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Pooled analysis of clinical outcomes with neoadjuvant cisplatin and gemcitabine chemotherapy for muscle invasive bladder cancer.

ABSTRACT: Neoadjuvant chemotherapy for muscle invasive bladder cancer has been shown to confer a survival advantage in phase III studies. Although cisplatin and gemcitabine are often used in this setting, a comprehensive evaluation of this regimen is lacking. In this review we summarize the efficacy of neoadjuvant cisplatin and gemcitabine chemotherapy for muscle invasive bladder cancer based on currently published studies.A systematic literature review was conducted in April 2012 searching MEDLINE® databases. Articles were selected if they included patients with muscle invasive bladder cancer, evaluated the combination of cisplatin and gemcitabine as neoadjuvant treatment, and reported pathological data after cystectomy. Cisplatin and gemcitabine dosing regimens and clinical data were further summarized using weighted averages.Seven studies encompassing 164 patients were published between 2007 and 2012. The majority of patients (79%) received cisplatin and gemcitabine on a 21-day cycle. A weighted average of 19.2 lymph nodes was obtained at cystectomy, and 29.7% of patients were found to have pN1 disease. Pathological down staging to pT0 and less than pT2 occurred in 42 (25.6%) and 67 (46.5%) patients, respectively.Neoadjuvant cisplatin and gemcitabine yield appreciable pathological response rates in patients with muscle invasive bladder cancer. Since pathological response has been implicated as a potential surrogate for survival in muscle invasive bladder cancer, these data suggest that neoadjuvant cisplatin and gemcitabine may warrant further prospective assessment.

SUBMITTER: Yuh BE

PROVIDER: S-EPMC3926865 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Pooled analysis of clinical outcomes with neoadjuvant cisplatin and gemcitabine chemotherapy for muscle invasive bladder cancer.

Yuh Bertram E BE Ruel Nora N Wilson Timothy G TG Vogelzang Nicholas N Pal Sumanta K SK

The Journal of urology 20121101 5

<h4>Purpose</h4>Neoadjuvant chemotherapy for muscle invasive bladder cancer has been shown to confer a survival advantage in phase III studies. Although cisplatin and gemcitabine are often used in this setting, a comprehensive evaluation of this regimen is lacking. In this review we summarize the efficacy of neoadjuvant cisplatin and gemcitabine chemotherapy for muscle invasive bladder cancer based on currently published studies.<h4>Materials and methods</h4>A systematic literature review was co ...[more]

PMID: 23123547

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Project description:Background:Accelerated (also termed dose-dense, DD) chemotherapy regimens such as accelerated methotrexate, vinblastine, doxorubicin, and cisplatin have shown better efficacy and tolerability in the metastatic setting, and shortened the time to surgery in the neoadjuvant setting compared to standard-schedule regimens. We hypothesized that a DD schedule of gemcitabine and cisplatin (GC) would shorten the time to surgery and yield similar pathologic complete response rates (pT0) in patients with muscle-invasive bladder cancer (MIBC) compared with historical controls with standard GC. Objective:To determine the safety and efficacy of neoadjuvant DDGC in MIBC. Design setting and participants:Patients with cT2-4a, N0-1, M0 MIBC were eligible and received three 14-d cycles of DDGC with pegfilgrastim support followed by radical cystectomy with lymph node dissection. The primary end point was the pT0 rate. Molecular subtypes were assigned and correlated with survival. Results and limitations:Thirty-one patients were evaluable for toxicity and response, of whom 58% had baseline clinical stage >T2N0M0; the median age was 69 yr. Ten patients (32%, 95% confidence interval [CI] 16-49%) achieved ypT0N0 status at cystectomy. Another four patients (13%, 95% CI 1-25%) were downstaged to non-muscle-invasive (<pT2N0) disease. Most patients (54.8%) experienced only grade 1-2 treatment-related toxicities. However, seven patients (23%) had clinically significant vascular events, leading to early closure of the study. Thirty patients (94%) underwent cystectomy. The median time from the start of chemotherapy to cystectomy was 9.3 wk. There was no correlation between molecular subtypes and survival. Conclusions:DDGC yielded a similar pT0 rate to that noted retrospectively with standard GC. Vascular events precluded, delayed, or increased the risk of surgery for 23% of patients, resulting in early closure of the study. Additional prospective studies with embedded biomarker correlatives of GC in the neoadjuvant setting are critical to accurately define both the activity and toxicity of this combination in MIBC. Patient summary:Neoadjuvant chemotherapy before cystectomy is the standard of care for muscle-invasive bladder cancer (MIBC). This prospective phase 2 study tested a dose-dense schedule of gemcitabine and cisplatin in MIBC. The study was closed early because of a higher than expected rate of vascular events. These data suggest that caution is required in using this regimen, particularly when there is better prospective evidence for the safety and efficacy of alternative regimens such as dose-dense or accelerated methotrexate, vinblastine, doxorubicin, and cisplatin.

