title: Cisplatin, Gemcitabine, and Lapatinib as Neoadjuvant Therapy for Muscle-Invasive Bladder Cancer.
abstract: OBJECTIVE
  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.
  
  
  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%).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Medical Oncology, Hospital of the University of Pennsylvania, Abramson Cancer Center, Philadelphia, PA, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Narayan
authors.affiliation: Division of Medical Oncology, Hospital of the University of Pennsylvania, Abramson Cancer Center, Philadelphia, PA, USA.
authors.forename: Ronac
authors.initials: R
authors.lastname: Mamtani
authors.affiliation: Division of Medical Oncology, Hospital of the University of Pennsylvania, Abramson Cancer Center, Philadelphia, PA, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Keefe
authors.affiliation: Department of Urology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Guzzo
authors.affiliation: Department of Urology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: S Bruce
authors.initials: SB
authors.lastname: Malkowicz
authors.affiliation: Division of Medical Oncology, Hospital of the University of Pennsylvania, Abramson Cancer Center, Philadelphia, PA, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Vaughn
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use* / Q000633:toxicity; D002945:Cisplatin / Q000627:therapeutic use / Q000633:toxicity; D015653:Cystectomy; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use / Q000633:toxicity; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008197:Lymph Node Excision; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D019042:Muscle Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary / Q000601:surgery; D020360:Neoadjuvant Therapy / Q000009:adverse effects / Q000379:methods*; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011446:Prospective Studies; D011799:Quinazolines / Q000627:therapeutic use / Q000633:toxicity; D016896:Treatment Outcome; D001743:Urinary Bladder / Q000473:pathology / Q000601:surgery; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D000093542:Gemcitabine
chemical_list: D011799:Quinazolines; D000077341:Lapatinib; D003841:Deoxycytidine; D002945:Cisplatin; D000093542:Gemcitabine
keywords: Cystectomy; Drug therapy; Epidermal growth factor receptor; Molecular targeted therapy; Urothelial carcinoma