Impact of adjuvant chemotherapy on patients with pathological Stage T3b and/or lymph node metastatic bladder cancer after radical cystectomy

Japanese Journal of Clinical Oncology, 2015, 45(10) 963 967 doi: 10.1093/jjco/hyv098 Advance Access Publication Date: 29 July 2015 Original Article Original Article Impact of adjuvant chemotherapy on patients with pathological Stage T3b and/or lymph node metastatic bladder cancer after radical cystectomy Mariko Tabata, Masaomi Ikeda*, Shinji Urakami, Shintaro Takahashi, Kazushige Sakaguchi, Kazuhiro Kurosawa, and Toshikazu Okaneya Department of Urology, Toranomon Hospital and Okinaka Memorial Institute for Medical Research, Tokyo, Japan *For reprints and all correspondence: Masaomi Ikeda, Department of Urology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo 105-8470, Japan. E-mail: ikeda.masaomi@grape.plala.or.jp Received 21 February 2015; Accepted 5 June 2015 Abstract Objective: To evaluate the effectiveness of adjuvant chemotherapy in patients with pathological Stage T3 bladder cancer who had undergone radical cystectomy, and to determine the prognostic survival factors for adjuvant chemotherapy treatment. Methods: From January 1990 to October 2013, 202 patients underwent radical cystectomy and pelvic lymphadenectomy. Among them, 65 patients with non-organ-confined disease ( pt3, N0 3, M0) diagnosed were investigated in this study. Thirty-one patients (48%) were treated with adjuvant chemotherapy and the remaining 34 patients (52%) were not. Results: Median age of all patients was 66 years, and median follow-up was 26.1 months. For all pt3 patients, overall survival and disease-free survival times were similar in the adjuvant chemotherapy and non-adjuvant chemotherapy groups. However, in the pt3b subgroup, median overall survival (47.0 vs. 10.6 months) and median disease-free survival (35.5 vs. 5.3 months) times were significantly prolonged for those who underwent adjuvant chemotherapy (P = 0.009 and 0.025). In patients with pathological lymph node metastatic ( pn+), median overall survival (30.1 vs. 6.4 months) and median disease-free survival (15.7 vs. 3.5 months) times were significantly prolonged in the adjuvant chemotherapy group (P = 0.016 and 0.027). In addition, according to multivariate analysis in pt3b and/or pn + subgroup patients, adjuvant chemotherapy status was an independent predictive factor for overall survival and disease-free survival. Conclusion: Adjuvant chemotherapy did not significantly improve overall survival and disease-free survival when compared with all patients with pt3 who had received radical cystectomy in the nonadjuvant chemotherapy group. However, in the pt3b and pn+ subgroup, adjuvant chemotherapy demonstrated statistically significant benefits regarding overall survival and disease-free survival. Although these results could not support adjuvant chemotherapy use for all pt3 patients, the pt3b substage and/or pn+ may help identify patients with pt3 who could benefit from adjuvant chemotherapy. Key words: adjuvant chemotherapy, urothelial carcinoma, pt3 bladder cancer The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com 963

964 Impact of AC on patients with pt3b and/or pn+ after RC Introduction Radical cystectomy (RC) with bilateral pelvic lymphadenectomy has been the gold standard treatment of muscle-invasive bladder cancer (MIBC) for the past three decades. However, the survival outcome is associated with the pathological tumor stage of the RC specimen. In patients with organ-confined disease without lymph node metastasis (Stage pt2 or lower, pn0), long-term survival has been reported to be 75 85%. However, 5-year overall survival (OS) estimates range from 45 to 55% for patients with pt3 4 diseaseandfrom25to 35% for patients with lymph node metastasis (ptany, pn1 3) (1 3). To extend OS in MIBC, various