Oncological Outcomes of Neoadjuvant Gemcitabine plus Carboplatin versus Gemcitabine plus Cisplatin in Locally Advanced Bladder Cancer: A Retrospective Analysis Bahram Mofid1, Abolfazl Razzaghdoust1, Mahdi Ghajari2, Abbas Basiri1, Mohammad-Reza Fattahi3, Mohammad Houshyari2, Anya Jafari2*, Farzad Taghizadeh-Hesary2* Purpose: Cisplatin-based neoadjuvant chemotherapy (NAC) is the standard of care in non-metastatic muscle-in- vasive bladder cancer (MIBC). There are limited data regarding the alternative choices for cisplatin-ineligible patients. This study has investigated the oncological outcomes of gemcitabine plus cisplatin (Gem/Cis) and gem- citabine plus carboplatin (Gem/Carbo) in this setting. Materials and Methods: One hundred forty consecutive patients with MIBC (cT2–T4a) receiving neoadjuvant Gem/Cis or Gem/Carbo before chemoradiation (CRT) or radical cystectomy (RC) were retrospectively evaluated between April 2009 and April 2019. Patients with ECOG performance status 2, creatinine clearance < 60 mL/min, hydronephrosis, ejection fraction < 50%, or single kidney received Gem/Carbo. The complete clinical response (cCR) and overall survival (OS) of NAC regimens were compared. Prognostic significance was assessed with Cox proportional hazards model. Results: In total, 79 patients (56.4%) received Gem/Cis. The cCR was not significantly different between Gem/ Cis and Gem/Carbo regimens (38.7% vs. 36.2%, P = .771). After NAC, 79 patients (56.4%) received CRT, and other cases underwent RC. After a median follow-up of 43 months, patients in the Gem/Cis group had significantly better OS than Gem/Carbo (median OS: 41.0 vs. 26.0 months, P = .008). Multivariable Cox proportional hazards models identified cT4a stage (95% confidence interval [95% CI]: 1.001–4.85, hazard ratio [HR] = 2.08, P = .03) and cCR (95% CI: 0.26–0.99, HR = 0.51, P = .04) as the only independent prognostic factors of OS, and ruled out the type of NAC regimen. Conclusion: The choice of NAC (between Gem/Cis and Gem/Carbo) is not the predictor of survival and both regimens had similar cCR. Keywords: bladder cancer; carboplatin; cisplatin; complete clinical response; neoadjuvant chemotherapy; overall survival; prognostic factors INTRODUCTION Bladder cancer (BC) is the 12th most common ma-lignancy and the 13th leading cause of cancer-re- lated mortality worldwide.(1) Urothelial cell carcinoma (UCC) is the most frequent primary BC that accounts for 95% of cases, most of which are diagnosed at an early stage. This highlights the importance of locore- gional therapy.(2) For better management, BC is classified into three dis- tinct categories: non-muscle invasive BC, muscle in- vasive BC (MIBC), and metastatic BC. Taking a step back, primary radical cystectomy (RC) was the stand- ard treatment in MIBC. Investigators realized that dis- tant metastasis was the main pattern of recurrence after RC.(3) Therefore, neoadjuvant chemotherapy (NAC) was proposed and dramatically improved the clinical outcomes of RC.(4) Alternative to RC, radiotherapy 1Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 2Department of Clinical Oncology, Shohada-e Tajrish Educational Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 3Nephrology and Urology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran. *Correspondence: Department of Clinical Oncology, Shohada-e Tajrish Hospital, Tehran, Postal code: 19839-63113, Iran. Tel: (+98)-912-6086713, Fax: (+98)-21026651517, E-mail: f_taghizadeh@sbmu.ac.ir **Department of Clinical Oncology, Shohada-e Tajrish Hospital, Tehran, Postal code: 19839-63113, Iran. Tel: (+98)-912-5491074, Fax: (+98)-21-22760999, E-mail: anyajafari@yahoo.com Received May 2021 & Accepted February 2022 is an available choice—in case of complete response to NAC—to exclude the morbidity of surgery.(5) Cur- rently, cisplatin-based neoadjuvant regimens such as gemcitabine plus cisplatin (Gem/Cis) and methotrex- ate, vinblastine, doxorubicin plus cisplatin (MVAC) are the standard regimens.(4) Despite these advantages, NAC is not widely employed in patients who are unfit for cisplatin-based NAC, including patients with East- ern Cooperative Oncology Group (ECOG) performance state of 2, single kidney, hydronephrosis, creatinine clearance (CrCl) < 60 mL/min, grade 2 of neuropathy, hearing loss, or cardiac failure class III (based on New York Heart Association classification).