Cisplatin, Gemcitabine, and Lapatinib as Neoadjuvant Therapy for Muscle-Invasive Bladder Cancer
0
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
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/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 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.
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/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 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.
참고문헌 (25)
- Stein JP, "Radical cystectomy for invasive bladder cancer : long-term results of a standard procedure", World J Urol, 24, pp.296~304 (2006)
- Grossman HB, "Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer", N Engl J Med, 349, pp.859~866 (2003)
- Advanced Bladder Cancer(ABC)Meta-analysis Collaboration, "Neoadjuvant chemotherapy in invasive bladder cancer : update of a systematic review and meta-analysis of individual patient data advanced bladder cancer(ABC)meta-analysis collaboration", Eur Urol, 48, pp.202~205 (2005)
- "NCCN guidelines:bladder cancer" (2015)[URL]
- von der Maase H, "Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer : results of a large, randomized, multinational, multicenter, phase III study", J Clin Oncol, 18, pp.3068~3077 (2000)
- Apolo AB, "Examining the management of muscle-invasive bladder cancer by medical oncologists in the United States", Urol Oncol, 32, pp.637~644 (2014)
- Bellmunt J, "Novel approaches with targeted therapies in bladder cancer. Therapy of bladder cancer by blockade of the epidermal growth factor receptor family", Crit Rev Oncol Hematol, 46, pp.85~104 (2003)
- Chow NH, "Expression profiles of ErbB family receptors and prognosis in primary transitional cell carcinoma of the urinary bladder", Clin Cancer Res, 7, pp.1957~1962 (2001)
- Wulfing C, "A single-arm, multicenter, open-label phase 2 study of lapatinib as the second-line treatment of patients with locally advanced or metastatic transitional cell carcinoma", Cancer, 115, pp.2881~2890 (2009)
- Xia W, "Anti-tumor activity of GW572016 : a dual tyrosine kinase inhibitor blocks EGF activation of EGFR", erbB2 and downstream Erk1, Oncogene, pp.2002, 21[DOI]
- Opdam FL, "Lapatinib for advanced or metastatic breast cancer", Oncologist, 17, pp.536~542 (2012)
- McHugh LA, "Combined treatment of bladder cancer cell lines with lapatinib and varying chemotherapy regimens : evidence of schedule-dependent synergy", Urology, 69, pp.390~394 (2007)
- Versola M, "Clinical activity of GW572016 in EGF10003 in patients with solid tumors", J Clin Oncol, 22(14 Suppl), pp.3047~ (2004)
- Burris HA 3rd, "Phase I safety, pharmacokinetics, and clinical activity study of lapatinib(GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas", J Clin Oncol, 23, pp.5305~5313 (2005)
- LoRusso PM, "Phase I and pharmacokinetic study of lapatinib and docetaxel in patients with advanced cancer", J Clin Oncol, 26, pp.3051~3056 (2008)
- Siegel-Lakhai WS, "Phase I pharmacokinetic study of the safety and tolerability of lapatinib(GW572016)in combination with oxaliplatin", fluorouracil, Clin Cancer Res, pp.2007, 13(15 Pt 1)[DOI]
- Daugaard G, "Phase I results from a study of lapatinib with gemcitabine and cisplatin(GC)in advanced", metastatic bladder cancer, 2013, pp.31(Suppl 6), 252~
- Postel-Vinay S, "Phase I trials of molecularly targeted agents : should we pay more attention to late toxicities?", J Clin Oncol, 29, pp.1728~1735 (2011)
- Galsky MD, "Gemcitabine, Cisplatin, and sunitinib for metastatic urothelial carcinoma and as preoperative therapy for muscle-invasive bladder cancer", Clin Genitourin Cancer, 11, pp.175~181 (2013)
- Postel-Vinay S, "Towards new methods for the determination of dose limiting toxicities and the assessment of the recommended dose for further studies of molecularly targeted agents : Dose-Limiting Toxicity and Toxicity Assessment Recommendation Group for Early Trials of Targeted therapies, an European Organisation for Research and Treatment of Cancer-led study", Eur J Cancer, 50, pp.2040~2049 (2014)
- Dash A, "A role for neoadjuvant gemcitabine plus cisplatin in muscle-invasive urothelial carcinoma of the bladder : a retrospective experience", Cancer, 113, pp.2471~2477 (2008)
- Galsky MD, "Target-specific, histology-independent, randomized discontinuation study of lapatinib in patients with HER2-amplified solid tumors", Invest New Drugs, 30, pp.695~701 (2012)
- Powles T, "A phase II", III, double-blind, randomized trial comparing maintenance lapatinib versus placebo after first line chemotherapy in HER1, J Clin Oncol, pp.2015, 33[DOI]
- Pruthi RS, "A phase II trial of neoadjuvant erlotinib in patients with muscle-invasive bladder cancer undergoing radical cystectomy : clinical and pathological results", BJU Int, 106, pp.349~354 (2010)
- Hussain MH, "Trastuzumab, paclitaxel, carboplatin, and gemcitabine in advanced human epidermal growth factor receptor-2", neu-positive urothelial carcinoma : results of a multicenter phase II National Cancer Institute trial, 2007, pp.25, 2218~2224