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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 RateFrom 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 ( CONCLUSION: IRINOGEM safely improved the tumor response rate compared with GEM but did not alter overall survival.
Carcinoma of the pancreas is the fourth leading cause of cancer deaths in the United States.1 The nonspecific nature of early symptoms of pancreatic cancer may result in delayed diagnosis such that 80% or more of patients present initially with locally advanced or metastatic disease that cannot be treated by surgical resection.2–4 Median survival time is 6 to 10 months for patients with locally advanced disease, and 3 to 6 months for those with metastatic disease.5 Chemotherapy options for advanced or metastatic pancreatic cancer are limited. Single-agent fluorouracil (FU) results in tumor response rates of 7% or less.6–9 Combination chemotherapy with FU has resulted in increased toxicity without higher efficacy.2–5 Gemcitabine (Gemzar; Eli Lilly and Co, Indianapolis, IN) in weekly infusions has been shown to be superior to bolus FU as monotherapy for advanced disease in a randomized phase III study involving 126 patients.8 A greater clinical benefit (22.2% v 4.8%; P = .0022), longer median survival time (5.7 v 4.4 months; P = .0025), and greater 12-month survival rate (18% v 2%) favoring gemcitabine were observed. A comprehensive experience reported in a large, multicenter, open-label study that enrolled more than 3,000 patients on a compassionate-need basis documented single-agent gemcitabine (GEM) to be reasonably safe and to offer a median overall survival of 4.8 months.9 Irinotecan (Camptosar; Pfizer Oncology, New York, NY), a camptothecin derivative, demonstrated efficacy results similar to those of gemcitabine in two phase II studies in chemotherapy-naive pancreatic cancer patients.10,11 Complimentary toxicity profiles and different mechanisms of cytotoxicity provided the rationale for development of a gemcitabine and irinotecan (IRINOGEM) combination. Preclinical studies suggested dose-dependent synergistic interactions between gemcitabine and irinotecan.8,11 In a phase I study with both drugs given on days 1 and 8 of repeated 3-week cycles, the maximum-tolerated doses were gemcitabine 1,000 mg/m2 given during a 30-minute infusion immediately followed by irinotecan 100 mg/m2 infused during 90 minutes.12 A phase II study at the maximum-tolerated dose and schedule defined by the phase I experience showed that the combination was active and had an acceptable toxicity profile.13 In this phase II trial, significant correlations between proportional changes in CA 19-9 and radiographically assessed tumor area were observed and CA 19-9 seemed to be a good indicator of response and progression. On the basis of these observations, a phase III study of the combination of IRINOGEM versus GEM was undertaken in patients with advanced or metastatic pancreatic cancer, with a primary end point of survival. To our knowledge this is also the first phase III study to examine CA 19-9 as a predictor of disease status in pancreatic cancer patients receiving chemotherapy.
Patient Eligibility The protocol was conducted according to the guidelines of the Declaration of Helsinki. All patients provided written informed consent before study enrollment. Male and female patients were eligible for the study if they were 18 years of age or older and had histologically or cytologically documented locally advanced or metastatic epithelial cancer (adenocarcinoma) of the exocrine pancreas. These patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2, and adequate hematologic, renal, and hepatic function as defined by the following: absolute neutrophil count  1,500/µL; platelet count 100,000/µL; creatinine and bilirubin levels  1.5x central laboratory upper limit of normal; and alkaline phosphatase, AST, and lactate dehydrogenase levels 5x upper limit of normal. In addition, all patients had to have measurable disease, as defined by Response Evaluation Criteria in Solid Tumors (RECIST).14 Patients were to have documented resolution (to National Cancer Institute Common Toxicity Criteria [Version 2.0] grade 1) of all acute toxic effects of any prior radiotherapy or FU given as a radiation sensitizer. Patients were excluded if they had received prior systemic therapy given as adjuvant chemotherapy or as therapy for advanced pancreatic cancer, except FU used strictly as a radiation sensitizer. Patients were excluded if they had prior irradiation to the only site of measurable disease; were pregnant or breast-feeding; had active inflammatory bowel disease, significant bowel obstruction, chronic diarrhea, known brain or leptomeningeal disease (unless such lesions were previously irradiated, not currently being treated with corticosteroids, and showed no clinical symptoms), myocardial infarction within the previous 6 months, uncontrolled high blood pressure, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia, known HIV infection or an AIDS-related illness, currently active second malignancy other than nonmelanoma skin cancers (patients with other malignancies must have been disease free for 5 years or longer), mental incapacitation or psychiatric illness that prevented the patient from giving informed consent, or other severe concurrent disease that, in the judgment of the investigator, made the patient inappropriate for entry onto this study.