(6) Studies have demonstrated that 30–50% of the BC patients are ineli- gible for cisplatin.(7) A carboplatin-based regimen could be a viable option for patients unfit for cisplatin. The use of carboplatin in- stead of cisplatin was investigated in other cancers such UROLOGICAL ONCOLOGY Urology Journal/Vol 19 No. 5/ September-October 2022/ pp. 371-378. [DOI:10.22037/uj.v19i.6841] as malignant mesothelioma and lung cancers.(8-10) Cur- rently, there is a paucity of convincing data supporting the use of carboplatin (as NAC) in MIBC patients who are ineligible for receiving cisplatin.(11) A few studies assigned a comparative response rate and survival;(12-15) however, a more recent retrospective cohort demon- strated superior pathologic response and survival in the cisplatin group.(16) This discrepancy might originate from selecting treatment regimens with totally differ- ent agents [i.e., MVAC (as the cisplatin-based regimen) vs. Gem/Carbo (as the carboplatin-based regimen)] in two studies(13,14) or unbalanced sample sizes in two other studies that could impact the power of the results.(12,16) Considering these issues, this retrospective cohort was therefore designed to compare the clinical response and survival of a standard cisplatin-based NAC (Gem/Cis) and a carboplatin-based regimen (gemcitabine plus car- boplatin [Gem/Carbo]) in MIBC. Neoadjuvant carboplatin in locally advanced bladder cancer-Mofid et al. Table 1. Baseline characteristics and treatment types of the study population Characteristics Total (N = 140) Gem/Cis (N = 79) Gem/Carbo (N = 61) P-value Age, Mean (SD), years 66.3 (10.4) 61.4 (9.0) 72.8 (8.4) < .001 Sex, N (%) .813 Female 10 (7.1) 6 (7.6) 4 (6.6) Male 130 (92.8) 73 (92.4) 57 (93.4) Tumor stage, N (%) .360 T2 80 (57.1) 47 (59.5) 33 (54.1) T3 48 (34.3) 28 (35.4) 20 (32.8) T4a 11 (7.9) 4 (5.1) 7 (11.5) Missing 1 (0.7) 0 1 (1.6) Nodal status, N (%) .831 Negative 102 (72.8) 57 (72.2) 45 (73.8) Positive 38 (27.2) 22 (27.8) 16 (26.2) Tumor grade, N (%) .279 Low 4 (2.8) 4 (5.1) 0 High 136 (97.2) 75 (94.9) 61 (100) Creatinine clearance, Mean (SD), mL/min 59.0 (20.5) 69.9 (18.6) 44.8 (12.9) .003 Previous BCG therapy, N (%) .129 No 106 (75.7) 56 (70.9) 50 (82.0) Yes 34 (24.3) 23 (29.1) 11 (18.0) Smoking status, N (%) .611 No 81 (57.8) 44 (55.7) 37 (60.6) Yes 59 (42.2) 35 (44.3) 24 (39.4) Following treatment, N (%) .510 Radical cystectomy 61 (43.6) 34 (43.1) 27 (44.3) Chemoradiotherapy 79 (56.4) 45 (56.9) 34 (55.7) Abbreviations: BCG, bacillus Calmette Guerin; Gem/Carbo, gemcitabine plus carboplatin; Gem/Cis, gemcitabine plus cisplatin; SD, standard deviation Covariates Without complete response (N = 83) With complete response (N = 50) P-value Age, N (%) .516 ≤ 65 yr 43 (65.1) 23 (34.9) > 65 yr 40 (59.7) 27 (40.3) Sex N (%) .999 Female 6 (60.0) 4 (40.0) Male 77 (62.6) 46 (37.4) Tumor stage, N (%) .536 T2 45 (58.4) 32 (41.6) T3 31 (67.4) 15 (32.6) T4a 7 (70.0) 3 (30.0) Nodal status, N (%) .320 Negative 63 (64.9) 34 (35.1) Positive 20 (55.5) 16 (44.6) Tumor grade, N (%) .999 High 81 (62.3) 49 (37.7) Low 2 (66.7) 1 (33.3) Chemotherapy regimen, N (%) .771 Gem/Cis 46 (61.3) 29 (38.7) Gem/Carbo 37 (63.8) 21 (36.2) Creatinine clearance, N (%) .570 ≥ 60 mL/min 34 (59.6) 23 (40.4) < 60 mL/min 49 (64.4) 27 (35.6) Previous BCG therapy, N (%) .806 Yes 63 (63.0) 13 (39.4) No 37 (37.0) Smoking status, N (%) .906 No 49 (64.5) 27 (35.5) Yes 34 (61.8) 21 (38.2) Table 2. Association of covariates with the clinical complete response to chemotherapy Abbreviations: BCG, bacillus Calmette Guerin; Gem/Carbo, gemcitabine plus carboplatin; Gem/Cis, gemcitabine plus cisplatin. Urological Oncology 372 Urological Oncology 291 MATERIALS AND METHODS The ethical approval was provided by the ethical com- mittee of the Shahid Beheshti University of Medical Sciences (XXX.REC.1399.016). Study Population In this retrospective cohort study, the data from all consecutive patients with MIBC treated with Gem/Cis or Gem/Carbo as the NAC (before CRT or RC) from April 2009 to April 2019 were collected. The diagno- sis of UCC was based on transurethral resection for bladder tumor (TURBT) results. Participants who had T2–T4aN0–1M0 (based on American Joint