Neoadjuvant Gemcitabine Plus Carboplatin for Locally Advanced Bladder Cancer

Jpn J Clin Oncol 2013;43(2)193 199 doi:10.1093/jjco/hys213 Advance Access Publication 28 December 2012 Neoadjuvant Gemcitabine Plus Carboplatin for Locally Advanced Bladder Cancer Kazuhiro Iwasaki, Wataru Obara, Yoichiro Kato, Ryo Takata, Susumu Tanji and Tomoaki Fujioka * Department of Urology, Iwate Medical University, Morioka, Iwate, Japan *For reprints and all correspondence: Tomoaki Fujioka, Department of Urology, Iwate Medical University, Uchimaru 19-1, Morioka, Iwate 020-8505, Japan. E-mail: tomof@iwate-med.ac.jp Received August 17, 2012; accepted November 25, 2012 Objective: Although cisplatin-based neoadjuvant chemotherapy followed by cystectomy was demonstrated to improve the survival among patients with locally advanced bladder cancer, its severe adverse events, including nephrotoxicity, are critical issues. We investigated the safety and activity of carboplatin, a mild nephrotoxic agent, combined with gemcitabine as a neoadjuvant chemotherapy compared with methotrexate, vinblastine, doxorubicin and cisplatin for patients with locally advanced bladder cancer. Methods: We retrospectively evaluated 68 patients with locally advanced bladder cancer who received neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin (n ¼ 34) or gemcitabine and carboplatin (n ¼ 34) followed by cystectomy at our institute. The adverse events, chemotherapy delivery profile, rate of down-stage and recurrence-free survival were assessed for methotrexate, vinblastine, doxorubicin and cisplatin compared with gemcitabine and carboplatin. Results: The mean cycles of methotrexate, vinblastine, doxorubicin and cisplatin, and gemcitabine and carboplatin, were 2.5 and 2.7, respectively. The hematologic adverse events of Grade 3 or 4 neutropenia, anemia and thrombocytopenia for methotrexate, vinblastine, doxorubicin and cisplatin were 15, 18 and 0%, respectively. The occurrences for gemcitabine and carboplatin were 53, 21 and 50%, respectively. Grade 3 or 4 non-hematologic toxicities for methotrexate, vinblastine, doxorubicin and cisplatin were nausea and vomiting in 24%, and were not observed for gemcitabine and carboplatin. The lowest median estimated glomerular filtration rate during methotrexate, vinblastine, doxorubicin, and cisplatin and gemcitabine and carboplatin was 55.8 and 70.6 ml/min/1.73 m 2,respectively(P ¼ 0.002). The rate of downstage to pt1 or less was 59% for methotrexate, vinblastine, doxorubicin and cisplatin, and 53% for gemcitabine and carboplatin (P ¼ 0.624). The recurrence-free survival of methotrexate, vinblastine, doxorubicin and cisplatin, and gemcitabine and carboplatin, at 36 months from the diagnosis was 79 and 75%, respectively (P ¼ 0.85). Conclusions: Neoadjuvant gemcitabine and carboplatin showed less non-hematologic toxicity than methotrexate, vinblastine, doxorubicin and cisplatin, and especially less nephrotoxicity was demonstrated for gemcitabine and carboplatin. Although observed during the short term, the recurrence-free survival for gemcitabine and carboplatin was comparable to that for methotrexate, vinblastine, doxorubicin and cisplatin. Key words: urology urologic-med chemo-urology # The Author 2012. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

194 Neoadjuvant CaG versus MVAC INTRODUCTION The standard of care for locally advanced bladder cancer had previously been total cystectomy and pelvic lymphadenectomy (1). As a result of the Southwest Oncology Group (SWOG)-8710 trial, cisplatin-based neoadjuvant chemotherapy followed by cystectomy has been recommended (2). The trial suggested that neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) chemotherapy followed by cystectomy improved the overall survival compared with cystectomy alone. In advanced metastatic bladder cancer, gemcitabine and cisplatin (GC) chemotherapy has been substituted for MVAC based on the evidence reported by von der Masse et al. (3), in which GC showed non-inferiority together with less toxicity as compared with MVAC in metastatic bladder cancer. Recently, GC as a neoadjuvant therapy in locally advanced bladder cancer has been investigated; however, its effectiveness is still controversial. While downstaging and prolonged disease-free survival in patients treated with GC were reported (4), there are reports of the absence of supportive