Study Design and Treatment
Supportive Care Prophylactic administration of granulocyte colony-stimulating factor was allowed at the investigator's discretion for recurrent neutropenia or therapeutically for serious neutropenic complications.
Efficacy and Safety Evaluations Patients were defined as not assessable for response if there was no postrandomization oncologic assessment (and were considered as having experienced treatment failure in the intent-to-treat [ITT] response assessment). The objective tumor response rate was the proportion of the ITT population with a confirmed complete response (CR) or partial response. Survival was defined as the time from random assignment to the date of death as a result of any cause. Patients lost to follow-up were censored at the date of last contact. TTP was defined as the time from random assignment to the first objective documentation of tumor progression or to the time of death as a result of progressive disease in the absence of previous documentation of objective progressive disease. TTP was censored for patients who did not have objective evidence of tumor progression and were removed from the study treatment, or died more than 30 days after last dose, or died as a result of causes unrelated to pancreatic cancer.
Assessments of serum tumor marker CA 19-9 were conducted at screening ( Safety evaluation parameters included weekly assessments of adverse events, hematology values, and blood chemistry assays (albumin, creatinine, total bilirubin, alkaline phosphatase, AST, and lactate dehydrogenase). Safety was characterized in terms of the frequency and severity of adverse events and laboratory abnormalities. Severity was graded according to the National Cancer Institute Common Toxicity Criteria, version 2.0.
Quality of Life Patients completed the questionnaires at the start of each cycle of therapy and before termination from the study. Other quality-of-life parameters included maintenance of body weight and ECOG performance status, which were assessed at baseline and at the beginning of every cycle. A decline in weight of less than 5% from baseline and no worsening on the ECOG scale were defined as criteria of success for weight and performance status, respectively.
Statistical Methods
Patient Characteristics A total of 360 patients were randomly assigned between February 10, 2000, and December 28, 2001: 180 each in the IRINOGEM and GEM arms. Of these, 173 patients and 169 patients were treated, respectively. The 18 patients who were randomly assigned but not treated discontinued because of withdrawal of consent (10 patients), progression of disease (three patients), protocol violations (four patients), and adverse events (one patient). Patient characteristics are listed in Table 1. The two treatment arms were well balanced with respect to age, sex, performance status, extent of disease, and prior radiotherapy. Approximately 80% of the patients had metastatic disease; 14% had locally advanced disease. Median baseline values of CA 19-9 were 1,798 and 1,766 U/mL, respectively.
Treatment Administration Median duration of therapy for IRINOGEM patients was 12.1 weeks (range, 3.0 to 83.9 weeks) and median duration of therapy for GEM patients was 12.9 weeks (range, 6.6 to 88.0 weeks). The median dose intensities for IRINOGEM patients were 54.9 mg/m2/wk (range, 25.2 to 72.3 mg/m2/wk) and 548.2 mg/m2/wk (range, 252.4 to 715.2 mg/m2/wk) for irinotecan and gemcitabine, respectively. GEM-treated patients received a median dose of 626.8 mg/m2/wk of gemcitabine (range, 123.3 to 929.2 mg/m2/wk). The relative dose intensities were 82.4% (range, 37.9 to 108.5%) for irinotecan and 82.2% (range, 37.9 to 107.3%) for gemcitabine in the IRINOGEM arm, and 76.0% (range, 14.1 to 118.9%) for gemcitabine in the single-agent GEM arm.
Efficacy
The best confirmed tumor response using RECIST criteria was 16.1% (29 of 180) for IRINOGEM patients versus 4.4% (eight of 180) for GEM patients (  2 P < .001; Table 2). Three IRINOGEM-treated patients with locally advanced disease had a confirmed CR; no GEM-treated patient had a CR.
Although no difference in TTP was observed (3.5 months [95% CI, 2.8 to 4.2 months] for IRINOGEM patients and 3.0 months [95% CI, 2.5 to 3.7 months] for GEM patients; log-rank P = .352; Fig 2 and Table 2;), exploratory analysis by extent of disease suggests that TTP may be longer in patients with locally advanced disease treated with IRINOGEM than in those treated with GEM (Fig 3). Median TTPs for patients with locally advanced disease were 7.7 months (95% CI, 5.3 to 12.1 months) and 3.9 months (95% CI, 2.4 to 5.9 months) for IRINOGEM and GEM, respectively. However, median survival in this small subset of patients numerically favored the GEM arm (11.7 months [95% CI, 8.7 to 15.2 months]) compared with the IRINOGEM arm (9.8 months [95% CI, 7.8 to 15.5 months]). The CIs overlapped significantly.
