Journal of Clinical Oncology, Vol 22, No 18 (September 15), 2004: pp. 3776-3783
© 2004 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2004.12.082
Irinotecan Plus Gemcitabine Results in No Survival Advantage Compared With Gemcitabine Monotherapy in Patients With Locally Advanced or Metastatic Pancreatic Cancer Despite Increased Tumor Response Rate
Caio M. Rocha Lima,
Mark R. Green,
Robert Rotche,
Wilson H. Miller, Jr,
G. Mark Jeffrey,
Laura A. Cisar,
Adele Morganti,
Nicoletta Orlando,
Gabriela Gruia,
Langdon L. Miller
From the University of Miami and Sylvester Cancer Center, Miami, FL; Medical University of South Carolina, Charleston, SC; US Oncology, Dallas, TX; Pfizer Corporation, New York, NY; Jewish General Hospital, Montreal, Quebec, Canada; Christchurch Hospital, Christchurch, New Zealand; and Pharmacia Italy SPA, Pfizer Group, Nerviano, Italy
Address reprint requests to Caio Max Sao Pedro Rocha Lima, MD, University of Miami and Sylvester Cancer Center, 1475 NW 12th Ave, Suite 3310, Miami, FL 33162; e-mail: crocha{at}med.miami.edu
PURPOSE: This phase III, randomized, open-label, multicenter study compared the overall survival associated with irinotecan plus gemcitabine (IRINOGEM) versus gemcitabine monotherapy (GEM) in patients with chemotherapy-naive, locally advanced or metastatic pancreatic cancer.
PATIENTS AND METHODS: IRINOGEM patients received starting doses of gemcitabine 1,000 mg/m2 and irinotecan 100 mg/m2 given weekly for 2 weeks every 3-week cycle. GEM patients received gemcitabine 1,000 mg/m2 weekly for 7 of 8 weeks (induction) and then weekly for 3 of 4 weeks. The primary end point of the trial was survival. Secondary end points included tumor response, time to tumor progression (TTP), changes in CA 19-9, and safety.
RESULTS: In each arm, 180 randomly assigned patients comprised the intent-to-treat population evaluated for efficacy; 173 IRINOGEM and 169 GEM patients were treated. Median survival times were 6.3 months for IRINOGEM (95% CI, 4.7 to 7.5 months) and 6.6 months for GEM (95% CI, 5.2 to 7.8 months; log-rank P = .789). Tumor response rates were 16.1% (95% CI, 11.1% to 22.3%) for IRINOGEM and 4.4% (95% CI, 1.9% to 8.6%) for GEM ( 2 P < .001). Median TTP was 3.5 months for IRINOGEM versus 3.0 months for GEM (log-rank P = .352). However, subset analyses in patients with locally advanced disease suggested a TTP advantage with IRINOGEM versus GEM (median, 7.7 v 3.9 months). CA 19-9 progression was positively correlated with tumor progression. The incidence of grade 3 diarrhea was higher in the IRINOGEM group but grade 3 to 4 hematologic toxicities and quality-of-life outcomes were similar.
CONCLUSION: IRINOGEM safely improved the tumor response rate compared with GEM but did not alter overall survival.
Supported by a grant from Pfizer Corp, New York, NY.
Presented in part at the 39th Annual Meeting of the American Society for Clinical Oncology, Chicago, IL, May 31-June 3, 2003.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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M. Galvez-Peralta, N. T. Dai, D. A. Loegering, K. S. Flatten, S. L. Safgren, J. M. Wagner, M. M. Ames, L. M. Karnitz, and S. H. Kaufmann
Overcoming S-Phase Checkpoint-Mediated Resistance: Sequence-Dependent Synergy of Gemcitabine and 7-Ethyl-10-hydroxycamptothecin (SN-38) in Human Carcinoma Cell Lines
Mol. Pharmacol.,
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74(3):
724 - 735.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. S. Pino, M. Balsamo, F. Di Modugno, M. Mottolese, M. Alessio, E. Melucci, M. Milella, D. J. McConkey, U. Philippar, F. B. Gertler, et al.
