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BACKGROUND:
It has been shown that the use of neoadjuvant chemotherapy improves survival in patients with locally advanced urothelial cancer (UC) undergoing radical cystectomy (RC). Unfortunately it can be associated with significant side effects, and does not uniformly cure patients. In an effort to improve both tolerance and survival, we explored the use of an alternative dosing regimen (dose-dense (DD) methotrexate, vinblastine, doxorubicin, cisplatin(MVAC)) followed by pegfilgrastim support in patients undergoing neoadjuvant chemotherapy prior to radical cystectomy.
METHODS:
Patients were enrolled from 4 US institutions. Patients had primary tumors arising in the bladder or other parts of the urothelial system,clinical T2-T4a disease and no evidence of distant metastatic disease. Patients all received 4 cycles (8 weeks) of DD-MVAC therapy followed by RC 4-10 weeks after last dose of chemotherapy. The primary endpoint was pathologic response rate defined as the absence of residual muscle invasive cancer in cystectomy specimen, pathologic down-staging to </=pT1, N0. A secondary endpoint was incidence of post-operative surgical complications.
RESULTS:
A total of 39 patients were enrolled between 2008 and 2012. The bladder was the primary UC site in 36 patients. Twenty-two patients had clinical stage T3 or higher disease predominantly by MRI imaging. Seventeen (45%) patients had clinical N1 disease. Nineteen of 39 eligible patients achieved </= pT1 pathologic response, corresponding to a 49% response rate (90% CI 35-63). Thirty-five patients (90%) were pathologic N0 (90% CI 78-96). One patient had progression of disease after the completion of chemotherapy and did not have surgery. Thirty-seven patients received the entire 4 cycles of chemotherapy, 2 patients received 3 cycles due to therapy related toxicities. In total, seven patients had surgical complications(3 with unlikely or no relation to surgery). Four patients (11%) had significant (grade 2 or higher per CTCAE version 3.0) surgical complications (90% CI 4-22). Significant surgical complications included small bowel obstruction, necrosis of the ileum, anastomotic leak and acute kidney injury. There were no perioperative or 90 day deaths.
CONCLUSIONS:
The use of neoadjuvant regimen consisting of DD-MVAC in patients with muscle invasive UCC treated with radical cystectomy is effective in achieving pathological downstaging with relatively low rate of significant surgical complications. Changing the dosing regimen would likely increase the number of patients who successfully complete treatment and improve overall cure rate.