Committee on Cancer, 7th edition) urothelial carcinoma based on physical exam, TURBT, and computed tomography (CT) scan of chest, abdomen, and pelvis were enrolled. The cases recruited before January 1, 2010 (the release date of AJCC 7th edition) were re-evaluated for the pos- sible changes in the T and N categories. Patients’ data, including demographic features, clinical and patholog- ic characteristics, treatment schedules, and outcomes, were collected from medical records. The IRB of the Shahid Beheshti University of Medical Sciences ap- proved the research. The IRB waived informed consent due to the retrospective nature of the study. The study was conducted per the principles of the Declaration of Helsinki and current ethical guidelines. Treatment and Evaluation Within four weeks after maximal TURBT, patients were permitted to receive NAC with four cycles of Gem/Cis (gemcitabine 1000 mg/m² on days 1 and 8 plus cisplatin 35 mg/m² on days 1 and 2, every 21 days) or Gem/Carbo regimen (gemcitabine 1000 mg/m² on days 1 and 8 plus carboplatin area under the curve [AUC] 4 on day 1, every 21 days). Patients with ECOG performance status 2, creatinine clearance < 60 mL/min (using Cockcroft-Gault equation (17)), hydronephrosis, ejection fraction < 50%, or single kidney received Gem/ Carbo regimen. Patients with ECOG 0-1 were eligible for Gem/Cis, and those with ECOG 3-4 were not can- didates for chemotherapy. During the administration of treatment, the daily dose of regimens could be adjust- ed according to the frequency and severity of adverse effects. Clinical response (ycTNM) was evaluated ac- cording to RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 criteria using cystoscopic tumor-site biopsy, urine cytology, and restaging CT scan within four weeks. Thereafter patients with incomplete re- sponses to NAC proceeded to immediate RC. Patients who were unfit for surgery, patients with a complete re- sponse to NAC, or those who were unwilling to under- go RC received CRT. CRT was carried out in 2 distinct approaches, 1) node-negative patients: whole bladder to a total prescribed dose of 64 Gy, 2) node-positive pa- Covariates Hazard ratio (95% CI) P-value Hazard ratio (95% CI) P-value Univariable analysis Multivariable analysis a Pre-treatment covariates NAC regimen, Gem/Cis 1 (reference) .010 1 (reference) .402 Gem/Carbo 1.88 (1.16-3.03) 1.28 (0.70-2.36) Creatinine clearance, ≥ 60 mL/min 1 (reference) .011 1 (reference) .333 < 60 mL/min 1.90 (1.16-3.11) 1.34 (0.71-2.52) Age, ≤ 65 yr 1 (reference) .014 1 (reference) .161 > 65 yr 1.82 (1.13-2.94) 1.47 (0.84-2.57) Tumor stage, T2 1 (reference) 1 (reference) T3 1.08 (0.65-1.78) .766 0.97 (0.58-1.63) .905 T4a 2.41 (1.06-5.46) .034 2.08 (1.001-4.85) .033 Nodal status, Negative 1 (reference) .095 Positive 1.52 (0.93-2.50) Tumor grade, High 1 (reference) .300 Low 2.89 (0.39-21.54) Gender, Female 1 (reference) .545 Male 1.36 (0.49-3.75) Smoking status, No 1 (reference) .741 Yes 1.08 (0.67-1.72) Previous BCG therapy, Yes 1 (reference) .836 No 1.05 (0.62-1.80) Post-treatment covariates cCR No 1 (reference) .007 1 (reference) .041 Yes 0.45 (0.26-0.80) 0.51 (0.26-0.99) Following treatment Radical cystectomy 1 (reference) .018 1 (reference) .399 Chemoradiotherapy 0.55 (0.34-0.90) 0.78 (044-1.38) Table 3. Univariable and multivariable analysis of factors related to overall survival. Abbreviations: BCG, bacillus Calmette Guerin; cCR, complete clinical response; Gem/Carbo, gemcitabine plus carboplatin; Gem/Cis, gemcitabine plus cisplatin; NAC, neoadjuvant chemotherapy. a Chemotherapy regimen, creatinine clearance, age, and tumor stage were included in the pre-treatment multivariable model. Besides, clinical complete response and fol- lowing treatment were included in the post-treatment model. Neoadjuvant carboplatin in locally advanced bladder cancer-Mofid et al. Vol 19 No 5 September-October 2022 373 tients: whole bladder + pelvic lymph nodes 45 Gy, then boost to the whole bladder to a total prescribed dose of 64 Gy. Radiotherapy was delivered five days per week at a 1.8 Gy daily dose. Cisplatin 15 mg/m2 plus fluoro- uracil 400 mg/m2 was administered during radiotherapy on days 1–3, 8–10, and 15–17. After chemoradiation, patients were re-evaluated with cystoscopy and chest, abdomen, and