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Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates.

ABSTRACT: PURPOSE:In advanced urothelial cancer, treatment with dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) results in a high response rate, less toxicity, and few dosing delays. We explored the efficacy and safety of neoadjuvant ddMVAC with pegfilgrastim support in muscle-invasive urothelial cancer (MIUC). PATIENTS AND METHODS:Patients with cT2-cT4, N0-1, M0 MIUC were enrolled. Four cycles of ddMVAC were administered, followed by radical cystectomy. The primary end point was pathologic response (PaR) defined by pathologic downstaging to ? pT1N0M0. The study used Simon's optimal two-stage design to evaluate null and alternative hypotheses of PaR rate of 35% versus 55%. Secondary end points included toxicity, disease-free survival (DFS), radiologic response (RaR), and biomarker correlates, including ERCC1. RESULTS:Between December 2008 and April 2012, 39 patients (cT2N0, 33%; cT3N0, 18%; cT4N0, 3%; cT2-4N1, 43%; unspecified, 3%) were enrolled. Median follow-up was 2 years. Overall, 49% (80% CI, 38 to 61) achieved PaR of ? pT1N0M0, and we concluded this regimen was effective. High-grade (grade ? 3) toxicities were observed in 10% of patients, with no neutropenic fevers or treatment-related death. One-year DFS was 89% versus 67% for patients who achieved PaR compared with those who did not (hazard ratio [HR], 2.6; 95% CI, 0.8 to 8.1; P = .08) and 86% versus 62% for patients who achieved RaR compared with those who did not (HR, 4.1; 95% CI, 1.3 to 12.5; P = .009). We found no association between serum tumor markers or ERCC1 expression with response or survival. CONCLUSION:In patients with MIUC, neoadjuvant ddMVAC was well tolerated and resulted in significant pathologic and radiologic downstaging.

SUBMITTER: Choueiri TK

PROVIDER: S-EPMC7057274 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates.

Choueiri Toni K TK Jacobus Susanna S Bellmunt Joaquim J Qu Angela A Appleman Leonard J LJ Tretter Christopher C Bubley Glenn J GJ Stack Edward C EC Signoretti Sabina S Walsh Meghara M Steele Graeme G Hirsch Michelle M Sweeney Christopher J CJ Taplin Mary-Ellen ME Kibel Adam S AS Krajewski Katherine M KM Kantoff Philip W PW Ross Robert W RW Rosenberg Jonathan E JE

Journal of clinical oncology : official journal of the American Society of Clinical Oncology 20140512 18

<h4>Purpose</h4>In advanced urothelial cancer, treatment with dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) results in a high response rate, less toxicity, and few dosing delays. We explored the efficacy and safety of neoadjuvant ddMVAC with pegfilgrastim support in muscle-invasive urothelial cancer (MIUC).<h4>Patients and methods</h4>Patients with cT2-cT4, N0-1, M0 MIUC were enrolled. Four cycles of ddMVAC were administered, followed by radical cystectomy. The primar ...[more]

PMID: 24821883

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Project description:BACKGROUND:Gene expression profiling (GEP) suggests there are three subtypes of muscle-invasive urothelial cancer (UC): basal, which has the worst prognosis; p53-like; and luminal. We hypothesized that GEP of transurethral resection (TUR) and cystectomy specimens would predict subtypes that could benefit from chemotherapy. OBJECTIVE:To explore clinical outcomes for patients treated with dose-dense (DD) methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) and bevacizumab (B) and the impact of UC subtype. DESIGN, SETTING, AND PARTICIPANTS:Sixty patients enrolled in a neoadjuvant trial of four cycles of DDMVAC + B between 2007 and 2010. TUR and cystectomy specimens for GEP were available from 38 and 23 patients, respectively, and from an additional confirmation cohort of 49 patients treated with perioperative MVAC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Relationships with outcomes were analyzed using multivariable Cox regression and log-rank tests. RESULTS AND LIMITATIONS:Chemotherapy was active, with pT0N0 and ?pT1N0 downstaging rates of 38% and 53%, respectively, and 5-yr overall survival (OS) of 63%. Bevacizumab had no appreciable impact on outcomes. Basal tumors had improved survival compared to luminal and p53-like tumors (5-yr OS 91%, 73%, and 36%, log-rank p=0.015), with similar findings on multivariate analysis. Bone metastases within 2 yr were exclusively associated with the p53-like subtype (p53-like 100%, luminal 0%, basal 0%; p ? 0.001). Tumors enriched with the p53-like subtype at cystectomy suggested chemoresistance for this subtype. A separate cohort treated with perioperative MVAC confirmed the UC subtype survival benefit (5-yr OS 77% for basal, 56% for luminal, and 56% for p53-like; p=0.021). Limitations include the small number of pretreatment specimens with sufficient tissue for GEP. CONCLUSION:GEP was predictive of clinical UC outcomes. The basal subtype was associated with better survival, and the p53-like subtype was associated with bone metastases and chemoresistant disease. PATIENT SUMMARY:We can no longer think of urothelial cancer as a single disease. Gene expression profiling identifies subtypes of urothelial cancer that differ in their natural history and sensitivity to chemotherapy.