data in down-staging and an efficacy for lymph nodes (5,6). Although cisplatin-based chemotherapy is effective, its nephrotoxic properties make it unsuitable for patients with renal dysfunction. Carboplatin is an alkylating anti-cancer agent and less nephrotoxic than cisplatin (7). A carboplatincontaining chemotherapy has been reported to play a potential role in advanced bladder cancer patients with renal impairment (8,9). In a neoadjuvant setting, less toxicity is an important matter, and in particular, the decline in renal dysfunction by chemotherapy affects the perioperative management of cystectomy (10) and may affect postoperative life. The rate of estimated glomerular filtration rate (egfr) declines was reported to be more than two times higher in patients with egfr,50 ml/min/m 2 than that in egfr of 60 70 ml/min/m 2 (11). Even if renal function is normal at pre-chemotherapy, impaired renal function by chemotherapy may further exacerbate, especially in elderly patients. As described above, less toxicity is an important matter in a neoadjuvant setting, and we think that less toxic neoadjuvant regimen is needed. We conducted a retrospective study, in which the safety and efficiency of neoadjuvant chemotherapy using carboplatin and gemcitabine (CaG) followed by cystectomy were investigated and compared with MVAC. the transurethral resection of the bladder tumor (TURBT). The distant metastasis or lymph node metastasis was evaluated by computed tomography. The patients gave informed consent to neoadjuvant chemotherapy followed by cystectomy. This clinical trial was approved by the Iwate Medical University ethical committee. TREATMENT PLAN In this study, the intravenous MVAC chemotherapy was performed as a neoadjuvant chemotherapy regimen between July 2002 and February 2008, and CaG chemotherapy was done between March 2008 and April 2011. The MVAC regimen was as follows: methotrexate 30 mg/m 2 (on Days 1, 15 and 22), vinblastine 3 mg/m 2 (on Days 2, 15 and 22), doxorubicin 30 mg/m 2 (on Day 2) and cisplatin 70 mg/m 2 (on Day 2) for a 28-day cycle. The CaG regimen was as follows: gemcitabine 1000 mg/m 2 (on Days 1, 8 and 15) and carboplatin area under the curve (AUC) ¼ 5 (on Day 2) for a 21-day cycle. All patients treated with MVAC and CaG routinely administered metoclopramide hydrochloride as an antiemetic agent. When nausea and vomiting were exacerbated, adrenocorticosteroid and/or 5-HT receptor agonist were administered. The administration of agents were delayed, reduced or omitted, according to the severity of adverse events. The patients were treated with two or three cycles of MVACorCaGchemotherapyfollowedbycystectomyand ileal conduit formation. After two cycles of chemotherapy, the efficacy was determined by two observations (World Health Organization criteria) using MRI, and then only those patients for whom there was an over 50% tumor reduction were treated with three cycles of chemotherapy. The toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. The extent of bilateral pelvic lymphadenectomy was from the bifurcation of common iliac vessels to external iliac and obturator nodes. There is no difference in the extent of lymphadenectomy between the MVAC and CaG groups. The efficiency was evaluated by the down-staging to pt1 or less and recurrence-free survival. The recurrence-free survival was measured from the date of diagnosis until progression. MATERIALS AND METHODS PATIENT CHARACTERISTICS The subjects of this study were patients with locally advanced bladder cancer, ct2a-4an0m0. TNM classification was based on the Union of International Cancer Control (UICC), 7th edition. The cystoscopic examination was performed, and when bladder muscle invasion was suspected, magnetic resonance imaging (MRI) was carried out. In this study, the muscle invasion was determined by MRI but not ENDPOINTS AND STATISTICAL ANALYSIS The endpoints of this study were toxicity, recurrence-free survival and proportion of down-staging in neoadjuvant CaG-treated patients compared with MVAC. Data were analyzed using the SPSS 20.0 statistical software (SPSS, Inc., Chicago, IL, USA). The statistical difference was estimated using the Mann Whitney U-test, x 2 test or Fisher s exact test with P,0.05 considered statistically significant. The Kaplan Meier method and the log-rank test were used for statistical analysis of recurrence.

