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 Final results

• Published in: Cancer Vol. 119; no. 3; pp. 540 - 547
• Main Authors: Siefker‐Radtke, Arlene O., Dinney, Colin P., Shen, Yu, Williams, Dallas L., Kamat, Ashish M., Grossman, H. Barton, Millikan, Randall E.
• Format: Journal Article
• Language: English
• Published: Hoboken, NJ Wiley-Blackwell 01.02.2013
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Biological and medical sciences; Carcinoma, Transitional Cell - drug therapy; Carcinoma, Transitional Cell - mortality; Carcinoma, Transitional Cell - pathology; Carcinoma, Transitional Cell - surgery; Cisplatin - administration & dosage; Cisplatin - adverse effects; Deoxycytidine - administration & dosage; Deoxycytidine - adverse effects; Deoxycytidine - analogs & derivatives; Doxorubicin - administration & dosage; Doxorubicin - adverse effects; Drug Administration Schedule; Female; Humans; Ifosfamide - administration & dosage; Ifosfamide - adverse effects; Male; Medical sciences; Middle Aged; Neoadjuvant Therapy - adverse effects; Neoadjuvant Therapy - methods; Neoplasm Staging; Nephrology. Urinary tract diseases; Survival Analysis; Treatment Outcome; Tumors; Tumors of the urinary system; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - mortality; Urinary Bladder Neoplasms - pathology; Urinary Bladder Neoplasms - surgery; Urinary tract. Prostate gland; Urothelium - pathology; Antineoplastic agent; neoadjuvant; Gemcitabine; Doxorubicin; Neoadjuvant treatment; Isomerases; Cancerology; Sequential; Surgery; Phase II trial; Clinical trial; Pyrimidine nucleoside; Platinum II Complexes; DNA topoisomerase (ATP-hydrolysing); Urothelial cancer; Urinary system disease; Enzyme; Ifosfamide; Enzyme inhibitor; Topoisomerase II inhibitor; Urinary tract disease; Malignant tumor; Bladder cancer; Cisplatin; Alkylating agent; Oxazaphosphinane derivatives; Chemotherapy; Treatment; Antimetabolic; Nitrogen mustard; Pyrimidine derivatives; Anthracyclins; Bladder disease; Locally advanced stage; Fluorine Organic compounds; Cancer
• ISSN: 0008-543X; 1097-0142; 1097-0142
• DOI: 10.1002/cncr.27751

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.