pelvic CT scans, and regular follow-up was performed for patients at 6-month intervals. Endpoints In this study, complete clinical response (cCR) and overall survival (OS) were evaluated as the primary and secondary objectives, respectively. The cCR was de- fined as negative results for cystoscopic tumor-site bi- opsy, urine cytology, and imaging (chest, abdomen, and pelvic CT scans) four weeks after NAC, and OS was defined as the time from the start of NAC until death from any cause. In addition, the association of covari- ates with cCR and the prognostic significance of them on the OS of patients were evaluated. Statistical Analysis Categorical variables were summarized as numbers and percentages and were compared using the Pearson chi- square test. Continuous variables were summarized us- ing mean and standard deviation, and intergroup values were compared using the independent t-test. OS was calculated using the Kaplan–Meier method, and inter- group differences were compared with a log-rank test. Potential prognostic factors for OS were assessed with univariable and multivariable Cox proportional hazards models. All factors exhibiting significant association with OS in the univariable analyses were included in a multivariable model. The follow-up time was estimated using the reverse Kaplan-Meier method.(18) All analyses were performed using IBM SPSS Statistics, version 26. The statistical significance level was set to 0.05, except for including covariates into multivariable analysis that P-value was set to 0.20 to impede missing the possible potential predictive factors.(19) RESULTS From April 2009 to April 2019, 140 patients with MIBC who received NAC before CRT or RC were enrolled in the study. Patients had a mean age of 66.3±10.4 years, and 130 cases (92.8%) were male. Compared to the Gem/Cis, patients in the Gem/Carbo group were older (mean age 61.4 ± 9 vs. 72.8 ± 8.4, P < .001). UCC was the only pathology diagnosis, which was high grade in 136 patients (97.2%). The tumor stage was clinical (c) T2 in 80 patients (57.1%), cT3 in 48 patients (34.3%), and cT4a in 11 patients (7.9%) (clinical staging of one patient was not available), and nodal status was nega- tive in 102 patients (72.8%) without significant differ- ence between groups (P > .05). In total, 79 (56.4%) and 61 (43.6%) patients received Gem/Cis and Gem/Car- bo as NAC. The mean CrCl was 59.0 mL/min, which was significantly higher in the cisplatin group (69.9 vs. 44.8 mL/min, P = .003). Other baseline characteristics were comparable across the groups (Table 1). Overall, 128 patients (91.7%) received optimal chemotherapy cycles, which was not statistically different between Gem/Cis (93.6%, 74 cases) and Gem/Carbo (88.5%, 54 cases) groups (P = 0 .44). This subgroup did not differ significantly in baseline characteristics compared to the suboptimal group [optimal vs. suboptimal: male sex P = .32, T stage P = .53, N status P = .36, tumor grade P = Studies Type Number of patients NAC regimen Treatment Outcomes P-value Cis Carbo Cis Carbo Cis Carbo Mertens et al. Retrospective cohort 83 23 Gem/Cis Gem/Carbo NAC + RC cCR (%) 33.7 26.7 .65 (2012) MVAC Median DSS (m) 20 18 .18 Median OS (m) 22 22 .36 Iwasaki et al. (2013) Retrospective cohort 34 34 MVAC Gem/Carbo NAC + RC pPR (%) 62 53 .62 3-years RFS (%) 79 75 .85 Schinzari et al. (2017) Clinical trial (phase II) 30 42 Gem/Cis Gem/Carbo NAC + RC pCR (%) 36 23.8 .35 Median DFS a (m) 40 22 .57 Median OS a (m) 48 > 50 .89 Anan et al. Retrospective cohort 43 280 Gem/Cis Gem/Carbo NAC + RC pCR (%) 5.7 17 NR (2017) 5-year PFS a (%) 78 70 .32 5-year OS a (%) 72 70 .24 Peyton et al. Retrospective cohort 250 32 ddMVAC Gem/Carbo NAC + RC pPR 52 (ddMVAC) 27 .03 (2018) Gem/Cis 41.3 (Gem/Cis) pCR 41.3 (ddMVAC) 9.4 .05 24.5 (Gem/Cis) 2-year OS (%) 73.3 (ddMVAC) 34.8 .002 62 (Gem/Cis) Current study Retrospective cohort 79 61 Gem/Cis Gem/Carbo NAC + RC cCR (%) 38.7 36.2 .77 (2021) NAC + CRT Median OS (m) 41 26 .008 Table 4. Characteristics of studies comparing clinical outcomes of a neoadjuvant carboplatin-based regimen with standard cisplatin-based regimen. Abbreviations: Carbo, carboplatin-based; cCR, complete clinical response; Cis, cisplatin-based; CRT, chemoradiation; ddMVAC, dose-dense MVAC; DFS, disease-free