9 patients were given gemcitabine and cisplatin, based on a published protocol protocol.10 In patients with hydronephrosis or impaired renal function, cisplatin was replaced with carboplatin. UROLOGY 76 (4), 2010
RESULTS Demographic Characteristics and Survival of Patients We included 72 men and 28 women (age 30-88 years; mean age 65.7 ⫾ 12.7 years; median age 67.0 years). Table 1 lists clinical and pathologic characteristics of the patients. The median follow-up time was 31.5 months (range 6-66 months, mean 32.6 ⫾ 16.9 months). The 5-year CSS rate was 68% and the mean length of CSS was 52.6 ⫾ 2.3 months in all patients who underwent bladder-sparing treatment. The 5-year CSS rates and lengths of CSS, subdivided by stage and grade, are shown in Table 2. At the end of the follow-up period, 24 (24%) patients had died of bladder cancer, and 71 patients (71%) had survived with intact bladders. The 5-year bladder-intact survival rate was 63%. 903
Table 1. Clinical and pathologic characteristics of patients with MIBC Variable
Patients with MIBC N
Gender Male Female Age ⱕ50 y 51-70 y ⬎70 y Pathologic staging T2 T3 T4 Grade Lowa Highb Growth pattern Papillary Nonpapillary Primary Yes No Number 1-3 ⬎3 LVI Yes No Size 3 cm ⱖ3 cm
72 28
72% 28%
10 52 38
10% 52% 38%
74 16 10
74% 16% 10%
36 64
36% 64%
14 86
14% 86%
62 38
62% 38%
84 16
84% 16%
16 84
16% 84%
18 82
18% 82%
LVI, lymphovascular invasion. a Grade 1 or 2. b Grade 3.
Table 2. Five-Year CSS rate and mean survival time according to stage and grade
Pathologic stage T2 T3 T4 Grade Lowa Highb
n 100
5-Year CSS Rate 68.0%
Mean ST (mo) 52.6
74 16 10
68.3% 87.5% 52.5%
53.2 57.8 27.7
.182
36 64
76.3% 63.4%
56.6 49.7
.091
P Value
CSS, cancer-specific survival; ST, survival time. Overall comparisons of 5-year cancer-specific survival rate and mean survival time according to different stages and tumor grades. Difference between stages and tumor grades were analyzed using the Kaplan–Meier method and log-rank test (Mantel– Cox). P ⬍ .05 was considered statistically significant. a Grade 1 or 2. b Grade 3.
Clinical Response and Local Recurrence in PC No positive margin was observed in the pathologic examination, and 5 patients (5%) were positive for pelvic lymph nodes. Two patients (2%) were confirmed to have residual muscle-invasive tumors at the re-evaluation TUR and received salvage RC. In all, 98 patients (98%) achieved CR. Adjuvant chemotherapy was completed in 904
21 of 24 patients (87.5%), and radiation therapy was completed in 18 of 21 patients (85.7%). Local recurrence was defined as a recurrence within the bladder. At the end of the follow-up, 46 patients (46%) had experienced superficial local recurrence and 14 (14%) had developed muscle-invasive local recurrence. The 5-year local recurrence-free survival rate was 29%, and the median RFI was 9.4 months (mean 14.0 ⫾ 13.3 months). In all, 75% (45/60) and 90% (54/60) of local recurrences occurred within 16 and 32 months, respectively. No wound recurrence was detected in our series during follow-up. Eight patients with muscle-invasive relapse underwent RC, for whom the mean interval from partial to salvage radical cystectomy was 20.6 ⫾ 5.6 months (range 4-46 months). In the subsequent 9-33 months of follow-up, 3 patients (3/8) died of bladder cancer metastasis. The mean length of CSS in patients who received salvage radical cystectomy was 42.4 ⫾ 5.9 months. Three patients who experienced muscle-invasive relapse developed concomitant distant metastasis and received palliative TURB, all of whom died within 6 months. The remaining 3 patients with muscle-invasive local recurrence refused RC and were treated with radical TURB, followed by radiochemotherapy (total radiation 60-65 Gy, combined with cisplatin as a radiation sensitizer) with curative intent. The 3 patients survived with intact bladders for at least 17, 13, and 18 months, respectively. Predictive Factors for Local Recurrence In our multivariate analysis, the presence of more than 3 tumors (P ⫽ .002, RR 2.718, 95% CI 1.455-5.079) and tumors that showed nonpapillary growth patterns (P ⫽ .005, RR 4.537, 95% CI 1.573-13.081) were risk factors for local cancer recurrence (Table 3). Predictive Factors for Cancer-Specific Survival In our multivariate analysis, a tumor number greater than 3 (P ⫽ .002, RR 4.109, 95% CI 1.676-10.072), LVI (P ⫽ .001, RR 6.098, 95% CI 2.038-18.246), and PC plus UR (P ⫽ .011, RR 0.129, 95% CI 0.027-0.627) were significant predictive factors for 5-year CSS rate, and PC plus UR was a protective factor for survival (Table 4). The 5-year CSS rate was higher in patients with 3 tumors or less (73.8% vs 37.5%, P ⫽ .000) and in patients who underwent PC plus UR (88.9% vs 60.2%, P ⫽ .032). The 5-year CSS rate was much lower (34.1% vs 72.6%, P ⫽ .000) in patients with lymphovascular invasion.