Project description:BackgroundCisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) is the standard of care for patients with muscle-invasive bladder cancer (MIBC). It is unknown whether this treatment strategy is appropriate for patients who progress to MIBC after treatment for prior noninvasive disease (secondary MIBC).ObjectiveTo determine whether clinical and genomic differences exist between primary and secondary MIBC treated with NAC and RC.Design, setting, and participantsClinicopathologic outcomes were compared between 245 patients with clinical T2-4aN0M0-stage primary MIBC and 43 with secondary MIBC treated with NAC and RC at Memorial Sloan Kettering Cancer Center (MSKCC) from 2001 to 2015. Genomic differences were assessed in a retrospective cohort of 385 prechemotherapy specimens sequenced by whole-exome or targeted exon capture by the Cancer Genome Atlas or at MSKCC. Findings were confirmed in an independent validation cohort of 94 MIBC patients undergoing prospective targeted exon sequencing at MSKCC.Outcome measurements and statistical analysisPathologic response rates, recurrence-free survival (RFS), bladder cancer-specific survival (CSS), and overall survival (OS) were measured. Differences in somatic genomic alteration rates were compared using Fisher's exact test and the Benjamini-Hochberg false discovery rate method.Results and limitationsPatients with secondary MIBC had lower pathologic response rates following NAC than those with primary MIBC (univariable: 26% vs 45%, multivariable: odds ratio=0.4 [95% confidence interval=0.18-0.84] p=0.02) and significantly worse RFS, CSS, and OS. Patients with secondary MIBC treated with NAC had worse CSS compared with cystectomy alone (p=0.002). In a separate genomic analysis, we detected significantly more likely deleterious somatic ERCC2 missense mutations in primary MIBC tumors in both the discovery (10.9% [36/330] vs 1.8% [1/55], p=0.04) and the validation (15.7% [12/70] vs 0% [0/24], p=0.03) cohort.ConclusionsPatients with secondary MIBC treated with NAC had worse clinical outcomes than similarly treated patients with primary MIBC. ERCC2 mutations predicted to result in increased cisplatin sensitivity were enriched in primary versus secondary MIBC. Prospective validation is still needed, but given the lack of clinical benefit with cisplatin-based NAC in patients with secondary MIBC, upfront RC or enrollment in clinical trials should be considered.Patient summaryA retrospective cohort study of patients with "primary" and "secondary" muscle-invasive bladder cancer (MIBC) treated with chemotherapy before surgical removal of the bladder identified lower response rates and shorter survival in patients with secondary MIBC. Tumor genetic sequencing of separate discovery and validation cohorts revealed that chemotherapy-sensitizing DNA damage repair gene mutations occur predominantly in primary MIBC tumors and may underlie the greater sensitivity of primary MIBC to chemotherapy. Prospective validation is still needed, but patients with secondary MIBC may derive greater benefit from upfront surgery or enrollment in clinical trials rather than from standard chemotherapy.