survival; DSS, disease-specific survival; Gem/Carbo, gemcitabine plus carboplatin; Gem/Cis, gemcitabine plus cisplatin; MVAC, methotrexate, vinblastine, doxorubicin plus cisplatin; NAC, neoadjuvant chemotherapy; NR, not reported; OS, overall survival; pCR, complete pathological response; PFS, progression-free survival; pPR, partial pathological response; RC, radical cystectomy; RFS, relapse-free survival. a Estimated based on the Kaplan-Meier curves Neoadjuvant carboplatin in locally advanced bladder cancer-Mofid et al. Urological Oncology 374 Urological Oncology 293 .54, smoking status P = .69, and previous BCG therapy P = .60). After NAC, 79 patients (56.4%) received CRT and other cases underwent immediate RC (P = .90). [Table 1 near hear] Association Between Chemotherapy Regimen and Tumor Response Of the study population, 50 cases (37.6%) attained cCR that was not significantly different between Gem/Cis and Gem/Carbo regimens (38.7 vs. 36.2%, P = .771). Likewise, the rate of cCR was not significantly associ- ated with age (P = .51), sex (P = .99), tumor stage (P = .53), nodal involvement (P = .32), tumor grade (P = .99), and CrCl (P = .57). The detailed results of cCR based on covariates are presented in Table 2. [Table 2 near hear] Association Between Chemotherapy Regimen and Survival Following a median follow-up of 43 months (95% confidence interval [95% CI]: 36.3–49.6 months), 71 patients (50.7%) died. In total, the median OS of pa- tients receiving NAC was 33 months (95% CI: 24.3– 41.6 months), which was significantly longer in Gem/ Cis group (median OS 41.0 months [95% CI: 37–44.9] vs. 26.0 months [95% CI: 17–35], P = .008) (Figure 1-A). Concerning patients who completed four cycles of NAC, the median OS was 33 months, including 40 months (95% CI: 32.3–47.6) and 26 months (95% CI: 17–34.9) for Gem/Cis and Gem/Carbo groups, respec- tively (P = .015). Prognostic Factors of Survival Univariable analysis of pre-treatment covariates re- Figure 1. Kaplan-Meier curves of overall survival based on the significant pre-treatment factors, A) NAC regimen, B) creatinine clearance, C) age, and D) tumor stage, and post-treatment factors, E) complete clinical response, F) post-neoadjuvant treatment. Neoadjuvant carboplatin in locally advanced bladder cancer-Mofid et al. Vol 19 No 5 September-October 2022 375 vealed that NAC regimen (Gem/Carbo: 95% CI: 1.16– 3.03, hazard ratio [HR] = 1.88, P = .01), CrCl (CrCl < 60 mL/min: 95% CI: 1.16–3.11, HR = 1.90, P = .01), age (> 65 years: 95% CI: 1.13–2.94, HR = 1.82, P = .01), and tumor stage (cT4a: 95% CI: 1.06–5.46, HR = 2.41, P = .03) were significantly associated with OS. Figure 1 illustrates the comparison of OS based on the significant pre- and post-treatment covariates. On mul- tivariable analysis, presence of cT4a disease (95% CI: 1.001–4.85, HR = 2.08, P = .03) was identified as an in- dependent risk factor for shorter OS. Of note, due to the significant correlation between nodal status and tumor stage (P < .0001), the nodal status was not included in the multivariable model. [Figure 1 near hear] In univariable analysis of post-treatment covariates, both cCR (95% CI: 0.26–0.80, HR = 0.45, P = .007) and the treatment following NAC (95% CI: 0.34–0.90, HR = 0.55, P = .01) were found to have significant as- sociation with OS. Multivariable analysis outlined cCR (95% CI: 0.26–0.99, HR = 0.51, P = .04) as the inde- pendent prognostic factor of OS (Table 3). [Table 3 near hear] DISCUSSION Level 1 evidence has demonstrated that cisplatin-based NAC (MVAC, Gem/Cis) has improved the OS of RC in MIBC.(4) The standard NAC regimen, however, has not been established for patients who are unfit for cis- platin that constitute 30–50% of BC patients.(4,7,20) Therefore, this study—among a few others (Table 4)— was conducted firstly to compare the clinical response and survival of a carboplatin-based (Gem/Carbo) NAC against the standard cisplatin-based regimen (Gem/ Cis); secondly, to find the relevant prognostic factors. [Table 4 near hear] In summary, this study demonstrated comparable cCR between induction Gem/Cis and Gem/Carb in patients with MIBC. In addition, the multivariable analysis showed that the choice of NAC between Gem/Cis and Gem/Carbo had no independent effect on OS. This might reside in the similar mode of action and phar- macodynamic between cisplatin and carboplatin; both platinum agents induce apoptosis through the formation of DNA adducts, and the intracellular concentration of both is regulated by a common influx (i.e., copper transporter CTR1) and efflux proteins (i.e., ATP7A-B). (21,22) The comparable results for cCR (Gem/Cis 38.7 vs. Gem/Carbo 36.2%, P = .77) is consistent with the Mertens et al. study.