COMMENT PC is usually the definitive treatment for MIBC with very strict inclusion criteria. In our institution, we expanded the inclusion criteria of PC. Tumors that are near the ureteral orifice are considered unsuitable for TURB and are excluded from PC by some urologists.8 In our series, UROLOGY 76 (4), 2010
Table 3. Univariate and multivariate analysis of potential prognostic factors affecting RFI
Variable Grade Lowa Highb Treatment PC/PC plus UR Primary cancer Yes/no Number 1-3/⬎3 Growth pattern Papillary/nonpapillary LVI Yes/no
5-Year RF Rate (%/%)
Mean RFI (mo)
49.4% 10.6%
38.8 25.8
Univariate P Value
RR
Multivariate (Cox model) 95% CI P Value
.013
.069
12.9%/63.6%
26.6/45.1
0.005
.075
36.2%/22.6%
36.7/19.9
.016
.723
33.4%/0.0%
34.7/9.4
.000
2.718
1.455-5.079
.002*
66.7%/14.3%
54.7/26.6
.001
4.537
1.573-13.081
.005*
20.0%/31.3%
15/2/2033.3
.046
.138
Predictive factors for RFI of patients in partial cystectomy (PC) group. Univariate analyses were performed using Kaplan–Meier Method and log-rank test. Only those factors that were significant in univariate analysis were entered into the multivariate analysis using Cox regression model (forward stepwise), P ⬍ .05 was considered statistically significant. RFI was defined as the interval from the time of surgery to the date of pathologically confirmed recurrence or the last follow-up. LVI, lymphovascular invasion; RF rate, recurrence-free rate; RFI: recurrence-free interval. * P ⬍ .05. a Grade 1 or 2. b Grade 3.
Table 4. Univariate and multivariate analysis of potential prognostic factors affecting CSS
Variable Gender Male/female Age ⬍50 y 50-70 y ⬎70 y Pathologic stage pT2 pT3 pT4 Grade Low/ahighb Treatment PC/PC plus UR Primary cancer Yes/no Number 1-3/⬎3 Sizec ⬍3 cm/ⱖ3 cm Growth patternc Papillary/nonpapillary LVI Yes/no Cytology With or without Hydronephrosis Yes/no
Univariate P Value
5-Year CSS (%/%)
Mean ST (mo)
74.2%/50.9%
53.9/49.0
50.0% 67.8% 70.7%
43.3 53.5 51.0
68.3% 87.5% 52.5%
53.2 57.8 27.7
75.3%/63.4%
56.6/49.7
.091
60.2%/88.9%
49.6/60.8
.032
80.4%/41.4%
57.2/38.7
.007
75.2%/24.3%
55.4/30.7
.001
RR
Multivariate (Cox model) 95% CI P Value
.466 .890
.182
100%/59.9%
.007
100%/60.9%
.014
32.3%/72.2%
27.7/54.6
.014
78.6%/81.8%
49.5/56.8
.319
66.1%/80.0%
38.3/52.3
.739
0.129
0.027-0.627
.011* .137
4.109
1.676-10.072
.002*
6.098
2.038-18.246
.001*
Predictive factors for cancer-specific survival (CSS) of patients in partial cystectomy (PC) group. Univariate analyses were performed using Kaplan–Meier Method and log-rank test. Only those factors that were significant in univariate analysis were entered into the multivariate analysis using Cox regression model (forward-stepwise), P ⬍ .05 was considered statistically significant. LVI, lymphovascular invasion; ST, survival time. a Grade 1 or 2. b Grade 3. c Size and growth pattern were not included in Cox regression analysis model because none of patients with tumor size ⬍3 cm or papillary tumors reached end point, with a censored rate of 100%. * P ⬍ .05.
