Integrated therapy for locally advanced bladder cancer: final report of a randomized trial of cystectomy plus adjuvant M-VAC versus cystectomy with both preoperative and postoperative M-VAC.
OBJECTIVE
We conducted a phase III trial to investigate the timing of chemotherapy with respect to surgery for patients with resectable but high-risk urothelial cancer. The trial was also designed to evaluate the accuracy of clinical staging in patients with locally advanced cancer and the prognostic significance of chemotherapy-induced downstaging.


METHODS
A total of 140 uniformly evaluated patients with locally advanced urothelial cancer were studied. Planned treatment was five cycles of chemotherapy (M-VAC: methotrexate, vinblastine, doxorubicin, and cisplatin) plus radical cystectomy and pelvic lymph node dissection. Patients were randomly assigned to receive either two courses of neoadjuvant M-VAC followed by surgery plus three additional cycles of chemotherapy, or, alternatively, to have initial cystectomy followed by five cycles of adjuvant chemotherapy.


RESULTS
There were no significant differences in outcome between the two groups. By intent-to-treat, 81 patients (58%) remain disease-free, with median follow-up of 6.8 years. We confirmed a high rate of clinical understaging in this cohort, especially among patients showing lymphovascular invasion on biopsy. Patients with no residual muscle-invasive disease at cystectomy after neoadjuvant chemotherapy were likely to be cured.


CONCLUSIONS
These results lend further support to the impression from small randomized trials that, in a high-risk cohort, there is an improved cure fraction by the combination of multiagent chemotherapy and surgery, although we found no preferred sequence. Importantly, it is possible to select appropriate patients for such therapy on the basis of clinical staging information. These results establish a benchmark of outcome for this cohort.
Millikan
R
R
Center for Genitourinary Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. rmillika@notes.mdacc.tmc.edu
Dinney
C
C
Swanson
D
D
Sweeney
P
P
Ro
J Y
JY
Smith
T L
TL
Williams
D
D
Logothetis
C
C
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D015653:Cystectomy; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D009367:Neoplasm Staging; D016609:Neoplasms, Second Primary / Q000473:pathology; D011182:Postoperative Care; D011183:Postoperative Complications; D011300:Preoperative Care; D016019:Survival Analysis; D013997:Time Factors; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000601:surgery*; D014747:Vinblastine / Q000008:administration & dosage
D014747:Vinblastine; D004317:Doxorubicin; D002945:Cisplatin; D008727:Methotrexate