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A phase 2 clinical trial of sequential neoadjuvant chemotherapy with ifosfamide, doxorubicin, and gemcitabine followed by cisplatin, gemcitabine, and ifosfamide in locally advanced urothelial cancer†
Article first published online: 22 AUG 2012
Copyright © 2012 American Cancer Society
Volume 119, Issue 3, pages 540–547, 1 February 2013
How to Cite
Siefker-Radtke, A. O., Dinney, C. P., Shen, Y., Williams, D. L., Kamat, A. M., Grossman, H. B. and Millikan, R. E. (2013), A phase 2 clinical trial of sequential neoadjuvant chemotherapy with ifosfamide, doxorubicin, and gemcitabine followed by cisplatin, gemcitabine, and ifosfamide in locally advanced urothelial cancer. Cancer, 119: 540–547. doi: 10.1002/cncr.27751
Presented at the 2008 Annual Meeting of the American Society of Clinical Oncology; May 30 to June 3, 2008; Chicago, IL.
- Issue published online: 22 JAN 2013
- Article first published online: 22 AUG 2012
- Manuscript Accepted: 12 JUN 2012
- Manuscript Revised: 9 JUN 2012
- Manuscript Received: 4 APR 2012
- bladder cancer;
- urothelial cancer;
- clinical trial;
Neoadjuvant chemotherapy improves the survival of patients with high-risk urothelial cancer. However, the lack of curative alternatives to cisplatin-based chemotherapy is limiting for patients with neuropathy or hearing loss. Sequential chemotherapy also has not been well studied in the neoadjuvant setting. The authors explored sequential neoadjuvant ifosfamide-based chemotherapy in a patient cohort at high risk of noncurative cystectomy.
Patients with muscle-invasive cancer and lymphovascular invasion, hydronephrosis, clinical T3b and T4a (cT3b-4a) disease (defined as a 3-dimensional mass on examination under anesthetic or invasion into local organs), micropapillary tumors, or upper tract disease received 3 cycles of combined ifosfamide, doxorubicin, and gemcitabine followed by 4 cycles of combined cisplatin, gemcitabine, and ifosfamide. The primary endpoint was downstaging to pT1N0M0 disease or lower.
At a median follow-up of 85.3 months, the 5-year overall survival (OS) and disease-specific survival (DSS) rates for all 65 patients were 63% and 68%, respectively (95% confidence interval: 5-year OS rate, 0.52%-0.76%; 5-year DSS rate, 0.58%-0.81%). Pathologic downstaging to pT1N0 disease or lower occurred in 50% of patients who underwent cystectomy and in 60% of patients who underwent nephroureterectomy and was correlated with the 5-year OS rate (pT1N0 disease or lower, 87%; pT2-pT3aN0 disease, 67%; and pT3b disease or higher or lymph node-negative disease, 27%; P ≤ .001 for pT1 or lower vs pT2 or higher). Variant histology was associated with an inferior 5-year DSS rate (50% vs 83% in pure transitional cell carcinoma; P = .02). The most frequent grade 3 toxicities were infection (38%), febrile neutropenia (22%), and mucositis (18%). There were 3 grade 4 toxicities (myocardial infarction, thrombocytopenia, and vomiting) and 1 grade 5 toxicity in a patient who refused antibiotics for pneumonia.
Sequential therapy was active and maintained the historic expectation of achieving a cure. The current results strongly reinforced previous experience suggesting that pathologic downstaging to pT1N0 disease or less is a useful surrogate for eventual cure in patients with urothelial cancer. Cancer 2013. © 2012 American Cancer Society.