UROLOGY 76 (4), 2010
905
PC plus UR was performed in 22% of patients with MIBC. Notably, our study revealed that UR was not associated with poor prognosis, effecting a higher 5-year CSS rate compared with the PC-only cohort (88.9% vs 60.2%, P ⫽ .032). By multivariate analysis, UR was a protective factor for 5-year CSS (P ⫽ .011, RR 0.129, 95% CI 0.027-0.627). This “unreasonable” result might be attributed to satisfactory surgical margins and more frequent follow-ups. Yet, the numbers of such patients were relatively low, suggesting that we should consider this conclusion cautiously. By multivariate analysis, the presence of more than 3 tumors was the only predictive factor for both local recurrence and 5-year CSS survival; LVI was another predictive factor for 5-year CSS survival in patients with MIBC after bladder-sparing treatment. Therefore, a tumor count of more than 3 should be considered an exclusion criterion for bladder-preservation protocols. LVI is indicative of bladder cancer that has the potential to metastasize; therefore, it should be treated more aggressively. Compared with RC, PC is advantageous in the treatment of MIBC because of its preservation of potency, preservation of a functional urinary reservoir and urinary continence in male patients, and minimal perioperative morbidity and complications.11 With regard to survival rate, our results suggest that the efficacy of PC plus multimodality therapy is comparable with RC. A major goal of PC is to achieve satisfactory long-term patient survival. The outcomes in our study are comparable to results from other large series. A study by the Memorial SloanKettering Cancer Center7 reported on 58 patients who were treated with PC, which represents the largest clinical study of this kind. With nearly the same mean follow-up period as in our series (33 vs 32.6 months), the percentage of patients who were alive with intact bladders at the last follow-up was 74% (vs 71% in our series), and the 5-year CSS survival rate was 69% vs 68% in our series. The M.D. Anderson Cancer Center also reported on 37 patients with MIBC who underwent PC; their 5-year CSS rate was higher than in our study (87% vs 68%), and the 5-year bladder-intact CSS rates were similar (65% vs 63%).8 These data suggest that PC-based multimodality therapy is undoubtedly an attractive option for the treatment of MIBC, even with our expanded inclusion criteria, and warrants a prospective randomized trial to evaluate the rationale of expanding the inclusion criteria of this bladder preservation treatment further. The inherent drawbacks of TURB, another bladdersparing therapy, include tumor understaging,2 high residual rates,12 and inaccurate staging because of the lack of pelvic lymph node dissection. In our series, the PC-based bladder-sparing protocol resulted in satisfactory local control, with a 2% residual rate and 0% positive margin 906
rate. Furthermore, positive pelvic lymph nodes were detected in 5 patients (5%) in whom lymphadenopathy was not detected by preoperative CT scan. With radical dissection of the pelvic lymph nodes, PC provides complete resection of local tumors within the bladder as well as occult metastases of regional lymph nodes. Robotic partial cystectomy is a new technique, and its feasibility recently has been demonstrated by Allaparthi et al.13 However the lack of tactile feedback, which affects the margins, and the cost of this technique render it unlikely replace open PC. The major limitation of PC is the associated high risk of local tumor recurrence. Local recurrence rates after PC range between 40% and 78%.9 In recent studies of PCbased multimodality treatment, despite strict inclusion criteria, the total local recurrence rate has ranged between 28% and 49% (superficial local recurrence rate 8%-24%, muscle-invasive local recurrence rate 20%28%).7-9,14 Because of the expanded inclusion criteria in our series, we observed a higher total local recurrence rate was (60%) compared with published data. However we must consider that, in contrast to other reports, the majority (77%) of local recurrences in our study comprised cases of superficial recurrence, which are amenable to TURB. The muscle-invasive recurrence rate (14%) in our series was lower than in other reports. Another limitation of PC is the risk of wound recurrence. In our series, there was no instance of wound recurrence, which could be attributed largely to the improved surgical technique, wherein the surrounding organs and wound were well packed before incision into the bladder. Our series is the largest clinical study on MIBC treatment with PC and multimodality adjuvant therapy. Our 5-year CSS rate (68%) and 5-year bladder-intact survival rate (63%) were comparable with those in published reports on partial or radical cystectomy therapy.7,8,15,16 Despite these encouraging results, we should not ignore the caveats of our study. The follow-up period (median 31.5 months) was relatively short. However, because 75% and 90% of local bladder cancer recurrence was observed within 16 and 32 months, respectively, we nevertheless obtained a reasonable assessment of outcomes after PC. Also, our series was a retrospective study with an apparent selection bias. As shown in Table 1, the majority (74%) of patients had stage pT2 disease. Therefore our conclusions should be considered carefully before any prospective randomized study on this treatment is performed.