(14) This finding is also in line with the Iwasaki et al. and Schinzari et al. studies that report- ed comparable partial pathological response (pPR) to MVAC versus Gem/Carbo regimens (53 vs. 62%, P = .6) and complete pathological response (pCR) to Gem/ Cis versus Gem/Carbo (36 vs. 23.8%, P = .35), respec- tively.(13,15) In the present study, in contrast to the Iwa- saki et al. and Anan et al. studies, the median survival rates between cisplatin- and carboplatin-based NAC (41 vs. 26 months, P = .008) were not comparable. (13,23) This might root in the selection bias of this study that patients in the Gem/Carbo group were significant- ly older with lower CrCl (both with poorer prognosis). Peyton et al. demonstrated shorter 2-year OS in carbo- platin-based regimen (34.8 [Gem/Carbo] vs. 73.3 [dose- dense MVAC (ddMVAC)], 62% [Gem/Cis], P = .002) that was confirmed in multivariable analysis (Gem/Cis [reference = 1], ddMVAC [95% CI: 0.17–1.06, HR = 0.42, P = .07], Gem/Carbo [95% CI: 1.16–3.44, HR = 2, P = .01]).(16) In the current study, however, the multivar- iable analysis did not confirm the preliminary results. This is explained in detail in the following paragraph. In summary, all the aforementioned studies except for one (Peyton et al. study) agree with the similar response (clinical, pathological) to NAC between carboplatin- and cisplatin-based regimens. On survival analysis, 4 of 6 studies showed comparable survival between study groups, and the other 2 (Peyton et al. and current stud- ies) reported shorter OS in the carboplatin-based group that might be affected by selection bias. On univariable analysis of pre-treatment covariates, predictors of worse OS were Gem/Carbo regimen, CrCl < 60 mL/min, age > 65 years, and T4 tumors. However, multivariable analysis ruled out the prognostic signifi- cance of the NAC regimen. It confirmed Peyton et al.’s findings, in which the advanced tumor stage was an in- dependent predictor for the poor OS.(16) In the current study, OS was considerably longer than that reported by Mertens et al. (median OS 33 vs. 22 months) using similar chemotherapy regimens, which could be due in part to the lower proportion of patients with cT4 disease in this study (7.9 vs. 48.3%). This finding highlights the advanced tumor stage as an independent prognostic fac- tor in this setting.(14) Univariable analysis of post-treat- ment covariates put forward the cCR and CRT—against RC—as the prognostic factors of OS. However, mul- tivariable analysis ruled out CRT that might originate from our approach, of which patients with cCR to NAC (with better prognosis) were proceeded to CRT and confirmed cCR as an independent prognostic factor of OS. This finding is consistent with the literature high- lighting the pCR as the prognostic factor of disease-spe- cific survival and OS.(14,15) In this study, the complete response to NAC was not associated with variables such as age, sex, clinical tu- mor stage, and smoking history. So far, few other stud- ies have intended to find predictive factors of response to NAC. In a large series, Zargar et al. stated that any downstaging of tumors (pPR and pCR) is reduced by nearly 40% in cT3–4 tumors.(24) Subsequently, Peyton et al. demonstrated that ddMVAC provides more down- staging of the tumor (vs. Gem/Cis: 95% CI: 1.10–3.09, odds ratio [OR] = 1.84, P = .02 ).(16) A more recent analysis showed that neutrophil-to-lymphocyte ratio (NLR) > 3 could predict decreased response to NAC; however, it did not demonstrate an association with age, sex, tumor stage, and smoking that confirms the find- ings of the present study.(25) Accordingly, over the last decade, investigators have tried to introduce predictive biomarkers (e.g., somatic ERCC2 mutation); however, none are yet validated for routine clinical use.