Project description:Purpose Neoadjuvant chemotherapy followed by radical cystectomy (RC) is a standard of care for the management of muscle-invasive bladder cancer (MIBC). Dose-dense cisplatin-based regimens have yielded favorable outcomes compared with standard-dose chemotherapy, yet the optimal neoadjuvant regimen remains undefined. We assessed the efficacy and tolerability of six cycles of neoadjuvant dose-dense gemcitabine and cisplatin (ddGC) in patients with MIBC. Patients and Methods In this prospective, multicenter phase II study, patients received ddGC (gemcitabine 2,500 mg/m2 on day 1 and cisplatin 35 mg/m2 on days 1 and 2) every 2 weeks for 6 cycles followed by RC. The primary end point was pathologic downstaging to non-muscle-invasive disease (< pT2N0). Patients who did not undergo RC were deemed nonresponders. Pretreatment tumors underwent next-generation sequencing to identify predictors of chemosensitivity. Results Forty-nine patients were enrolled from three institutions. The primary end point was met, with 57% of 46 evaluable patients downstaged to < pT2N0. Pathologic response correlated with improved recurrence-free survival and overall survival. Nineteen patients (39%) required toxicity-related dose modifications. Sixty-seven percent of patients completed all six planned cycles. No patient failed to undergo RC as a result of chemotherapy-associated toxicities. The most frequent treatment-related toxicity was anemia (12%; grade 3). The presence of a presumed deleterious DNA damage response (DDR) gene alteration was associated with chemosensitivity (positive predictive value for < pT2N0 [89%]). No patient with a deleterious DDR gene alteration has experienced recurrence at a median follow-up of 2 years. Conclusion Six cycles of ddGC is an active, well-tolerated neoadjuvant regimen for the treatment of patients with MIBC. The presence of a putative deleterious DDR gene alteration in pretreatment tumor tissue strongly predicted for chemosensitivity, durable response, and superior long-term survival.

Project description:BACKGROUND:Cisplatin-based neoadjuvant chemotherapy (NAC) before cystectomy is the standard of care for muscle-invasive bladder cancer (MIBC), with 25-50% of patients expected to achieve a pathologic response. Validated biomarkers predictive of response are currently lacking. OBJECTIVE:To discover and validate biomarkers predictive of response to NAC for MIBC. DESIGN, SETTING, AND PARTICIPANTS:Pretreatment MIBC samples prospectively collected from patients treated in two separate clinical trials of cisplatin-based NAC provided the discovery and validation sets. DNA from pretreatment tumor tissue was sequenced for all coding exons of 287 cancer-related genes and was analyzed for base substitutions, indels, copy number alterations, and selected rearrangements in a Clinical Laboratory Improvements Amendments-certified laboratory. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:The mean number of variants and variant status for each gene were correlated with response. Variant data from the discovery cohort were used to create a classification tree to discriminate responders from nonresponders. The resulting decision rule was then tested in the independent validation set. RESULTS AND LIMITATIONS:Patients with a pathologic complete response had more alterations than those with residual tumor in both the discovery (p=0.024) and validation (p=0.018) sets. In the discovery set, alteration in one or more of the three DNA repair genes ATM, RB1, and FANCC predicted pathologic response (p<0.001; 87% sensitivity, 100% specificity) and better overall survival (p=0.007). This test remained predictive for pathologic response in the validation set (p=0.033), with a trend towards better overall survival (p=0.055). These results require further validation in additional sample sets. CONCLUSIONS:Genomic alterations in the DNA repair-associated genes ATM, RB1, and FANCC predict response and clinical benefit after cisplatin-based chemotherapy for MIBC. The results suggest that defective DNA repair renders tumors sensitive to cisplatin. PATIENT SUMMARY:Chemotherapy given before bladder removal (cystectomy) improves the chance of cure for some but not all patients with muscle-invasive bladder cancer. We found a set of genetic mutations that when present in tumor tissue predict benefit from neoadjuvant chemotherapy, suggesting that testing before chemotherapy may help in selecting patients for whom this approach is recommended.