Jpn J Clin Oncol 2013;43(2) 195 RESULTS Table 1 lists the patient characteristics. Thirty-four patients received neoadjuvant MVAC, and 34 received CaG. The median age of patients was 65 (49 78) years for MVAC and 67 (45 78) for CaG. The median follow-up period was 61 months (15 115) for MVAC and 37 months for CaG (10 50). There were no significant differences in age, gender, clinical and histology between the MVAC and CaG groups. The CaG group received more cycles of chemotherapy than the MVAC group. The toxicities of neoadjuvant MVAC and CaG are shown in Table 2. The hematologic adverse events of Grade 3 or 4 neutropenia, anemia and thrombocytopenia for MVAC were 15, 18 and 0%, respectively. The rate for CaG was 53, 21, Table 1. Patient characteristics MVAC (n ¼ 34) CaG (n ¼ 34) P value Age (years) Median 65.0 66.5 0.995 Range 49 78 45 78 Sex, no. (%) Male 31 (91) 30 (88) 0.690 Female 3 (9) 4 (12) Clinical stage [n (%)] ct2 12 (35) 13 (41) 0.179 ct3 22 (65) 18 (53) ct4 0 (0) 3 (9) Histology [n (%)] Urothelial carcinoma 34 (100) 33 (97) 1.000 Non-urothelial carinoma 0 (0) 1 (3) Chemotherapy cycles [n (%)] 1 cycle 0 (0) 0 (0) 0.013 2 cycles 18 (53) 8 (24) 3 cycles 16 (47) 26 (76) Mean number of cycles 2.5 2.7 Relative dose intensity (%) MTX 96.1 VBL 98.9 ADM 98.2 CDDP 97.1 GEM 99.2 CBDCA 99.2 Follow-up period (months) Median 61 37 Range 15 115 10 50 MVAC, methotrexate, vinblastine, doxorubicin and cisplatin; CaG, gemcitabine and carboplatin; MTX, methotrexate; VLP, vinblastine; ADM, doxorubicin; CDDP, cisplatin; GEM, gemcitabine; CBDCA, carboplatin. 50%, respectively. Because of a high rate of hematologic adverse events in the CaG group, we needed platelet transfusion in nine patients and red blood cell transfusion in eight patients in order to safely perform the operation. Grade 3 or 4 non-hematologic toxicities for MVAC were nausea and vomiting in 24%, and were not observed for CaG. The renal function affected by MVAC and CaG was also investigated (Fig. 1). The median egfr as of pre-chemotherapy for MVAC and CaG was 75.8 and 77.0 ml/min/1.73 m 2, respectively (P ¼ 0.844), and the lowest median egfr during chemotherapy was 55.8 and 70.6 ml/min/1.73 m 2, respectively (P ¼ 0.002). The median egfr for MVAC and CaG at 6 months after cystectomy was 57.0 and 74.5 ml/min/1.73 m 2, respectively (P ¼ 0.012). The number of patients with egfr,60 ml/min/1.73 m 2 treated with MVAC and CaG were 1 (3%) and 4 (12%) at pre-chemotherapy, 19 (56%) and 7 (21%) during chemotherapy and 19 (56%) and 9 (26%) 6 months after cystectomy, respectively (Table 3). The median time to cystectomy after neoadjuvant MVAC and CaG was 24 and 26 days, respectively (P ¼ 0.313). The median of dissected lymph node number in the MVAC and CaG groups was 14.0 and 17.5, respectively (P ¼ 0.494). The number of patients with lymph node metastasis in the Table 2. The toxicity profile of neoadjuvant MVAC and CaG therapy Number of patients (%) G1 G2 G3 G4 MVAC Hematologic Neutropenia 2 (6) 20 (59) 5 (15) 0 (0) Anemia 9 (26) 17 (50) 4 (12) 2 (6) Thrombocytopenia 0 (0) 2 (6) 0 (0) 0 (0) Febrile neutropenia 0 (0) 0 (0) Non-hematologic Nausea, vomiting 7 (21) 13 (38) 7 (21) 1 (3) Fever 2 (6) 1 (3) 0 (0) 0 (0) Liver dysfunction 4 (12) 0 (0) 0 (0) 0 (0) Erythema 2 (6) 0 (0) 0 (0) 0 (0) CaG Hematologic Neutropenia 4 (12) 12 (35) 13 (38) 5 (15) Anemia 7 (20) 20 (59) 6 (18) 1 (3) Thrombocytopenia 8 (24) 9 (26) 17 (50) 0 (0) Febrile neutropenia 1 (3) 0 (0) Non-hematologic Nausea, vomiting 12 (35) 1 (3) 0 (0) 0 (0) Fever 3 (9) 2 (6) 0 (0) 0 (0) Liver dysfunction 5 (15) 0 (0) 0 (0) 0 (0) Erythema 8 (24) 0 (0) 0 (0) 0 (0)

