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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
Author(s) -
SiefkerRadtke Arlene O.,
Dinney Colin P.,
Shen Yu,
Williams Dallas L.,
Kamat Ashish M.,
Grossman H. Barton,
Millikan Randall E.
Publication year - 2012
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.27751
Subject(s) - medicine , gemcitabine , ifosfamide , cystectomy , bladder cancer , oncology , urology , chemotherapy , neoadjuvant therapy , surgery , cisplatin , cancer , breast cancer
Abstract BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.