neoadjuvant chemotherapy and adjuvant chemotherapy (AC) have been investigated. Neoadjuvant chemotherapy has been used to treat micrometastatic disease and improve OS. In a meta-analysis of 11 trials involving 3005 patients, platinum-based neoadjuvant chemotherapy was associated with 5% absolute improvement in survival at 5 years (4). Neoadjuvant chemotherapy is recommended based on the high level evidence showing survival benefits in the European Association of Urology and National Comprehensive Cancer Network guidelines (5,6). However, the last meta-analysis evaluating AC, conducted in 2005, had limited power to fully support its use (7). The role of AC for patients with high-risk MIBC remains controversial and there is no sufficient evidence to suggest routinely administrating AC after RC. In clinical practice, we suggest AC to patients with high-risk factors [pt3 or higher, pn+, present lymphovascular invasion (LVI) etc.] after RC. However, the impact of AC on high-risk patients remains undetermined, and the patient group receiving true benefits is not yet known. The aim of this study was to evaluate the efficacy of AC in patients with pt3 locally advanced bladder cancer and to determine prognostic factors of survival with AC treatment. Patients and methods This study was a non-randomized retrospective study. From January 1990 to October 2013, 202 patients with bladder cancer underwent RC and pelvic lymphadenectomy in our institution. Among them, 71 patients had pt3 locally advanced bladder cancer (N0 3, M0). Six patients who had received neoadjuvant chemotherapy were excluded and the remaining 65 pt3 patients were investigated in this study. All patients had urothelial carcinoma, and patients with pure adenocarcinoma or small cell carcinoma were excluded from this study. Thirty-one patients (48%) received AC and 34 (52%) did not. Seventeen patients with locally advanced bladder cancer received neoadjuvant radiotherapy in the early 1990s. A standard fractionation with a daily dose of 2.0 Gy was used, with a median total dose of 24 Gy (range, 20 26 Gy) over 2 weeks. Generally, the bladder tumor, bladder and regional lymph nodes were treated with anterior posterior opposing portal irradiation. TNM staging was based on the 2009 (seventh) TNM Classification of the International Union for Cancer Control and the American Joint Committee on Cancer Guidelines. After institutional review board approval, comprehensive clinical, pre-operative laboratory and final pathological data from the eligible patients were retrieved and reviewed. The study was conducted in accordance with the Declaration of Helsinki. In males, standard RC involved resection of the bladder, prostate, seminal vesicles and distal ureters; in females, an anterior pelvic exenteration included the removal of the bladder, entire urethra and adjacent vagina, uterus and distal ureters. Standard pelvic lymphadenectomy is defined as the removal of all lymphatic tissues around the external iliac, internal iliac and obturator region bilaterally. Urinary diversion was performed after RC as follows: neobladder in 12 patients; ileal conduit in 52 patients; and ureterocutaneostomy in 1 patient. Although AC was usually recommended for patients with stage pt3 (or higher) or positive lymph node metastasis in our institution, AC was determined by consultation with a urologist in charge and the patient based on performance status, renal function, patient wishes and other reasons. All patients received three or four cycles of cisplatin-based chemotherapy within 3 months after RC in the AC group. Patients were generally followed-up every 3 4 months for 2 years after RC, then every 6 months for the subsequent 3 years, and, finally, annually thereafter. Follow-up included a physical examination and routine serum chemistry studies. Radiographic evaluation (with