A phase II study evaluating bevacizumab in combination with fixed-dose rate gemcitabine and low-dose cisplatin for metastatic pancreatic cancer: is an anti-VEGF strategy still applicable?
- 211 Downloads
Background: The role of bevacizumab, a recombinant humanized monoclonal antibody directed against vascular endothelial growth factor, in the treatment of pancreatic cancer remains unclear. The objectives of this study were to determine safety and efficacy in chemotherapy-naive patients with metastatic pancreatic cancer receiving bevacizumab in combination with fixed-dose rate (FDR) gemcitabine and low-dose cisplatin. Methods: Eligible patients received gemcitabine 1,000 mg/m2 at FDR infusion (10 mg/m2 per minute), cisplatin 20 mg/m2, and bevacizumab 10 mg/kg, on days 1 and 15 of a 28-day cycle. Patients were monitored by computed tomography scans every two cycles and monthly serum CA19-9 measurements. Results: Of 52 patients eligible for analysis, ten (19.2%) had an unconfirmed response and 30 (57.7%) had stable disease. Of 35 patients with elevated baseline CA19-9 levels, 20 (57.1%) had ≥50% biomarker decline during treatment. Median time to tumor progression was 6.6 months and median survival was 8.2 months (estimated 1-year survival, 36%). Grade 3/4 toxicities possibly related to bevacizumab included thromboembolic events (15.1%), hypertension (13.2%), gastrointestinal bleeding (9.4%), cardiac events (7.5%), and bowel perforation (5.7%). Plasma vascular endothelial growth factor and basic fibroblast growth factor levels and circulating tumor cell concentration did not correlate with overall survival, either at baseline or after 2 months of therapy. Conclusions: This bevacizumab-containing study regimen is modestly effective in patients with metastatic pancreatic cancer, although occasional serious complications may occur. Given the negative results of CALGB 80303, future efforts should be focused on identifying those specific patients who are most likely to benefit from bevacizumab-based therapy.
KeywordsPancreatic cancer Chemotherapy Gemcitabine Fixed-dose rate Bevacizumab Vascular endothelial growth factor Phase II clinical trial
- 9.Tokunaga T, Abe Y, Tsuchida T, Hatanaka H, Oshika Y, Tomisawa M, Yoshimura M, Ohnishi Y, Kijima H, Yamazaki H, Ueyama Y, Nakamura M (2002) Ribozyme mediated cleavage of cell-associated isoform of vascular endothelial growth factor inhibits liver metastasis of a pancreatic cancer cell line. Int J Oncol 21:1027–1032PubMedGoogle Scholar
- 11.Ogawa T, Takayama K, Takakura N, Kitano S, Ueno H (2002) Anti-tumor angiogenesis therapy using soluble receptors: enhanced inhibition of tumor growth when soluble fibroblast growth factor receptor-1 is used with soluble vascular endothelial growth factor receptor. Cancer Gene Ther 9:633–640PubMedCrossRefGoogle Scholar
- 13.Kindler HL, Niedzwiecki D, Hollis D, Oraefo E, Schrag D, Hurwitz H, McLeod HL, Mulcahy MF, Schilsky RL, Goldberg RM (2007) A double-blind, placebo-controlled, randomized phase III trial of gemcitabine plus bevacizumab versus gemcitabine plus placebo in patients with advanced pancreatic cancer: A preliminary analysis of Cancer and Leukemia Group B. J Clin Oncol, 2007 ASCO Annu Meet Proc Part I. 25:4508Google Scholar
- 16.Heinemann V, Quietzsch D, Gieseler F, Gonnermann M, Schonekas H, Rost A, Neuhaus H, Haag C, Clemens M, Heinrich B, Vehling-Kaiser U, Fuchs M, Fleckenstein D, Gesierich W, Uthgenannt D, Einsele H, Holstege A, Hinke A, Schalhorn A, Wilkowski R (2006) Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol 24:3946–3952PubMedCrossRefGoogle Scholar
- 17.Louvet C, Labianca R, Hammel P, Lledo G, Zampino MG, Andre T, Zaniboni A, Ducreux M, Aitini E, Taieb J, Faroux R, Lepere C, de Gramont A (2005) Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol 23:3509–3516PubMedCrossRefGoogle Scholar
- 18.Colucci G, Giuliani F, Gebbia V, Biglietto M, Rabitti P, Uomo G, Cigolari S, Testa A, Maiello E, Lopez M (2002) Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: a prospective, randomized phase III study of the Gruppo Oncologia dell’Italia Meridionale. Cancer 94:902–910PubMedCrossRefGoogle Scholar
- 19.Tempero M, Plunkett W, Ruiz Van Haperen V, Hainsworth J, Hochster H, Lenzi R, Abbruzzese J (2003) Randomized phase II comparison of dose-intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma. J Clin Oncol 21:3402–3408PubMedCrossRefGoogle Scholar
- 20.Poplin E, Levy DE, Berlin J, Rothenberg M, Cella D, Mitchell E, Alberts S, Benson A (2006) Phase III trial of gemcitabine (30-minute infusion) versus gemcitabine (fixed-dose rate infusion) versus gemcitabine + oxaliplatin in patients with advanced pancreatic cancer (E6201). J Clin Oncol 2006 ASCO Annu Meet Proc 24:LBA4004Google Scholar
- 29.Cascinu S, Labianca R, Catalano V, Barni S, Ferrau F, Beretta GD, Frontini L, Foa P, Pancera G, Priolo D, Graziano F, Mare M, Catalano G (2003) Weekly gemcitabine and cisplatin chemotherapy: a well-tolerated but ineffective chemotherapeutic regimen in advanced pancreatic cancer patients. A report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD). Ann Oncol 14:205–208PubMedCrossRefGoogle Scholar