(25,26) Along with preceding comparative studies, several oth- er retrospective studies have reported the clinical out- comes of carboplatin-based NAC in MIBC. Koie et al. (2015) showed a significant reduction in local (5.4 vs. 14.3%), regional (5.4 vs. 22.3%), and distant recurrence (3.8 vs. 20%) after neoadjuvant Gem/Carbo compared to RC alone.(27) Murasawa et al. reported improvement in 5-year OS (79.5 vs. 53.8%), 5-year disease-free sur- vival (DFS) (75.5 vs. 55.4%), pCR (16.3%), and RC with negative surgical margins (100 vs. 87.7%) after ne- oadjuvant Gem/Carbo versus RC alone in cisplatin-in- eligible MIBC patients.(28) Likewise, Koie et al. (2014) Vol 19 No 4 July-August 2022 294 Neoadjuvant carboplatin in locally advanced bladder cancer-Mofid et al. Urological Oncology 376 demonstrated a significant improvement in 5-year OS and DFS with neoadjuvant Gem/Carbo before RC (98.6 vs. 66.6% and 94.2 vs. 72.7% respectively) in patients with cT2 bladder cancer.(29) Overall, these findings might address the feasibility of neoadjuvant carbopla- tin-based chemotherapy for patients who are ineligible for cisplatin. The limitations of the present study need to be consid- ered, including its retrospective design, no randomiza- tion, variable post NAC treatments. Due to its retro- spective nature, selection and information bias cannot be totally excluded. The bias effect of uncontrolled confounding factors is required to be acknowledged as well. The NAC dose density, treatment delay, dose ad- justment, or safety were not included in the analysis. In addition, using clinical response as a primary endpoint, a proportion of patients who had a persistent disease in RC specimen were ignored. Also, the short follow-up for the survival data and failure to report the other onco- logical endpoints (e.g., DSS, DFS) are acknowledged. Despite these limitations, this is one of the largest se- ries comparing the oncological outcomes of a carbopla- tin-based NAC with a standard cisplatin-based regimen in MIBC. Moreover, the study groups of the current study are more balanced in sample size (in comparison with Peyton et al. and Anan et al. studies) that could enhance the power of the results. CONCLUSIONS This study showed that the choice of NAC between Gem/Carbo and Gem/Cis in MIBC has no impact on cCR and OS. Also, it suggested that advanced tumor stage and cCR are two independent prognostic factors in this setting. Hence, Gem/Carbo seems to be an ap- propriate option for patients with MIBC who are unfit for cisplatin to enable them to benefit from NAC advan- tages. Randomized comparative trials are required to delineate the efficacy of neoadjuvant carboplatin-based regimens definitively. ACKNOWLEDGMENTS This study was supported by the Urology and Neph- rology Research Center, Shahid Beheshti University of Medical Sciences. REFERENCES 1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin.n/a. 2. Al-Husseini MJ, Kunbaz A, Saad AM, et al. Trends in the incidence and mortality of transitional cell carcinoma of the bladder for the last four decades in the USA: a SEER- based analysis. BMC Cancer. 2019;19:46. 3. Li G, Niu H-m, Wu H-t, et al. Effect of cisplatin-based neoadjuvant chemotherapy on survival in patients with bladder cancer: a meta-analysis. Clinical and Investigative Medicine. 2017E81-E94. 4. Hamid ARAH, Ridwan FR, Parikesit D, Widia F, Mochtar CA, Umbas R. Meta-analysis of neoadjuvant chemotherapy compared to radical cystectomy alone in improving overall survival of muscle-invasive bladder cancer patients. BMC Urol. 2020;20:158. 5. Mirza A, Choudhury A. Bladder preservation for muscle invasive bladder cancer. Bladder Cancer. 2016;2:151-63. 6. Galsky MD, Hahn NM, Rosenberg J, et al. A consensus definition of patients with metastatic urothelial carcinoma who are unfit for cisplatin-based chemotherapy. The lancet oncology. 2011;12:211-4. 7. Einstein DJ, Sonpavde G. Treatment approaches for cisplatin-ineligible patients with invasive bladder cancer. Curr Treat Options Oncol. 2019;20:1-13. 8. Santoro A, O'Brien ME, Stahel RA, et al. Pemetrexed plus cisplatin or pemetrexed plus carboplatin for chemonaive patients with malignant pleural mesothelioma: results of the International Expanded Access Program. J Thorac Oncol. 2008;3:756-63. 