or without contrast-enhanced computerized tomography) of urinary diversion, the upper urinary tract and the local region, as well as a chest X-ray, were performed at 3 or 6 months post-operatively and annually thereafter. Bone scans and other radiographic evaluations were performed when clinically indicated. Based on patient medical records, OS was calculated from the date of RC until death from any cause or was censored at the last follow-up, and disease-free survival (DFS) was calculated from RC to the date of documented progression or death from any cause. Comparison of clinical and pathological data between the two groups was performed by χ 2 test or Fisher s exact test. Survival curves were estimated by the Kaplan Meier method and differences between the two groups were determined with the log-rank test. Multivariate survival analyses were performed with the Cox proportional hazards regression model, controlling for age (younger than 66 vs. 66 or older), sex (male vs. female), pt stage (pt3a vs. pt3b), lymph node status (pn0 or Nx vs. pn+), LVI (absent vs. present), soft tissue surgical margin (STSM) (negative vs. positive) and AC status (no vs. yes). All statistical analyses were performed with JMP software version 11.2 (SAS, Cary, NC), and P < 0.05 was considered statistically significant; all P values are two-sided. Results The median age of all cohort patients was 66 years [interquartile range (IQR), 60 73 years] and median follow-up period was 26.1 months (IQR, 7.9 73.8 months). The clinical and pathological characteristics of all patients are listed in Table 1. Although there were statistically significant differences in pathological tumor stage (P = 0.005) and median follow-up period (P = 0.007) between the AC and non-ac groups, there were no statistically significant differences regarding other factors. Furthermore, in the pt3b or pn+ subgroup, renal function and performance status that can affect the decision to perform AC were not statistically different. Thirty-one patients received cisplatinbased AC for a median of three courses (range, 1 6). Twenty-five patients (81%) received a methotrexate, vinblastine, doxorubicin and cisplatin regimen, one (3%) received a gemcitabine and cisplatin regimen, and five (16%) received other regimens. The majority of patients received MVAC regimen, and relative dose intensity was 75%. Especially, cisplatin was reduced by 25 50% in cases of impaired renal function after RC, and most of those patients used prophylactic granulocyte-colony stimulating factor. Therefore, there was no severe myelosuppresion and febrile neutropenia. When we included all patients for analysis, median OS time was 47.0 months versus 44.7 months for the AC group and the non-ac group, respectively [hazard ratio (HR), 0.66; 95% confidence interval (CI), 0.32 1.34; P = 0.245). Median DFS time was 38.6 months versus 42.1 months in the AC group and the non-ac group, respectively (HR, 0.79; 95% CI, 0.39 1.61; P = 0.505). AC did not significantly

Jpn J Clin Oncol, 2015, Vol. 45, No. 10 965 improve OS and DFS as compared with the non-ac group (Fig. 1A and B). In the pt3a subgroup patients, OS and DFS times were similar in the AC and non-ac groups. However, in 41 patients in the pt3b subgroup, median OS time was 47.0 months in the AC group and was 10.6 months in the non-ac group, respectively (HR, 0.38; 95% CI, 0.17 0.81; P = 0.009) (Fig. 2A). Median DFS time was 35.5 months versus 5.3 months, respectively (HR, 0.43; 95% CI, 0.20 0.94; P = 0.025) (Fig. 2B). In patients with pathological lymph node metastatic ( pn+), median OS time was significantly prolonged in Table 1. Clinical and pathological characteristics of patients receiving adjuvant and non-adjuvant chemotherapy Characteristics AC (n = 31) Non-AC (n = 34) Age, years Median (IQR) 66 (61 71) 66 (59 74) 0.875 Sex (%) Male 27 (87) 27 (79) 0.409 Female 4 (13) 7 (21) ECOG performance status (%) 0 or 1 28 (90) 31 (91) 0.905 2 3 (10) 3 (9) Post-operative serum creatinine, mg/dl Median (IQR) 1.0 (0.8 1.3) 1.1 (0.9 1.5) 0.354 Pathological T stage (%) pt3a 6 (19) 18 (53) 0.005 pt3b 25 (81) 16 (47) Lymph node status (%) pn0 or pnx 20 (65) 26 (76) 0.290 pn+ 11 (35) 8 (24) Lymphovascular invasion (%) Absent 5 (16) 7 (21) 0.644 Present 26 (84) 27 (79) Neoadjuvant radiotherapy Yes 9 (29) 8 (24) 0.614 No 22 (71) 26 (76) Tumor grade (%) G2 5 (16) 6 (18) 0.871 G3 26 (84) 28 (82) Soft tissue surgical 0.259 margin (%) Negative 28 (90) 33 (97) Positive 3 (10) 1 (3) Follow-up, months Median (IQR) 35 (16.4 101.1) 16.3 (4.4 45.6) 0.007 AC, adjuvant chemotherapy; IQR, interquartile range; ECOG, Eastern Cooperative Oncology Group. * P < 0.05. P the AC group (30.1 vs. 6.4 months) (HR, 0.31; 95% CI, 0.11 0.86; P = 0.016) (Fig. 2C). Median DFS time was 15.7 months versus 3.5 months in the AC group and non-ac group, respectively (HR, 0.33; 95% CI, 0.12 0.95; P = 0.027) (Fig. 2D). In addition, according to multivariate Cox proportional hazards regression analysis of the pt3b and/or pn+ subgroup, AC status was independent predictive factor for OS and DFS, along with age and lymph node status (Table 2). Discussion During the past three decades, several randomized controlled trials (RCTs) and meta-analyses investigated the role of AC in MIBC (7 9). Nevertheless, the decision to administer AC to MIBC patients who are at high risk for clinical recurrence is controversial. In the meta-analysis published in 2005 based on 491 patients from six trials, the overall HR for survival of 0.75 represents a 25% relative decrease in the risk of death with AC compared with that of controls (P = 0.019) (7). Although this meta-analysis analyzed individual patient data (IPD), it was limited by small numbers, with only 491 patients and 283 deaths. There was insufficient evidence regarding how to make reliable decisions regarding AC. An updated meta-analysis of nine RCTs (five previously analyzed, one updated, and three new), which included 945patients, was performed in 2013 (10). It showed 23% relative decrease in the risk of death with AC compared with controls and 34% relative decrease in the risk of recurrence. Although it was thought that this updated meta-analysis offered further evidence of OS and DFS benefits, there were some limitations and it is still controversial. First, IPD for this meta-analysis was not available. Second, the most recent Italian (11) and Spanish trials (12) had completely opposite results (10,13). Those different results may be attributable to the different regimens used and because of patient selection bias. The Italian trial enrolled 194 patients and reported a nonsignificant OS HR of 1.29 (95% CI, 0.84 1.99) and a nonsignificant DFS HR of 1.08 (95% CI, 0.73 1.59). In contrast, the Spanish trial, which is not yet published, enrolled 142 patients and demonstrated statistically significant benefits of OS and DFS, with HR of 0.38 (95% CI, 0.22 0.65) and HR of 0.38 (95% CI, 0.25 0.058), respectively. The optimal targets of AC treatment have never been identified, but we thought that patients with pt3 after RC would receive the most benefit from AC. Although the Italian trial was underpowered to demonstrate that AC improves OS and DFS in patients with MIBC, mortality hazards were significantly correlated with pt stage (stage pt3 or higher) and lymph node status in a multivariate analysis (11). In fact, Yelfimov et al. investigated 675 patients who underwent RC for pt2 4N0 3. A total of 80 patients (12%) received AC and were compared with the non-ac group. In this study, when Figure 1. Kaplan Meier plots for overall survival (A) and disease-free survival (B) in patients with pt3 who had undergone radical cystectomy. AC, adjuvant chemotherapy.

