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Journal of Clinical Oncology, Vol 23, No 36 (December 20), 2005: pp. 9250-9256 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.02.1980
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 GroupFrom the University of Ulm, Ulm; Westdeutsches Tumorzentrum, Essen; University of Dresden, Dresden; University Hospital Charite, Berlin; Horst-Schmidt-Kliniken, Wiesbaden, Germany; University Hospital Gasthuisberg, Leuven; Hôpital Universitaire Erasme, Brussels; European Organisation for Research and Treatment of Cancer Data Center, Brussels, Belgium; University Medical Center, Nijmegen; Laurentius Ziekenhuis, Roermond, the Netherlands; Centre Hospitalier Universitaire Angers; Centre P. Papin, Angers; Centre Hospitalier Universitaire Ambroise Pare, Boulogne; Hôpital Pasteur, Colmar; Clinique Armoricaine de Radiotherapie, Saint Brieuc; Institut Gustave Roussy, Villejuif, France; and National Cancer Institute, Cairo, Egypt. Address reprint requests to Manfred P. Lutz, MD, Caritasklinik St Theresia, Rheinstr 2, 66113 Saarbruecken, Germany; e-mail: m.lutz{at}caritasklinik.de
PURPOSE: To define the efficacy and toxicity of docetaxel plus gemcitabine or docetaxel plus cisplatin for advanced pancreatic carcinoma. PATIENTS AND METHODS: Chemotherapy-naive patients with measurable disease and WHO performance status less than 2 were randomly assigned to receive 21-day cycles of gemcitabine 800 mg/m2 on days 1 and 8 plus docetaxel 85 mg/m2 on day 8 (arm A) or docetaxel 75 mg/m2 on day 1 plus cisplatin 75 mg/m2 on day 1 (arm B). Primary end points were tumor response and rate of febrile neutropenia grade. RESULTS: Of 96 randomly assigned patients (49 patients in arm A and 47 patients in arm B), 70 patients were analyzed for response (36 in arm A and 34 in arm B) and 89 patients were analyzed for safety (45 in arm A and 44 in arm B). Confirmed responses were observed in 19.4% (95% CI, 8.2% to 36.0%) of patients in arm A and 23.5% (95% CI, 10.7% to 41.2%) in arm B. In arm A, the median progression-free survival (PFS) was 3.9 months (95% CI, 3.0 to 4.7 months), median survival was 7.4 months (95% CI, 5.6 to 11.0 months), and 1-year survival was 30%. In arm B, the median PFS was 2.8 months (95% CI, 2.6 to 4.6 months), median survival was 7.1 months (95% CI, 4.8 to 8.7 months), and 1-year survival was 16%. Febrile neutropenia occurred in 9% and 16% of patients in arms A and B, respectively. CONCLUSION: Both regimens are well tolerated and show activity in advanced pancreatic carcinoma. The safety profile and survival analyses favor docetaxel plus gemcitabine for further evaluation.
Adenocarcinoma of the pancreas remains a major cause of tumor-related deaths worldwide.1 Although complete surgical resection offers a small chance for cure,2 most patients present with advanced disease, and despite improvements in surgical techniques, nearly all will develop local recurrence and/or metastases.1 These patients have a poor prognosis, and the median survival time with standard chemotherapy is less than 6 months.3,4 Gemcitabine, a fluorinated deoxycytidine analog,5 became the standard of care for advanced pancreatic cancer after a recent phase III trial with 126 patients demonstrated a modest increase in survival (5.7 v 4.4 months) with gemcitabine versus fluorouracil (FU) that was accompanied by an improvement in the disease-related symptoms of pain, weight, and performance status (24% v 4% of patients).3 However, subsequent observational studies6 or phase III trials have rarely shown objective response rates exceeding 5.4% or 1-year survival rates more than 20%, indicating a need for further improvement in pancreatic cancer treatment.4,7-9 Docetaxel, a semisynthetic taxane with a broad spectrum of antitumor activity,10 has shown activity as a single agent in phase II trials. One trial of 40 patients with pancreatic cancer reported a response rate of 15% and stable disease rate of 38%.11 In another study, 33 patients who received docetaxel plus supportive granulocyte colony-stimulating factor achieved a median survival of 36 weeks and a 1-year survival rate of 36.4%.12 Docetaxel has previously been investigated in combination with gemcitabine in other tumor types. Both drugs exhibit collateral sensitivity in vitro in drug-resistant small-cell lung cancer cell lines,13 and a phase I study in non–small-cell lung cancer defined a 3-weekly regimen of gemcitabine 800 mg/m2 on days 1 and 8 plus docetaxel 85 mg/m2 on day 8 as the recommended regimen for further testing. Neutropenia was the dose-limiting toxicity.14 There is increasing interest in the combination of docetaxel plus cisplatin because both drugs are synergistic in vitro in ovarian cancer cell lines15 