CA 19-9 Status Only 238 patients (66% of randomly assigned patients) were considered assessable for the analysis of tumor marker versus radiologic and clinical assessment. As listed in Table 3, the overall diagnostic accuracy of CA 19-9 values in the prediction of tumor response and tumor progression from the radiologic evaluation was low: 57.6% and 59.0%, respectively. However a less than 50% decline in CA 19-9 values was predictive of a lack of response as determined by RECIST criteria (negative predictive value, 94.8%). Furthermore, progression of tumor marker values was predictive of disease progression (positive predicted value, 82.8%). Figure 4 shows the positive correlation of time to CA 19-9 progression with TTP in the subgroup of patients with both events.
Safety In both treatment groups, similar incidences were seen for the most common adverse events such as nausea (67% and 65%), fatigue (56% and 60%), and vomiting (54% and 53%). Diarrhea was more common with IRINOGEM treatment (62%) than with GEM treatment (31%) and was more severe. Table 4 summarizes the most common grade 3 or 4 nonhematologic adverse events. Neutropenia, leukopenia, and thrombocytopenia were the most common grade 3 or 4 hematologic adverse events in both groups (Table 5). There were 64 (37%) IRINOGEM-treated patients and 54 (32%) GEM-treated patients who withdrew from treatment because of adverse events; approximately half of the patients in both groups had adverse events associated with progression of disease. Only five of the IRINOGEM patients discontinued therapy because of diarrhea.
Quality of Life Compliance in completing the FACT-Hep questionnaires was 80% for IRINOGEM-treated patients and 73% for GEM-treated patients during the first 30 weeks of the study. The addition of irinotecan to gemcitabine did not influence quality of life as measured by the questionnaire. No differences were observed between the two treatment groups in the means of the best and worst scores for any of the functional scales.
In addition, the analysis of time to worsening of performance status and time to weight loss
This multicenter, phase III study evaluated the efficacy and safety of IRINOGEM when compared with GEM monotherapy with respect to survival, tumor response, TTP, and CA 19-9 response in patients with locally advanced or metastatic pancreatic cancer. The primary end point, improvement in survival, was not met and this phase III trial should be regarded as negative. The design of the phase III study was based on preclinical data18 and phase I and II data12,13 assessing the combination of irinotecan and gemcitabine in pancreatic cancer. A small randomized phase II study in pancreatic cancer patients previously treated with gemcitabine suggests that irinotecan and gemcitabine are not cross-resistant.19 In this trial, the combination of irinotecan and raltitrexed resulted in a higher response rate and longer median progression-free survival compared with raltitrexed alone. The trial was closed early because of the superiority of the two-drug combination. The results of our phase III study corroborate the preliminary evidence of activity observed in phase I and II trials. For all patients, the confirmed tumor response rate was almost four-fold higher favoring IRINOGEM compared with GEM alone (16.1% v 4.4%; P < .001), and subset analyses suggest that the incremental tumor response with IRINOGEM compared with GEM may be higher in patients with locally advanced disease (25.9% v 4.2%, respectively). The patients with locally advanced disease also had the longest median TTP (7.7 months). This last observation should be interpreted with caution because it represents only a small group of patients in this randomized trial. Despite the higher response rate for the two-drug combination, no survival advantage was detected. This negative result cannot be explained by second-line therapy, which was similar between the two treatment groups. Moreover, demography, baseline disease characteristics and laboratory values, and other possible contributing factors (such as body-surface area and early withdrawal from the trial) were similar between the two groups and cannot explain the results. The 40% improvement in median survival as the primary end point was ambitious. However, had we designed this trial with a larger sample size it is unlikely that the results would have changed because the survival curves are almost identical. Given that the serum tumor marker CA 19-9 is commonly increased in patients with pancreatic cancer and can change in association