Project description:BackgroundBladder-sparing chemoradiation therapy is a definitive first-line treatment option for muscle-invasive bladder cancer. Randomized trials have demonstrated that the addition of neoadjuvant chemotherapy to radical cystectomy or radiation monotherapy results in a survival benefit. Whether neoadjuvant chemotherapy improves outcomes when used with definitive chemoradiation is unknown.Patients and methodsWe identified 2566 patients in the National Cancer Data Base with cT2-4N0M0 urothelial cell carcinoma of the bladder treated with definitive intent concurrent chemoradiation from 2004 to 2015. The exposure of interest was receipt of neoadjuvant chemotherapy versus those without neoadjuvant chemotherapy. The primary outcome was overall survival defined from the time of diagnosis. Kaplan-Meier and multivariable Cox proportional hazard analyses were used to compare survival between groups. Sensitivity analyses tested (1) an interaction term for clinical T stage and (2) defining survival from start of radiation (as opposed to time of diagnosis) to address potential leading time bias.ResultsWe identified 462 patients treated with neoadjuvant chemotherapy followed by chemoradiation and 2104 patients treated with chemoradiation alone. With a median follow-up of 6.2 years, we found no difference in survival between groups: 5-year or 10-year overall survival of 30.6% (95% confidence interval [CI], 28.4%-32.9%) in the neoadjuvant group versus 31.8% (95% CI, 27.0%-36.8%) in the standard chemoradiation therapy group and 13.3% (95% CI, 11.2%-15.5%) in the neoadjuvant group versus 13.0% (95% CI, 8.4%-18.7%) in the standard chemoradiation therapy group, respectively (log-rank P = .19). On multivariable analysis we found no association between receipt of neoadjuvant chemotherapy and overall survival (hazard ratio, 1.01; 95% CI, 0.88-1.15; P = .921). The sensitivity analyses did not identify any differential effect by clinical T stage nor by defining survival from start of radiation.ConclusionThese results do not support the routine addition of neoadjuvant chemotherapy to definitive chemoradiation for bladder cancer, and optimizing the chemotherapy sequencing and regimens for bladder-preserving approaches to muscle invasive bladder cancer should continue to be studied under prospective clinical trials.

Project description:Importance:Neoadjuvant chemotherapy (NAC) followed by radical cystectomy improves survival compared with cystectomy alone for patients with bladder cancer. Although gemcitabine with cisplatin has become a standard NAC regimen, a dose-dense combination of methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) is being adopted at some institutions. Objective:To assess the association of neoadjuvant ddMVAC vs standard regimens with downstaging and overall survival among patients treated with radical cystectomy for bladder cancer. Design, Setting, and Participants:Cross-sectional analysis of data extracted from the medical records of a consecutive sample, after exclusions, of 1113 patients with bladder cancer of whom 824 had disease stage T2 or greater, who were treated with cystectomy at the Moffitt Cancer Center in Tampa, Florida, a tertiary care cancer center, between January 1, 2007, and May 31, 2017. Data were collected between November 14, 2016, and July 21, 2017, and analyzed between August 21, 2017, and December 8, 2017. Patients were compared based on type of NAC. Those who did not receive NAC were included as controls. Main Outcomes and Measures:Comparative rates and the association of any downstaging, complete response, and overall survival with ddMVAC and other NAC regimens and surgery alone. Outcomes were examined using Kaplan-Meier, adjusted logistic, Cox regression, and propensity-weighted models. Results:Of the 1113 patients who underwent cystectomy for bladder cancer, 861 (77.4%) were male, the median (interquartile range) age was 67 (60-74) years, 1051 (94.4%) were white, 27 (2.4%) black, 37 (3.3%) Hispanic/Latino, and 35 (3.1%) other race/ethnicity. Of 824 patients with muscle-invasive bladder cancer, 332 (40%) received NAC. Downstaging rates were 52.2% for ddMVAC, 41.3% for gemcitabine-cisplatin, and 27.0% for gemcitabine with carboplatin, and complete response (pT0N0) rates were 41.3% for ddMVAC, 24.5% for gemcitabine-cisplatin, and 9.4% for gemcitabine-carboplatin (2-sided P < .001). Adjusted analysis comparing ddMVAC with gemcitabine-cisplatin demonstrated a higher likelihood of downstaging (odds ratio [OR], 1.84; 95% CI, 1.10-3.09) and complete response (OR, 2.67; 95% CI, 1.50-4.77) with ddMVAC. Similar results were achieved with propensity score matching (OR, 1.52; 95% CI, 0.99-2.35). Patients who received ddMVAC had better overall survival than those treated with other chemotherapy regimens, although the observed survival benefit did not reach statistical significance in adjusted or propensity-matched models (hazard ratio, 0.44; 95% CI, 0.14-1.38; P = .16). Conclusions and Relevance:This study suggest that neoadjuvant ddMVAC followed by cystectomy is associated with a higher complete response (ypT0N0) rate than standard NAC. These data highlight and suggest the need to further investigate ddMVAC vs standard NAC in a prospective, randomized fashion.

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Pooled analysis of clinical outcomes with neoadjuvant cisplatin and gemcitabine chemotherapy for muscle invasive bladder cancer.

Publications

Pooled analysis of clinical outcomes with neoadjuvant cisplatin and gemcitabine chemotherapy for muscle invasive bladder cancer.

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