Human Mena+11a Isoform Serves as a Marker of Epithelial Phenotype and Sensitivity to Epidermal Growth Factor Receptor Inhibition in Human Pancreatic Cancer Cell Lines
Clin. Cancer Res.,
August 1, 2008;
14(15):
4943 - 4950.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. J. Chua and J. R. Zalcberg
Pancreatic cancer--is the wall crumbling?
Ann. Onc.,
July 1, 2008;
19(7):
1224 - 1230.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Nieto, M. L. Grossbard, and P. Kozuch
Metastatic Pancreatic Cancer 2008: Is the Glass Less Empty?
Oncologist,
May 1, 2008;
13(5):
562 - 576.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Miyanishi, H. Ishiwatari, T. Hayashi, M. Takahashi, Y. Kawano, K. Takada, H. Ihara, T. Okuda, K. Takanashi, S. Takahashi, et al.
A Phase I Trial of Arterial Infusion Chemotherapy with Gemcitabine and 5-Fluorouracil for Unresectable Advanced Pancreatic Cancer after Vascular Supply Distribution via Superselective Embolization
Jpn. J. Clin. Oncol.,
April 1, 2008;
38(4):
268 - 274.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Cao, M. Bloomston, T. Zhang, W. L. Frankel, G. Jia, B. Wang, N. C. Hall, R. M. Koch, H. Cheng, M. V. Knopp, et al.
Synergistic Antipancreatic Tumor Effect by Simultaneously Targeting Hypoxic Cancer Cells With HSP90 Inhibitor and Glycolysis Inhibitor
Clin. Cancer Res.,
March 15, 2008;
14(6):
1831 - 1839.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Sapra, H. Zhao, M. Mehlig, J. Malaby, P. Kraft, C. Longley, L. M. Greenberger, and I. D. Horak
Novel Delivery of SN38 Markedly Inhibits Tumor Growth in Xenografts, Including a Camptothecin-11-Refractory Model
Clin. Cancer Res.,
March 15, 2008;
14(6):
1888 - 1896.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Moureau-Zabotto, J.-M. Phelip, P. Afchain, L. Mineur, T. Andre, V. Vendrely, G. Lledo, O. Dupuis, F. Huguet, E. Touboul, et al.
Concomitant Administration of Weekly Oxaliplatin, Fluorouracil Continuous Infusion, and Radiotherapy After 2 Months of Gemcitabine and Oxaliplatin Induction in Patients With Locally Advanced Pancreatic Cancer: A Groupe Coordinateur Multidisciplinaire en Oncologie Phase II Study
J. Clin. Oncol.,
March 1, 2008;
26(7):
1080 - 1085.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Laheru, E. Lutz, J. Burke, B. Biedrzycki, S. Solt, B. Onners, I. Tartakovsky, J. Nemunaitis, D. Le, E. Sugar, et al.
Allogeneic Granulocyte Macrophage Colony-Stimulating Factor-Secreting Tumor Immunotherapy Alone or in Sequence with Cyclophosphamide for Metastatic Pancreatic Cancer: A Pilot Study of Safety, Feasibility, and Immune Activation
Clin. Cancer Res.,
March 1, 2008;
14(5):
1455 - 1463.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Burris III and C. Rocha-Lima
New Therapeutic Directions for Advanced Pancreatic Cancer: Targeting the Epidermal Growth Factor and Vascular Endothelial Growth Factor Pathways
Oncologist,
March 1, 2008;
13(3):
289 - 298.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. C. DeRosier, S. M. Vickers, K. R. Zinn, Z. Huang, W. Wang, W. E. Grizzle, J. Sellers, C. R. Stockard Jr., T. Zhou, P. G. Oliver, et al.
TRA-8 anti-DR5 monoclonal antibody and gemcitabine induce apoptosis and inhibit radiologically validated orthotopic pancreatic tumor growth
Mol. Cancer Ther.,
December 1, 2007;
6(12):
3198 - 3207.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. C. DeRosier, D. J. Buchsbaum, P. G. Oliver, Z.-Q. Huang, J. C. Sellers, W. E. Grizzle, W. Wang, T. Zhou, K. R. Zinn, J. W. Long, et al.