with tumor shrinkage or disease progression, CA 19-9 levels were assessed for potential use in determining the antitumor activity of the treatment regimens. In a phase II trial from our group, CA 19-9 had a significant correlation with the radiographically assessed tumor area with regard to extent of change from baseline (r = 0.67), timing of minimum on-study values (r = 0.85), and tumor progression (r = 0.89).13 In this study, there was significant positive correlation between CA 19-9 progression and tumor progression as determined with RECIST criteria. These results suggest that CA 19-9 levels may provide an adjunct, not a substitute, to radiographic tumor evaluation for assessing treatment effect, notably disease progression, in patients with pancreatic cancer. The IRINOGEM combination had no detrimental effects on QOL compared with GEM. Few randomized phase III trials in pancreatic cancer published to date have evaluated QOL and other functional outcomes in this group of patients. Compliance with completion of the questionnaire was good: 80% for the IRINOGEM patients and 73% for the GEM patients. However, there were no significant differences between the two treatment arms for any of the tested domains (social, emotional, physical, new symptoms, and functional). Given that the combination resulted in higher response rates, studying improvement on disease-related symptoms potentially dependent on tumor volume (such as biliary obstruction, pain, bowel obstruction, gastric outlet syndrome, and others) may have been of interest, but the study was not designed to collect this information systematically. Patients receiving the IRINOGEM combination had a higher incidence of any grade of diarrhea (62%) than the GEM-treated patients (31%). This did not affect the start of new treatment cycles or the duration of treatment; only five patients discontinued treatment due to diarrhea. The most common toxicities in more than 50% of patients in both arms of the study were nausea, vomiting, and fatigue. Incidences of hematologic toxicities were similar in both arms. The median relative dose intensities of 82% for both irinotecan and gemcitabine over the entire study were not significantly different from that of gemcitabine monotherapy (76%). The results of this study indicate that the IRINOGEM regimen, given on days 1 and 8 of repeated 3-week cycles, does not improve survival compared with GEM for patients with advanced and metastatic pancreatic cancer, despite higher response rates and manageable safety profile.
The following groups and investigators participated in the IRINOGEM Pancreatic Cancer Study Group. Australia: Steve Ackland, Newcastle Mater Miscericordiae Hospital, Waratah, NSW; Philip Beale, Royal Prince Hospital, Camperdown, NSW; Stephen Della Fiorentina, The Cancer Therapy Centre, Liverpool BC, NSW; Richard de Boer, Paul Mitchell, Austin and Repatriation Medical Centre, Heidelberg, VIC; Howard Gurney, Westmead Hospital, NSW; Chris Karapetis, St. Vincents Hospital, Darlinghurst, NSW; Michael Michael, Peter MacCallum Cancer Institute, East Melbourne, VIC; Ian Olver, Royal Adelaide Hospital Cancer Centre, Adelaide, SA. Canada: Mario Belanger, Hotel-Dieu de Levis, Levis, Quebec; Ronald Burkes, Mount Sinai Hospital, Toronto, Ontario; Felix Couture, Hotel-Dieu de Quebec, Quebec, Quebec; Rakesh Goel, Ottawa Regional Cancer Centre, Ottawa, Ontario; Kara Laing and T. Wasil, Dr H. B. Murphy Cancer Centre, St. John's Newfoundland; Ursula Lee, Fraser Valley Cancer Centre, Surrey, British Columbia; Wycliffe Lofters, Kingston Regional Cancer Centre, Kingston, Ontario; Marc Trudeau, Jewish General Hospital, Montreal, Quebec; Sheila Souliere, Harry Rayner, British Columbia Cancer Agency, Vancouver, BC; Marianne Taylor, Cancer Center for the Southern Interior, Kelowna, BC; Chris Williams, Nanaimo Cancer Clinic, Nanaimo, BC. New Zealand: Michael Findley Wellington Cancer Centre, Newtown, Wellington. United States: Fakhiuddin Ahmed, HemOnCare, Brooklyn, NY; Thomas Anderson, Texas Oncology, PA, Beford, TX; Rafat Ansari, Northen Indiana Cancer Research Consortium, South Bend, IN; Lowell Anthony, Louisiana State University Medical Center, New Orleans, LA; Stephen Anthony, Cancer Care Northwest, Spokane, WA; James Arseneau, Albany Regional Cancer Center, Albany, NY; Barry Berman, Cancer Center of Florida, Orlando, FL; William Berry, Raleigh Hematology/Oncology Clinic, Cary, NC; James Cantrell, Birmingham Hematology & Oncology Associates, Birmingham, AL; Thomas Cartwright, Ocala Oncology Center, Ocala, FL; Panjaj