196 Neoadjuvant CaG versus MVAC Table 4. Clinical and pathological in neoadjuvant MVAC and CaG therapy MVAC CaG Pre-treatment Pathological Pre-treatment Pathological Figure 1. The change in egfr at pre-chemotherapy, during chemotherapy and at 6 months after cystectomy. The two bars in the left side show the egfr at pre-chemotherapy. The middle bars show the lowest egfr during chemotherapy. The right bars show the egfr at 6 months after cystectomy. The black and white dots indicate the deviated values from the quartile. MVAC, methotrexate, vinblastine, doxorubicin and cisplatin; CaG, gemcitabine and carboplatin; egfr, estimated glomerular filtration rate. Table 3. The number of patients with egfr,60 ml/min/1.73 m MVAC and CaG groups were 2 (5.9%) and 5 (14.7%), respectively (P ¼ 0.231). The number of main peri-operative complications was infection (nineandsixformvacand CaG, respectively), ileus (four and two, respectively), rectal injury (one and none, respectively). The efficiency of neoadjuvant chemotherapy was evaluated by pathological (Table 4) and recurrence-free survival (Fig. 2). The rates of down-stage to pt1 or less for MVAC and CaG were 21 patients (62%) and 18 (53%), respectively (P ¼ 0.624). The recurrence-free survival at 36 months from the diagnosis was 79% for MVAC and 75% for CaG (P ¼ 0.853). There is no patient receiving adjuvant chemotherapy in the MVAC group. On the other hand, one patient who was pt4n2m0 in the CaG group received adjuvant TIP (paclitaxel, ifosfamide and cisplatin). DISCUSSION Pre-chemotherapy During chemotherapy 6 months after cystectomy MVAC 1 (3%) 19 (56%) 19 (56%) CaG 4 (12%) 7 (21%) 9 (26%) egfr, estimated glomerular filtration rate. The SWOG-8710 trial provided an evidence that neoadjuvant MVAC chemotherapy followed by cystectomy provided T0 0 (0) 2 (6) 0 (0) 5 (15) T1 and 0 (0) 19 (56) 0 (0) 13 (38) Tis T2 12 (35) 10 (29) 13 (38) 11 (32) T3 22 (65) 2 (6) 18 (53) 4 (12) T4 0 (0) 1 (3) 3 (9) 1 (3) MVAC CaG P value pt1 21 (62%) 18 (53%) pt2 13 (38%) 16 (47%) 0.624 Figure 2. Recurrence-free survival of patients treated with neoadjuvant MVAC and CaG therapy. No significant difference was observed (P ¼ 0.85, log-rank test). a higher pt0 rate than cystectomy alone, and suggested that neoadjuvant MVAC improved the overall survival compared with that in the control (2). Although neoadjuvant MVAC chemotherapy was shown to have the merits of neoadjuvant chemotherapy, severe adverse events occur frequently (2,12). Furthermore, some of the population was resistant to MVAC and did not down-stage occur frequently (2,13). Recently, the effect of GC on advanced bladder cancer was reported to be similar to MVAC and with less non-hematologic adverse events (3,14,15), and furthermore, neoadjuvant GC for locally advanced bladder cancer has been investigated (4,6,16). However, the validity of neoadjuvant GC is still

Jpn J Clin Oncol 2013;43(2) 197 controversial; there are reports of the absence of supportive data in down-staging (5) and an effectiveness for lymph nodes (6). Both the MVAC and GC chemotherapy contain cisplatin and so these regimens are not suitable for patients with impaired renal function. At present, there is no report as to an appropriate neoadjuvant chemotherapy regimen for locally advanced bladder cancer patients with impaired renal function. Carboplatin has the greatest benefit in reducing side effects, especially the elimination of the nephrotoxic effect compared with cisplatin (7). There are many reports as to the safety and efficacy of carboplatin-based chemotherapy for metastatic advanced bladder cancer (8,9,17,18). Regrettably, several reports demonstrated that the survival was shorter for CaG than GC. On the other hand, carboplatin is