Combination Treatment with TRA-8 Anti Death Receptor 5 Antibody and CPT-11 Induces Tumor Regression in an Orthotopic Model of Pancreatic Cancer
Clin. Cancer Res.,
September 15, 2007;
13(18):
5535s - 5543s.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. A. Welch and M. J. Moore
Combination Chemotherapy in Advanced Pancreatic Cancer: Time to Raise the White Flag?
J. Clin. Oncol.,
June 1, 2007;
25(16):
2159 - 2161.
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Herrmann, G. Bodoky, T. Ruhstaller, B. Glimelius, E. Bajetta, J. Schuller, P. Saletti, J. Bauer, A. Figer, B. Pestalozzi, et al.
Gemcitabine Plus Capecitabine Compared With Gemcitabine Alone in Advanced Pancreatic Cancer: A Randomized, Multicenter, Phase III Trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group
J. Clin. Oncol.,
June 1, 2007;
25(16):
2212 - 2217.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Moore, D. Goldstein, J. Hamm, A. Figer, J. R. Hecht, S. Gallinger, H. J. Au, P. Murawa, D. Walde, R. A. Wolff, et al.
Erlotinib Plus Gemcitabine Compared With Gemcitabine Alone in Patients With Advanced Pancreatic Cancer: A Phase III Trial of the National Cancer Institute of Canada Clinical Trials Group
J. Clin. Oncol.,
May 20, 2007;
25(15):
1960 - 1966.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Van Cutsem, C. Verslype, and P. A. Grusenmeyer
Lessons Learned in the Management of Advanced Pancreatic Cancer
J. Clin. Oncol.,
May 20, 2007;
25(15):
1949 - 1952.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J Taieb, T Lecomte, T Aparicio, A Asnacios, T Mansourbakht, P Artru, D Fallik, J. Spano, B Landi, G Lledo, et al.
FOLFIRI.3, a new regimen combining 5-fluorouracil, folinic acid and irinotecan, for advanced pancreatic cancer: results of an Association des Gastro-Enterologues Oncologues (Gastroenterologist Oncologist Association) multicenter phase II study
Ann. Onc.,
March 1, 2007;
18(3):
498 - 503.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Huguet, T. Andre, P. Hammel, P. Artru, J. Balosso, F. Selle, E. Deniaud-Alexandre, P. Ruszniewski, E. Touboul, R. Labianca, et al.
Impact of Chemoradiotherapy After Disease Control With Chemotherapy in Locally Advanced Pancreatic Adenocarcinoma in GERCOR Phase II and III Studies
J. Clin. Oncol.,
January 20, 2007;
25(3):
326 - 331.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Baranowska-Kortylewicz, M. Abe, J. Nearman, and C. A. Enke
Emerging Role of Platelet-Derived Growth Factor Receptor-{beta} Inhibition in Radioimmunotherapy of Experimental Pancreatic Cancer
Clin. Cancer Res.,
January 1, 2007;
13(1):
299 - 306.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Van Cutsem, V. M. Moiseyenko, S. Tjulandin, A. Majlis, M. Constenla, C. Boni, A. Rodrigues, M. Fodor, Y. Chao, E. Voznyi, et al.
Phase III Study of Docetaxel and Cisplatin Plus Fluorouracil Compared With Cisplatin and Fluorouracil As First-Line Therapy for Advanced Gastric Cancer: A Report of the V325 Study Group
J. Clin. Oncol.,
November 1, 2006;
24(31):
4991 - 4997.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. K. Abou-Alfa, R. Letourneau, G. Harker, M. Modiano, H. Hurwitz, N. S. Tchekmedyian, K. Feit, J. Ackerman, R. L. De Jager, S. G. Eckhardt, et al.
Randomized Phase III Study of Exatecan and Gemcitabine Compared With Gemcitabine Alone in Untreated Advanced Pancreatic Cancer
J. Clin. Oncol.,
September 20, 2006;
24(27):
4441 - 4447.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. A. Richards, K. A. Boehm, D. M. Waterhouse, D. J. Wagener, S. S. Krishnamurthi, A. Rosemurgy, W. Grove, K. Macdonald, S. Gulyas, M. Clark, et al.