Bharjava, University of Massachusetts Medical Center, Worcester, MA; Cynthia Cathcart, New Mexico Cancer Care Associates, Santa Fe, NM; Ashis Chakrabarti, Hope Center, Terre Haute, IN; Hoo Chun, New York Medical College, Valhalla, NY; Emmanuel Cirenza, Albany Medical Center, Albany, NY; Patrick Cobb, Billings Interhospital Oncology Project, Billings, MT; Ernest Cochran, Paris Regional Cancer Center, Paris, TX; Paul Conkling, Virginia Oncology Associates, Norfolk, VA; Walter Davis, Regional Hematology/Oncology Durham, NC; John Eckardt, St. John's Mercy Medical Center, St. Louis, MO; Peter Eisenberg, Marin Oncology Associates/California Research Cancer Network, Greenbrae, CA; Louis Fehrenbacher, Kaiser Permanente Medical Center, Vallejo, CA; Lawrence Garbo, New York Oncology/Hematology Capital District Associates Albany, NY; Rudolf Good, Texoma Regional Cancer Center, TX; Charles Graham, Trident Palmetto Hematology-Oncology, Charleston, SC; Marc Greenblatt, Vermont Cancer Center, Burlington, VT; Edward Greeno, University of Minnesota Research Services Organization, Minneapolis, MN; Stephen Grund, Albany Medical Center, Albany, NY; John Hainsworth, The Sarah Cannon Cancer Center, Nashville, TN; John Hanson, St. Luke's Medical Center, Milwaukee, WI; Charles Henderson, Peachtree Hematology, Atlanta, GA; Judith Hopkins, Triad Hematology & Oncology Association, Winston-Salem, NC; Clyde M. Jones, ICSL Clinical Studies, Germantown, TN; Leonard Kalman, Oncology-Hematology Group of South Florida, PA, Miami, FL: Robert Kerr, Southwestern Regional Cancer Center, Austin, TX; Phyllis Klein, National Institute of Clinical Research, Los Angeles, CA; John Leighton, Albert Einstein Cancer Center, Philadelphia, PA; Barry Lembersky, Oncology and Hematology Associates, Pittsburg, PA; Eric Lester, Oncology Care Associates, St. Joseph, MI; Deborah Lindquist, Northern Arizona Hematology & Oncology Associates, Sedona, AZ; Gershon Locker Evanston Northwestern Healthcare, Evanston, IL; David Loesch, Oncology & Hematology Associates, Indianapolis, IN; Samuel McCachren, Thompson, Cancer Survival Center, Knoxville, TN; Scott McKenny, Mamie McFadden Ward, Beaumont, TX; Kenneth Micetich, LUMC/Cardinal Bernadin Cancer Center, Maywood, IL; John Michalak, Siouxland Hem/Onc Associates, Sioux City, IA; William Miller, Scripps Clinic, La Jolla, CA; Manuel Modiano, Arizona Oncology Associates, Tucson, AZ; Melvin Moore, Georgia Cancer Specialist; Decatur, GA; Yutaka Niihara, Harbor-University of California, Los Angeles Research and Education Institute, Torrance, CA; Jose Noy, Mercy Hospital/Cancer Research, Miami FL; Jairo Olivares, Texas Oncology, PA, Garland, TX; Gregory Parker, Cancer Care Associates-Baptist Campus, Oklahoma City, OK; R. Paulson, Texas Oncology, PA, Dallas, TX; Joel Picus, Washington University School of Medicine, St. Louis, MO; Charles Redfern, Sharp Healthcare, San Diego, CA; Donald Richards, US Oncology, Dallas, TX; Gerald Robbins, Florida Community Cancer Center, New Port Richey, FL; Michael Roberts, Arizona Hematology and Oncology Associates, Phoenix, AZ; Robert Ruxer, Jr., US Oncology, Fort Worth, TX; Bruce Saidman, Medical Oncology Associates, Kingston, PA; Diane Savarese, University of Massachusetts Medical Center, Worcester, MA; Michael Savin, Texas Cancer Center of Medical City, Dallas, TX; Andrew Schneider, South Florida Oncology and Hematology Consultants, Lauderhill, FL; Arthur Staddon, Pennsylvania Oncology Hematology Associates, Philadelphia, PA; Philip Stella, St. Joseph Mercy Hospital, Ann Arbor, MI; Michael Tanaka, UC Davis Cancer Center, Sacramento, CA; Michael Theodorakis, North Shore Hematology Oncology Associates, East Setauket, NY; Piyapong Vongkovit, Northwestern Carolina Oncology and Hematology, PA, Hickory, NC; David Watkins, Allison Cancer Center, Midland, TX; and Furhan Yunus, The Boston Cancer Group, PLC, Memphis, TN.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Employment: Laura A Cisar, Pfizer; Adele Morganti, Pfizer; Nicoletta Orlando, Pfizer; Gabriela Gruia, Pfizer; Langdon L. Miller, Pfizer. Consultant/Advisory Role: Caio M. Rocha Lima, Pfizer, Eli Lilly; Mark R. Green, Pfizer, Eli Lilly. Stock Ownership: Mark R. Green, Pfizer; Laura A. Cisar, Pfizer; Nicoletta Orlando, Pfizer; Gabriela Gruia, Pfizer; Langdon L. Miller, Pfizer. Honoraria: Caio M. Rocha Lima, Pfizer, Eli Lilly; Mark R. Green, Pfizer, Eli Lilly. Research Funding: Caio M. Rocha Lima, Eli Lilly. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration form and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue.