and because cross-resistance between these two agents in small-cell lung cancer cell lines is negligible.13 The toxicity profile of docetaxel plus cisplatin is generally described as manageable, with neutropenia being the main toxicity. A phase I/II trial in advanced non–small-cell lung cancer recommended a regimen of 75 mg/m2 doses of both drugs given 3-weekly, based on the low incidence (one of 13 patients) of grade 4 neutropenia and diarrhea seen with this dose level.16 The European Organisation for Research and Treatment of Cancer (EORTC) Gastrointestinal Group selected docetaxel plus gemcitabine and docetaxel plus cisplatin for further investigation in a randomized phase II trial based on the evidence supporting single-agent activity of these drugs in pancreatic cancer, the additive cytotoxicity and lack of cross-resistance of these combinations, and the moderate overlap of the toxicity profiles. The aim of the study was to select the optimal regimen for future comparison against a standard treatment in the phase III setting.
This trial was an open, randomized, multicenter, two-stage, phase II study. Patients were centrally randomly assigned at the EORTC Data Center, Brussels, Belgium, and stratified using the minimization technique according to institution, performance status (0 v 1), and extent of disease (metastatic v locoregionally advanced). The primary end points were response rate and severe acute toxicity rate (defined as hematotoxicity grade 3 to 4 with fever > 38.5°C). Secondary end points were duration of response, progression-free survival, and overall survival.
Patient Population Written informed consent was obtained according to national and local regulations. The protocol was approved by the review boards of the participating institutions and by the protocol review committee of the EORTC.
Treatment Plan In both arms, premedication included adequate antiemetic therapy and dexamethasone 16 mg IV before each docetaxel infusion, followed by 8 mg orally bid for 2 days to limit the frequency of adverse events. Prophylactic granulocyte colony-stimulating factor treatment was encouraged in case of severe hematotoxicity. Radiotherapy to bone metastases was allowed providing indicator lesions were outside the irradiation field.
Treatment was delayed for up to 2 weeks in the event of WBC count less than 3,000/µL, platelets less than 100,000/µL, creatinine greater than the ULN, or nonhematologic toxicity
Dose adjustments at the start of a new cycle were based on the worst toxicity observed during the previous cycle. Both drugs were dose-reduced to 80% of the previous dose level if granulocytes were less than 500/µL or 1,000/µL with fever greater than 38.5°C; if platelets were less than 25,000/µL; or if nonhematologic toxicity
Pretreatment Evaluation and Follow-Up During the study treatment, a physical examination and adverse events assessment were performed before each cycle; adverse events (clinical and laboratory) were monitored weekly. Tumor response was evaluated before every second cycle. After stopping study treatment, patients who had not progressed were evaluated every 6 weeks until documented disease progression. Thereafter, patients were followed every 8 weeks.
Response and Toxicity Evaluation Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria version 2.0.
Statistical Design
The trial was conducted using the Bryant and Day two-stage design.17 For the sample size calculation, a response rate of 25% and a severe acute toxicity rate of
Patient Accrual and Study Populations Between October 1999 and March 2001, 96 patients were enrolled at 17 institutions from five countries. The median number of patients included per institution was five (range, one to 15), with six centers entering fewer than four patients. Stage 1 of the study included 16 patients per arm and met the criteria for continuation to stage 2. Of the 96 patients enrolled in total, 49 patients were included in arm A and 47 patients were included in arm B. Seven patients were considered to have not started treatment (four patients in arm A, two of whom had no information available, and three patients in arm B). Therefore, 45 and 44 patients started treatment in arms A and B, respectively, and were assessable for toxicity. Thirty-six and 34 patients in arms A and B, respectively, were assessable for response. Reasons for nonassessability were involvement of the primary site only (three patients in arm A and four patients in arm B), measurable lesions not meeting the minimum size requirement (four patients in arm A and three patients in arm B), nonmeasurable lesions in the kidney and liver (two patients in arm A and one patient in arm B), and unidimensional measurements only (two patients in arm B).
