We sought to investigate the safety and efficacy of gemcitabine, cisplatin, and lapatinib (GCL) as neoadjuvant therapy in patients with muscle-invasive bladder cancer (MIBC) planned for radical cystectomy.
Four cycles of GCL were administered as neoadjuvant therapy for patients with MIBC. Although initially designed as a phase II efficacy study with a primary endpoint of pathologic complete response at the time of radical cystectomy, the dose selected for investigation proved excessively toxic. A total of 6 patients were enrolled.
The initial 4 patients received gemcitabine 1000 mg/m2 intravenously on days 1 and 8 and cisplatin 70 mg/m2 intravenously on day 1 of each 21-day treatment cycle. Lapatinib was administered as 1000 mg orally daily starting one week prior to the initiation of cycle 1 of GC and continuing until the completion of cycle 4 of GC. These initial doses were poorly tolerated, and the final 2 enrolled patients received a reduced lapatinib dose of 750 mg orally daily. However, reduction of the lapatinib dose did not result in improved tolerance or drug-delivery, and the trial was terminated early due to excessive toxicity. Grade 3/4 toxicities included diarrhea (33%), nausea/vomiting (33%), and thrombocytopenia (33%).
The addition of lapatinib to GC as neoadjuvant therapy for MIBC was limited by excessive treatment-related toxicity. These findings highlight the importance of thorough dose-escalation investigation of combination therapies prior to evaluation in the neoadjuvant setting, as well as the limitations of determination of maximum tolerated dose for novel targeted combination regimens.
Cancer research and treatment : official journal of Korean Cancer Association. 2015 Dec 02 [Epub ahead of print]
Vivek Narayan, Ronac Mamtani, Stephen Keefe, Thomas Guzzo, S Bruce Malkowicz, David J Vaughn
Division of Medical Oncology, Hospital of the University of Pennsylvania, Abramson Cancer Center, Philadelphia, PA, USA. , Division of Medical Oncology, Hospital of the University of Pennsylvania, Abramson Cancer Center, Philadelphia, PA, USA. , Division of Medical Oncology, Hospital of the University of Pennsylvania, Abramson Cancer Center, Philadelphia, PA, USA. , Department of Urology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA. , Department of Urology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA. , Division of Medical Oncology, Hospital of the University of Pennsylvania, Abramson Cancer Center, Philadelphia, PA, USA.