We thank Dimitri Petratchenko for the programming support on this trial.
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.
1. Greenlee RT, Hill-Harmon MB, Thun TM: Cancer statistics 2001. CA Cancer J Clin 51:15–36, 2001 2. Brennan MF, Kinsella TJ, Casper ES: Cancer of the pancreas, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology (ed 4). Philadelphia, PA, Lippincott, 1993, pp849–882 3. Schnall SF, Macdonald JS: Chemotherapy of adenocarcinoma of the pancreas. Semin Oncol 23:220–228, 1996[Medline] 4. Stephens CD: Gemcitabine: A new approach to treating pancreatic cancer. Oncol Nurs Forum 25:87–93, 1998[Medline] 5. Evans DB, Abbruzzese JL, Tyvin AR: Cancer of the pancreas, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology (ed 4). Philadelphia, PA, Lippincott, 1997, pp1054–1087 6. Casper ES: Pancreatic Cancer: How can we do better? Eur J Cancer 29A:171–172, 1993 7. Cullinan S, Moertel CG, Wieand HS, et al: A phase III trial on the therapy of advanced pancreatic carcinoma: Evaluations of the Malinson regimen and combined 5-fluorouracil, doxorubicin, and cisplatin. Cancer 65:2207–2212, 1990[CrossRef][Medline]
8. Burris HA, Moore MJ, Andersen J, et al: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol 15:2403–2413, 1997 9. Storniolo AM, Enas NH, Brown CA, et al: An investigational new drug treatment program for patients with gemcitabine. Cancer 85:1261–1268, 1999[CrossRef][Medline] 10. Sakata Y, Shimada Y, Yoshino M, et al: A late phase II study of CPT-11, irinotecan hydrochloride, in patients with advanced pancreatic cancer: CPT-11 study group on gastrointestinal cancer. Jpn J Cancer Chemother 21:1039–1046, 1994
11. Wagener DJ, Verdonk HE, Dirix LY, et al: Phase II trial of CPT-11 in patients with advanced pancreatic cancer, an EORTC early clinical trials group study. Ann Oncol 6:129–132, 1995 12. Rocha Lima CM, Leong SS, Sherman CA, et al: Phase I study of CPT-11 and gemcitabine in patients with solid tumors. Cancer Ther 2:58–66, 1999
13. Rocha Lima CM, Savarese D, Bruckner H, et al: Irinotecan plus gemcitabine induces both radiographic and CA 19-9 tumor marker responses in patients with previously untreated advanced pancreatic cancer. J Clin Oncol 20:1182–1191, 2002
14. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205–216, 2000
15. Cella DF, Tulsky DS, Gray G, et al: The functional assessment of cancer therapy scale: Development and validation of the general measure. J Clin Oncol 11:570–579, 1993 16. Overcash J, Extermann M, Parr J, et al: Validity and reliability of the FACT-G scale use in the older person with cancer. Am J Clin Oncol 24:591–596, 2001[CrossRef][Medline]
17. Heffernan N, Cella D, Webster K, et al: Measuring health-related quality of life in patients with hepatobiliary cancers: The functional assessment of cancer therapy-hepatobiliary questionnaire. J Clin Oncol 20:2229–2239, 2002 18. Bahadori HR, Rocha Lima CM, Green MR, et al: Synergistic effect of gemcitabine and irinotecan (CPT-11) on breast and small cell lung cancer cell lines. Anticancer Res 19:5423–5428, 1999[Medline] 19. Ulrich-Pur H, Raderer M, Verena Kornek G, et al: Irinotecan plus raltitrexed vs raltitrexed alone in patients with gemcitabine-pretreated advanced pancreatic adenocarcinoma. Br J Cancer 88:1180–1184, 2003[CrossRef][Medline] Submitted December 11, 2003; accepted June 18, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