966 Impact of AC on patients with pt3b and/or pn+ after RC Figure 2. (A, B) Kaplan Meier plots for overall survival (OS) and disease-free survival (DFS) in the pt3b subgroup. Median OS (47.0 vs. 10.6 months; P = 0.009) and DFS (35.5 vs. 8.0 months; P = 0.025) were significantly prolonged in the AC group. (C, D) Kaplan Meier plots for OS and DFS in pn+. Median OS (30.1 vs. 6.4 months; P = 0.016) and DFS (15.7 vs. 3.5 months; P = 0.027) were significantly prolonged in the AC group. Table 2. Multivariate Cox proportional hazards analysis of parameters predicting disease-free survival and overall survival in pt3b and/or pn+ subgroup patients Parameter Disease-free survival Overall survival HR (95% CI) P HR (95% CI) P Age at surgery 66 years (reference: <66 years) 3.34 (1.265 9.833) 0.014 3.12 (1.195 9.113) 0.019 Female (reference: male) 1.54 (0.455 4.623) 0.469 1.88 (0.587 5.651) 0.278 pt3b (reference: pt3a) 0.28 (0.038 5.755) 0.330 0.20 (0.028 4.210) 0.240 Positive lymph nodes (reference: pn0 or pnx) 2.79 (1.173 6.927) 0.020 2.47 (1.018 6.190) 0.046 Present LVI (reference: absent) 1.26 (0.396 5.613) 0.721 1.28 (0.391 5.827) 0.704 Positive STSM (reference: negative) 0.78 (0.173 2.526) 0.700 0.69 (0.151 2.318) 0.577 Adjuvant chemotherapy (reference: non-ac) 0.25 (0.096 0.648) 0.004 0.26 (0.105 0.644) 0.004 HR, hazard ratio; CI, confidence interval; LVI, lymphovascular invasion; STSM, soft tissue surgical margin. controlling for age, sex, stage, and performance status in multivariate analysis, AC was associated with a 29% decrease in the risk of bladder cancer death and a 39% decrease in the risk of OS. The pt stage and lymph node status were also associated with bladder cancer death and OS (14). Svatek et al. (15) also retrospectively analyzed their large cohort consisting of 3947 patients, 932 (23.6%) of whom received AC. Advanced pt stage (stage pt3 or higher) and nodal involvement were most likely to benefit from AC. Furthermore, another study reported that post-operative cisplatin-based AC improved survival in locally advanced (stage pt3 or higher) or node-positive bladder cancer (16). However, it is controversial whether there is a prognostic difference between microscopic (pt3a) and macroscopic (pt3b) perivesical fat invasion. Neuzillet et al. (17) retrospectively analyzed 327 patients (pt2b-pt3b) who underwent RC and bilateral pelvic lymphadenectomy without neoadjuvant chemotherapy. AC was routinely proposed to all patients with pt3 tumors and/or positive lymph node status, and 152 patients (47%) received AC. In pn0 disease, the differences between 5-year metastases-free survival for pt2b-pt3a and pt3b were not significant for patients who had received AC, but they were significant for patients without AC. Therefore, they concluded that the pt3b stage might benefit more from AC. In addition, the other study that examined the prognosis factors in pt3n0 bladder cancer after RC without neoadjuvant chemotherapy reported that the pt3 substage had an independent association with RFS in multivariate analysis (18,19). According to multivariate analysis of the pt3b and/or pn+ subgroup, AC status was a significant predictor of OS and DFS in our study. Our results were consistent with the results of other studies. We acknowledge that there are some limitations in this study that are inherent to any retrospective study. AC was not randomly prescribed, as is often the case in clinical practice. Such selection bias may be related to the difference in OS or DFS between the AC and non-ac groups. Finally, our sample size was small and the study was performed in a single institution. In the future we will investigate