9. Rossi A, Di Maio M, Chiodini P, et al. Carboplatin-or cisplatin-based chemotherapy in first-line treatment of small-cell lung cancer: the COCIS meta-analysis of individual patient data. Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. 2012. 10. Vasconcellos VF, Marta GN, da Silva EM, Gois AF, de Castria TB, Riera R. Cisplatin versus carboplatin in combination with third‐ generation drugs for advanced non‐small cell lung cancer. Cochrane Database Syst Rev. 2020. 11. Ho GY, Woodward N, Coward JI. Cisplatin versus carboplatin: comparative review of therapeutic management in solid malignancies. Crit Rev Oncol Hematol. 2016;102:37-46. 12. Anan G, Hatakeyama S, Fujita N, et al. Trends in neoadjuvant chemotherapy use and oncological outcomes for muscle-invasive bladder cancer in Japan: a multicenter study. Oncotarget. 2017;8:86130. 13. Iwasaki K, Obara W, Kato Y, Takata R, Tanji S, Fujioka T. Neoadjuvant gemcitabine plus carboplatin for locally advanced bladder cancer. Jpn J Clin Oncol. 2013;43:193-9. 14. Mertens LS, Meijer RP, Kerst JM, et al. Carboplatin based induction chemotherapy for nonorgan confined bladder cancer—a reasonable alternative for cisplatin unfit patients? The Journal of urology. 2012;188:1108-14. 15. Schinzari G, Monterisi S, Pierconti F, et al. Neoadjuvant chemotherapy for patients with muscle-invasive urothelial bladder cancer candidates for curative surgery: A prospective clinical trial based on cisplatin feasibility. Anticancer Res. 2017;37:6453-8. 16. Peyton CC, Tang D, Reich RR, et al. Downstaging and Survival Outcomes Associated With Neoadjuvant Chemotherapy Regimens Among Patients Treated With Cystectomy for Muscle-Invasive Bladder Cancer. JAMA Oncol. 2018;4:1535-42. 17. Cockcroft DW, Gault H. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31-41. Neoadjuvant carboplatin in locally advanced bladder cancer-Mofid et al. Vol 19 No 5 September-October 2022 377 Urological Oncology 378 18. Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Control Clin Trials. 1996;17:343-6. 19. Schwender H. David W. Hosmer, Stanley Lemeshow, Susanne May: Applied survival analysis: regression modeling of time-to-event data: Springer Nature BV; 2012. 20. Koshkin VS, Barata PC, Rybicki LA, et al. Feasibility of Cisplatin-Based Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer Patients With Diminished Renal Function. Clin Genitourin Cancer. 2018;16:e879-e92. 21. Sousa GFd, Wlodarczyk SR, Monteiro G. Carboplatin: molecular mechanisms of action associated with chemoresistance. Brazilian Journal of Pharmaceutical Sciences. 2014;50:693-701. 22. Li T, Peng J, Zeng F, et al. Association between polymorphisms in CTR1, CTR2, ATP7A, and ATP7B and platinum resistance in epithelial ovarian cancer. Int J Clin Pharmacol Ther. 2017;55:774-80. 23. Anan G, Hatakeyama S, Fujita N, et al. Trends in neoadjuvant chemotherapy use and oncological outcomes for muscle-invasive bladder cancer in Japan: a multicenter study. Oncotarget. 2017;8:86130-42. 24. Zargar H, Espiritu PN, Fairey AS, et al. Multicenter assessment of neoadjuvant chemotherapy for muscle-invasive bladder cancer. Eur Urol. 2015;67:241-9. 25. Black AJ, Zargar H, Zargar-Shoshtari K, et al. The prognostic value of the neutrophil- to-lymphocyte ratio in patients with muscle-invasive bladder cancer treated with neoadjuvant chemotherapy and radical cystectomy. Paper presented at: Urologic Oncology: Seminars and Original Investigations, 2020. 26. Van Allen EM, Mouw KW, Kim P, et al. Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma. Cancer Discov. 2014;4:1140-53. 27. Koie T, Ohyama C, Yamamoto H, et al. Differences in the recurrence pattern after neoadjuvant chemotherapy compared to surgery alone in patients with muscle-invasive bladder cancer. Med Oncol. 2015;32:421. 28. Murasawa H, Koie T, Ohyama C, et al. The utility of neoadjuvant gemcitabine plus carboplatin followed by immediate radical cystectomy in patients with muscle-invasive bladder cancer who are ineligible for cisplatin- based chemotherapy. Int J Clin Oncol. 2017;22:159-65. 29. Koie T, Ohyama C, Yamamoto H, et al. Neoadjuvant gemcitabine and carboplatin followed by immediate cystectomy may be associated with a survival benefit in patients with clinical T2 bladder cancer. Med Oncol. 2014;31:949. Neoadjuvant carboplatin in locally advanced bladder cancer-Mofid et al.