Project description:BackgroundThe standard of care (SOC) for muscle-invasive bladder cancer (MIBC) includes cisplatin-based combination chemotherapy in the neoadjuvant setting followed by radical cystectomy. Older patients often do not receive SOC due to perceived toxicity concerns despite guideline-directed recommendations.ObjectiveTo characterize the safety and efficacy of neoadjuvant accelerated methotrexate, vinblastine, adriamycin, and cisplatin (aMVAC) in MIBC patients as a function of age.Design, setting, and participantsA retrospective analysis was conducted in 186 MIBC patients treated at Fox Chase Cancer Center between January 1, 2002 and December 31, 2018. Adults with histologically proven muscle-invasive urothelial cancer were eligible. The exclusion criteria included nonurothelial histology, lack of muscularis propria invasion, and primary upper tract or metastatic disease.InterventionNeoadjuvant chemotherapy with aMVAC.Outcome measurements and statistical analysisPatients were stratified by age (<65, 65-74, and >75 yr old). Renal function was assessed at baseline and at time points after treatment. Clinicopathologic variables were compared between age groups to determine efficacy.Results and limitationsThere were no statistically significant differences in dose reductions, treatment interruptions, time to surgery, or adverse events when patients were stratified by age in univariate and multivariate analyses. Full safety data were not available due to the retrospective nature of the study. Baseline renal function was significantly worse among older patients, and the percent decline in creatinine clearance was greater with older age. We found comparable efficacy of aMVAC regardless of age.ConclusionsAccelerated MVAC was safe and demonstrated efficacy in MIBC irrespective of age in this single-center, retrospective study. Careful selection based on clinical variables, and not age, should identify patients able to receive neoadjuvant chemotherapy.Patient summaryWe examined the feasibility of the standard cisplatin-based chemotherapy regimen given prior to surgery in patients with muscle-invasive bladder cancer. Elderly patients experienced a greater decline in kidney function with treatment but not more complications than younger patients and tolerated therapy with minimal dose changes, resulting in benefit regardless of age.

Project description:Level 1 evidence has demonstrated increased overall survival with cisplatin-based neoadjuvant chemotherapy for patients with muscle-invasive urothelial cancer. Usage remains low, however, in part because neoadjuvant chemotherapy will not be effective for every patient. To identify the patients most likely to benefit, we evaluated germline pharmacogenomic markers for association with neoadjuvant chemotherapy sensitivity in 2 large cohorts of patients with urothelial cancer.Patients receiving neoadjuvant cisplatin-based chemotherapy for muscle-invasive urothelial cancer were eligible. Nine germline single nucleotide polymorphisms (SNPs) potentially conferring platinum sensitivity were tested for an association with a complete pathologic response to neoadjuvant chemotherapy (pT0) or elimination of muscle-invasive cancer (<pT2).The data from 205 patients were analyzed-59 patients were included in the discovery set and 146 in an independent replication cohort-from 3 institutions. The stage pT0 (26%) and < pT2 (50%) rates were consistent across the discovery and replication populations. Using a multivariate recessive genetic model, rs244898 in RARS (odds ratio, 6.8; 95% confidence interval, 1.8-28.9; P = .006) and rs7937567 in GALNTL4 (odds ratio, 4.8; 95% confidence interval, 1.1-22.6; P = .04) were associated with pT0 in the discovery set. Despite these large effects, neither were associated with achievement of pT0 in the replication set. A third SNP, rs10964552, was associated with stage < pT2 in the discovery set but also failed to replicate.Germline SNPs previously associated with platinum sensitivity were not associated with the neoadjuvant chemotherapy response in a large replication cohort of patients with urothelial cancer. These results emphasize the need for replication when evaluating pharmacogenomic markers and demonstrate that multi-institutional efforts are feasible and will be necessary to achieve advances in urothelial cancer pharmacogenomics.

Dataset Information

Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates.

Publications

Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates.

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