Cisplatin, Gemcitabine, and Lapatinib as Neoadjuvant Therapy for Muscle-Invasive Bladder Cancer

Cancer Res Treat. 2016 Jul;48(3):1084-91. doi: 10.4143/crt.2015.405. Epub 2015 Dec 2.

Abstract

Purpose: 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.

Materials and methods: 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 six patients were enrolled.

Results: The initial four patients received gemcitabine 1,000 mg/m(2) intravenously on days 1 and 8 and cisplatin 70 mg/m(2) intravenously on day 1 of each 21-day treatment cycle. Lapatinib was administered as 1,000 mg orally daily starting one week prior to the initiation of cycle 1 of gemcitabine and cisplatin (GC) and continuing until the completion of cycle 4 of GC. These initial doses were poorly tolerated, and the final two 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%).

Conclusion: 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.

Keywords: Cystectomy; Drug therapy; Epidermal growth factor receptor; Molecular targeted therapy; Urothelial carcinoma.

Publication types

  • Clinical Trial, Phase II

MeSH terms

  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / toxicity
  • Cisplatin / therapeutic use
  • Cisplatin / toxicity
  • Cystectomy*
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / therapeutic use
  • Deoxycytidine / toxicity
  • Disease-Free Survival
  • Female
  • Gemcitabine
  • Humans
  • Lapatinib
  • Lymph Node Excision
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Muscle Neoplasms / drug therapy*
  • Muscle Neoplasms / pathology
  • Muscle Neoplasms / secondary
  • Muscle Neoplasms / surgery
  • Neoadjuvant Therapy / adverse effects
  • Neoadjuvant Therapy / methods*
  • Neoplasm Invasiveness
  • Neoplasm Staging
  • Prospective Studies
  • Quinazolines / therapeutic use
  • Quinazolines / toxicity
  • Treatment Outcome
  • Urinary Bladder / pathology
  • Urinary Bladder / surgery
  • Urinary Bladder Neoplasms / drug therapy*
  • Urinary Bladder Neoplasms / pathology
  • Urinary Bladder Neoplasms / surgery

Substances

  • Quinazolines
  • Lapatinib
  • Deoxycytidine
  • Cisplatin
  • Gemcitabine