thought to be acceptable for the elderly and those unfit for cisplatin-based chemotherapy because of renal dysfunction (19,20). In the European Association of Urology, National Comprehensive Cancer Network and Japanese Urological Association guidelines as to metastatic bladder cancer, carboplatin can be substituted for cisplatin in patients with impaired renal function (21 23). Although the efficacy of carboplatin has been investigated in advanced bladder cancer, the validity for locally advanced bladder cancer as a neoadjuvant setting has not been sufficiently investigated. In this study, we investigated the safety and efficiency of neoadjuvant CaG chemotherapy. The hematologic toxicities of Grades 3 and 4 in the CaG group were much greater than in the MVAC group; however, severe non-hematologic adverse events were not observed. Because of the hematologic adverse events in the CaG group, we needed to manage the toxicities by postponement, reduction or omission of agents and blood transfusion. Thus, operations were safely performed and peri-operative complications did not occur frequently in the CaG group compared with the MVAC group. Although hematologic toxicities could be recovered by blood transfusion, the complication by blood transfusion and medical cost are critical issues. The study of neoadjuvant CaG subjected to the Japanese population was recently reported (24). In that study, the dose of gemcitabine was 800 mg/m 2 (1000 mg/m 2 in this manuscript) and carboplatin was AUC 4 (AUC 5 in this manuscript), and G3/4 thrombocytopenia and anemia were 19.8 and 8.6%, respectively. Although we decided the dose of gemcitabine and carboplatin in this study according to the reports for the patients of Europe and the USA, dose reduction may be needed for the Japanese population. Renal function during CaG chemotherapy was less affected, but neoadjuvant MVAC, on the other hand, significantly decreased egfr (Fig. 1 and Table 3). These data indicated that the renal toxicity influenced by MVAC was not a temporary but a prolonged issue. The CaG also affected renal function, but the number of renal impaired patients was less than that by MVAC. In addition, one chronic renal failure patient requiring dialysis was included in the CaG group. This patient could be safely treated with neoadjuvant CaG followed by cystectomy and ileal conduit formation. These data indicated that neoadjuvant CaG shows less renal toxicity than the cisplatin-containing regimen and so neoadjuvant CaG may be thought to be a candidate regimen for the patients who cannot be treated with a cisplatin-containing regimen. However, the study for the only patients with renal dysfunction was needed in order to validate the safety of neoadjuvant CaG for the renal impaired patients. Next, the efficacy of neoadjuvant CaG was an important concern. It was reported that carboplatin-containing regimens were inferior to cisplatin-containing regimens in advanced bladder cancer. In this study, the rate of down-stage to pt1 or less was 62% for MVAC and 53% for CaG (P ¼ 0.624). Dash et al. (4) reported that the rate of down-stage to pt1 or less in patients who received neoadjuvant GC chemotherapy was 36%, and Kaneko et al. (16) reported that the rate was 63%. Since patients background was different, it cannot be easily compared; however, the down-stage rate of neoadjuvant CaG chemotherapy may be comparable to neoadjuvant GC. The rate of pt0 in this study was very low compared with previous reports. In our institute, the complete TURBT is not performed before neoadjuvant chemotherapy. This may be the one of the reasons for the low pt0 rate in this study. The recurrence of locally advanced