Gemcitabine plus CI-994 offers no advantage over gemcitabine alone in the treatment of patients with advanced pancreatic cancer: results of a phase II randomized, double-blind, placebo-controlled, multicenter study
Ann. Onc.,
July 1, 2006;
17(7):
1096 - 1102.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Giovannetti, V. Mey, S. Nannizzi, G. Pasqualetti, M. Del Tacca, and R. Danesi
Pharmacogenetics of anticancer drug sensitivity in pancreatic cancer.
Mol. Cancer Ther.,
June 1, 2006;
5(6):
1387 - 1395.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. R. Cardenes, E. G. Chiorean, J. DeWitt, M. Schmidt, and P. Loehrer
Locally advanced pancreatic cancer: current therapeutic approach.
Oncologist,
June 1, 2006;
11(6):
612 - 623.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Sebastiani, F. Ricci, B. Rubio-Viquiera, P. Kulesza, C. J. Yeo, M. Hidalgo, A. Klein, D. Laheru, and C. A. Iacobuzio-Donahue
Immunohistochemical and Genetic Evaluation of Deoxycytidine Kinase in Pancreatic Cancer: Relationship to Molecular Mechanisms of Gemcitabine Resistance and Survival
Clin. Cancer Res.,
April 15, 2006;
12(8):
2492 - 2497.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. A. Huff, W. Matsui, B. D. Smith, and R. J. Jones
The paradox of response and survival in cancer therapeutics
Blood,
January 15, 2006;
107(2):
431 - 434.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Giroux, C. Malicet, M. Barthet, M. Gironella, C. Archange, J.-C. Dagorn, S. Vasseur, and J. L. Iovanna
p8 Is a New Target of Gemcitabine in Pancreatic Cancer Cells
Clin. Cancer Res.,
January 1, 2006;
12(1):
235 - 241.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. P. Lutz, E. V. Cutsem, T. Wagener, J.-L. Van Laethem, U. Vanhoefer, J. A. Wils, E. Gamelin, C. H. Koehne, J. P. Arnaud, E. Mitry, et al.
Docetaxel Plus Gemcitabine or Docetaxel Plus Cisplatin in Advanced Pancreatic Carcinoma: Randomized Phase II Study 40984 of the European Organisation for Research and Treatment of Cancer Gastrointestinal Group
J. Clin. Oncol.,
December 20, 2005;
23(36):
9250 - 9256.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Furuse, H. Ishii, T. Okusaka, M. Nagase, K. Nakachi, H. Ueno, M. Ikeda, C. Morizane, and M. Yoshino
Phase I Study of Fixed Dose Rate Infusion of Gemcitabine in Patients with Unresectable Pancreatic Cancer
Jpn. J. Clin. Oncol.,
December 1, 2005;
35(12):
733 - 738.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. L. Kindler, G. Friberg, D. A. Singh, G. Locker, S. Nattam, M. Kozloff, D. A. Taber, T. Karrison, A. Dachman, W. M. Stadler, et al.
Phase II Trial of Bevacizumab Plus Gemcitabine in Patients With Advanced Pancreatic Cancer
J. Clin. Oncol.,
November 1, 2005;
23(31):
8033 - 8040.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Oettle, D. Richards, R. K. Ramanathan, J. L. van Laethem, M. Peeters, M. Fuchs, A. Zimmermann, W. John, D. Von Hoff, M. Arning, et al.
A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer
Ann. Onc.,
October 1, 2005;
16(10):
1639 - 1645.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Louvet, R. Labianca, P. Hammel, G. Lledo, M.G. Zampino, T. Andre, A. Zaniboni, M. Ducreux, E. Aitini, J. Taieb, et al.
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.,
May 20, 2005;
23(15):
3509 - 3516.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Conroy, B. Paillot, E. Francois, R. Bugat, J.-H. Jacob, U. Stein, S. Nasca, J.-P. Metges, O. Rixe, P. Michel, et al.
Irinotecan Plus Oxaliplatin and Leucovorin-Modulated Fluorouracil in Advanced Pancreatic Cancer--A Groupe Tumeurs Digestives of the Federation Nationale des Centres de Lutte Contre le Cancer Study
J. Clin. Oncol.,
February 20, 2005;
23(6):
1228 - 1236.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