CONCLUSIONS Collectively, our results confirm that in combination with adjuvant chemotherapy and radiation therapy, PC is an effective alternative treatment for certain patients with MIBC who are unwilling to undergo total cystectomy. The rationale for this regimen includes less tumor residue and lower muscle-invasive local recurrence rates, UROLOGY 76 (4), 2010
as well as comparable survival and bladder preservation rates. Our study also indicates that despite the traditionally strict inclusion criteria, PC can be used more widely as the primary component of multimodality bladder-sparing treatment for MIBC with curative intent. For tumors that are adjacent to the ureteral orifice, UR should be performed, because the long-term prognosis is comparable to, if not better than, that for patients who do not undergo ureteral reimplantation. LVI and a tumor number greater than 3 are risk factors that are associated with poor prognosis in patients with MIBC. Patients with more than 3 tumors should be excluded from bladdersparing treatment modalities.
References 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;76:71-96. 2. Herr HW, Bajorin DF, Scher HI. Neoadjuvant chemotherapy and bladder-sparing surgery for invasive bladder cancer: ten-year outcome. J Clin Oncol. 1998;16:1298-1301. 3. Splinter T, Denis L. Restaging procedures, criteria of response, and relationship between pathological response and survival. Semin Oncol. 1990;17:606-612. 4. Herr HW. Transurethral resection of muscle-invasive bladder cancer: 10-year outcome. J Clin Oncol. 2001;19:89-93. 5. Zapatero A, Martin de Vidales C, Arellano R, et al. Updated results of bladder-sparing trimodality approach for invasive bladder cancer. Urol Oncol. 2009;27:1-7. 6. Sweeney P, Kursh ED, Resnik MI. Partial cystectomy. Urol Clin North Am. 1992;19:701-711.
UROLOGY 76 (4), 2010
7. 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. J Urol. 2004;172:878-881. 8. Kassouf W, Swanson D, Ashish M, Kamat, et al. Partial cystectomy for muscle invasive urothelial carcinoma of the bladder: a contemporary review of the M. D. Anderson Cancer Center experience. J Urol. 2006;175:2058-2062. 9. Smaldone MC, Jacobs BL, Smaldone AM, et al. Long-term results of selective partial cystectomy for invasive urothelial bladder carcinoma. Urology. 2008;72:613-616. 10. Moore MJ, Winquist EW, Murray N, et al. Gemcitabine plus cisplatin, an active regimen in advanced urothelial cancer: a phase II trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1999;17:2876-2881. 11. Laufer M. Transurethral resection and partial cystectomy for invasive bladder cancer. Semin Urol Oncol. 2000;18:296-299. 12. Sternberg CN, Parmar MK. Neoadjuvant chemotherapy is not (yet) standard treatment for muscle-invasive bladder cancer. J Clin Oncol. 2001;19(Suppl):21S-26S. 13. Allaparthi S, Ramanathan R, Balaji KC. Robotic partial cystectomy for bladder cancer: a single-institutional pilot study. J Endourol. 2010;24:223-227. 14. Sternberg CN, Pansadoro V, Fabio Calabro, et al. Can patient selection for bladder preservation be based on response to chemotherapy? Cancer. 2003;97:1644-1652. 15. Solsona E, Climent MA, Iborra I, et al. Bladder preservation in selected patients with muscle-invasive bladder cancer by complete transurethral resection of the bladder plus systemic chemotherapy: long-term follow-up of a phase 2 nonrandomized comparative trial with radical cystectomy. Eur Urol. 2009;55:911-921. 16. Shipley WU, Kaufman DS, Zehr E, et al. Selective bladder preservation by combined modality protocol treatment: long-term outcomes of 190 patients with invasive bladder cancer. Urology. 2002; 60:62-68.
907