bladder cancer mainly occurred within 3 years after cystectomy. Solsona et al. (25) reported that 90% of all recurrence occurred within 3 years after cystectomy. The median follow-up duration of the CaG group in this study was 37 months and so it is thought to meet a minimal observation period to investigate the recurrence-free survival. The recurrence-free survival at 36 months after diagnosis was 79% in the MVAC group and 75% in the CaG. Dash et al. (4) reported that the recurrencefree survival in the neoadjuvant GC group at the same time was 65%. Although this cannot also be easily compared, neoadjuvant CaG chemotherapy may be comparable to neoadjuvant GC in the recurrence-free survival. Although neoadjuvant CaG chemotherapy was statistically comparable to MVAC as to the effect on the rate of downstage to pt1 or less and the recurrence-free survival in our study, the CaG group is thought to be somewhat inferior compared with the MVAC group. In order to determine whether neoadjuvant CaG is comparable to MVAC in the efficacy, a sufficient observation period is needed and overall survival should be investigated. Considering the current evidence, we think that MVAC is an appropriate regimen for the first line of neoadjuvant chemotherapy, because MVAC is the only neoadjuvant regimen to have a potential of survival prolongation. Neoadjuvant GC may be substituted for MVAC by new evidence. And, neoadjuvant CaG chemotherapy has a good safety profile, so it might be better for the elderly and the patients with impaired renal function. There are limitations to our study. This is a retrospective study and patients were not randomized and the sample size

198 Neoadjuvant CaG versus MVAC was small. Secondly, the observation was only for a short period and so overall survival still remains to be determined. Interestingly, why is CaG chemotherapy active for locally advanced bladder cancer, but not effective for metastatic bladder cancer? One of the reasons may be due to the patients conditions and cancer characteristics. The patients with metastases often have lower immunocompetence and performance status (26,27). Furthermore, metastatic cancer cells are more resistant to anti-cancer agents (28). The patients in this study had no metastasis and so carboplatinbased chemotherapy might be effective. The second reason may be different sensitivity between races. The previous studies on carboplatin-based chemotherapy had been mainly performed in Europe and the USA but not Asia. The subjects in this study were all Japanese. An additional problem is that the rate of pt2 or over was 34% for MVAC and 47% for CaG. Should we perform neoadjuvant chemotherapy followed by cystectomy or cystectomy alone for these patients? To elucidate this issue, we determined the genes involved in the sensitivity for MVAC and CaG through a genome-wide gene expression profile (29 31). We currently have carried out a prospective cohort study using the MVAC and CaG sensitivity system. This personalized medicine will enable us to select an appropriate regimen or immediate cystectomy for these patients. In conclusion, neoadjuvant CaG for locally advanced bladder cancer had a high grade of hematologic toxicities but no high grade non-hematologic toxicity, especially renal toxicity. The dose reduction of gemcitabine and carboplatin may be needed to reduce hematologic toxicities. The MVAV group was statistically equivalent but slightly superior to the CaG group in down-staging and recurrence-free survival. However, the MVAC regimen had more renal toxicity than the CaG and its toxicity prolonged 6 months after cystectomy. 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