Jpn J Clin Oncol, 2015, Vol. 45, No. 10 967 more cases using a multicenter study, and we will examine the appropriate patient groups receiving benefits from AC. In conclusion, OS and DFS of the pt3b and pn+ subgroup were significantly prolonged in the AC arm. However, AC did not significantly improve OS and DFS as compared with the non-ac group of all pt3 patients who underwent RC. According to multivariate analysis in pt3b and/or pn+ subgroup patients, AC status was independent predictive factor for OS and DFS. That is, pt3b substage and/or pn+ may help identify patients with pt3 who could benefit from AC. Conflict of interest statement None declared. References 1. Hautmann RE, de Petriconi RC, Pfeiffer C, Volkmer BG. Radical cystectomy for urothelial carcinoma of the bladder without neoadjuvant or adjuvant therapy: long-term results in 1100 patients. Eur Urol 2012;61:1039 47. 2. Shariat SF, Karakiewicz PI, Palapattu GS, et al. Outcomes of radical cystectomy for transitional cell carcinoma of the bladder: a contemporary series from the Bladder Cancer Research Consortium. JUrol2006;176:2414 22. 3. Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol 2001;19:666 75. 4. Advanced bladder cancer (ABC) meta-analysis collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data. Eur Urol 2005;48:202 6. 5. Witjes JA, Comperat E, Cowan NC, et al. EAU Guidelines on Muscleinvasive and Metastatic Bladder Cancer: Summary of the 2013 Guidelines. Eur Urol 2014;65:778 92. 6. Clark PE, Agarwal N, Biagioli MC, et al. Bladder cancer. J Natl Compr Canc Netw 2013;11:446 75. 7. Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Adjuvant chemotherapy in invasive bladder cancer: a systematic review and metaanalysis of individual patient data. Eur Urol 2005;48:189 201. 8. Einstein AB Jr, Shipley W, Coombs J, Cummings KB, Soloway MS, Hawkins I. Cisplatin as adjunctive treatment for invasive bladder carcinoma: tolerance and toxicities. Urology 1984;23:110 7. 9. Richards B, Bastable JR, Freedman L, et al. Adjuvant chemotherapy with doxorubicin (adriamycin) and 5-fluorouracil in T3, NX, MO bladder cancer treated with radiotherapy. Br J Urol 1983;55:386 91. 10. Leow JJ, Martin-Doyle W, Rajagopal PS, et al. Adjuvant chemotherapy for invasive bladder cancer: a 2013 updated systematic review and metaanalysis of randomized trials. Eur Urol 2014;66:42 54. 11. Cognetti F, Ruggeri EM, Felici A, et al. Adjuvant chemotherapy with cisplatin and gemcitabine versus chemotherapy at relapse in patients with muscle-invasive bladder cancer submitted to radical cystectomy: an Italian, multicenter, randomized phase III trial. Ann Oncol 2012;23: 695 700. 12. Paz-Ares LG, Solsona E, Esteban E, et al. Randomized phase III trial comparing adjuvant paclitaxel/gemcitabin/cisplatin (PGC) to observation in patients with resected invasive bladder cancer: results of the Spanish Oncology Genitourinary Group (SOGUG) 99/01 study [abstract LBA4518]. J Clin Oncol 2010;28:18. 13. Sternberg CN, Sylvester R. Thoughts on a systematic review and metaanalysis of adjuvant chemotherapy in muscle-invasive bladder cancer. Eur Urol 2014;66:55 6. 14. Yelfimov DA, Frank I, Boorjian SA, Thapa P, Cheville JC, Tollefson MK. Adjuvant chemotherapy is associated with decreased mortality after radical cystectomy for locally advanced bladder cancer. World J Urol 2014;32: 1463 8. 15. Svatek RS, Shariat SF, Lasky RE, et al. The effectiveness of off-protocol adjuvant chemotherapy for patients with urothelial carcinoma of the urinary bladder. Clin Cancer Res 2010;16:4461 7. 16. Kanatani A, Nakagawa T, Kawai T, et al. Adjuvant chemotherapy is possibly beneficial for locally advanced or node-positive bladder cancer. Clin Genitourin Cancer 2015;13:107 12. 17. Neuzillet Y, Lebret T, Molinie V, et al. Perivesical fat invasion in bladder cancer: implications for prognosis comparing pt2b, pt3a and pt3b stages and consequences for adjuvant chemotherapy indications. BJU Int 2012;110:1736 41. 18. May M, Bastian PJ, Brookman-May S, et al. External validation of a risk model to predict recurrence-free survival after radical cystectomy in patients with pathological tumor stage T3N0 urothelial carcinoma of the bladder. JUrol2012;187:1210 4. 19. Sonpavde G, Khan MM, Svatek RS, et al. Prognostic risk stratification of pathological stage T3N0 bladder cancer after radical cystectomy. J Urol 2011;185:1216 21.