Baseline Characteristics
Treatment Duration and Dose-Intensity Of the 89 patients who started treatment, 14 patients (16%) received only one cycle, and 22 patients (25%) completed two treatment cycles. Median treatment duration was four cycles (range, one to 12 cycles) in both arms. Nine patients (20%) in arm A and three patients (7%) in arm B received six treatment cycles; eight patients (18%) in arm A and nine patients (21%) in arm B received more than six cycles. The main reasons for treatment discontinuation in arms A and B were disease progression or disease-related death (64% and 56%, respectively), toxicity (13% and 26%, respectively), and completion of six treatment cycles (11% and 2%, respectively). Follow-up treatment was documented in 26 patients in arm A and in 20 patients in arm B. For patients treated with docetaxel plus cisplatin (arm B), the median relative dose-intensity was 96% of the theoretical dose for both drugs. The median dose-intensity was slightly lower in the docetaxel plus gemcitabine arm (arm A), with 84% of the theoretical dose for gemcitabine and 83% for docetaxel.
Response and Survival
The median progression-free survival in the eligible and treated patients was 3.9 months (95% CI, 2.5 to 4.5 months) with docetaxel plus gemcitabine (arm A) and 2.8 months (95% CI, 2.6 to 5.5 months) with docetaxel plus cisplatin (arm B); 1-year progression-free survival rates were 2.8% (95% CI, 0.0% to 8.2%) and 6.2% (95% CI, 0.0% to 14.4%), respectively. Their median overall survival was 7.0 months (95% CI, 5.5 to 9.3 months) in arm A and 7.5 months (95% CI, 4.9 to 10.0 months) in arm B. In the same population, 1-year overall survival rates were 27.8% (95% CI, 13.2% to 42.4%) and 15.8% (95% CI, 3.1% to 28.5%), respectively. The median survival in eligible and treated patients with metastatic disease was 7.2 months (95% CI, 5.6 to 11.2 months) in arm A and 7.1 months (95% CI, 4.6 to 10.0 months) in arm B. Survival analyses were repeated on all patients entered onto the trial regardless of whether the patients had measurable lesions (intent-to-treat population). The median progression-free survival in all patients was 3.9 months (95% CI, 3.0 to 4.7 months) in arm A and 2.8 months (95% CI, 2.6 to 4.6 months) in arm B; overall 1-year progression-free survival rates were 6.4% (95% CI, 0.0% to 13.4%) and 4.4% (95% CI, 0.0% to 10.3%), respectively. The median overall survival in all patients was 7.4 months (95% CI, 5.6 to 11.0 months) with docetaxel plus gemcitabine (arm A) and 7.1 months (95% CI, 4.8 to 8.7 months) with docetaxel plus cisplatin (arm B); 1-year overall survival rates were 29.8% (95% CI, 16.7% to 42.9%) and 16.1% (95% CI, 5.2% to 27.0%), respectively (Fig 1A). The median survival in all patients with metastatic disease was 7.8 months (95% CI, 5.7 to 11.5 months) in arm A and 7.1 months (95% CI, 4.6 to 8.7 months) in arm B.
Toxicity Adverse events are summarized in Table 3 for the treated population. Neutropenia was the most relevant hematologic toxicity in both arms. Grade 3 to 4 neutropenia was reported in 47% and 55% of patients in arms A and B, respectively, and was complicated by febrile neutropenia grade  3 in 9% and 16% of patients, respectively. Severe acute toxicity (primary end point) was thus observed in four (9%) of 45 patients in arm A and seven (16%) of 44 patients in arm B. Both treatment arms thus pass the statistical rule of less than 15 severe acute toxicities in 41 patients to warrant further investigation.
Alopecia of any grade was the most common nonhematologic toxicity reported (64% in arm A and 57% in arm B). The major ( 10%) grade 3 to 4 nonhematologic toxicities were skin toxicity (11%; all grade 3) and abnormal alkaline phosphatase levels (11%) in arm A and nausea (16%) and vomiting (14%) in arm B. One toxic death occurred in arm A as a result of pneumonia in the absence of neutropenia. A second toxic death was initially reported in arm A but was later clarified to be a treatment-unrelated pulmonary embolism. Dose delays for more than 4 days as a result of toxicity were reported for 19 patients (42%) in arm A and five patients (11%) in arm B. The main reasons for the first dose delay in arm A were leukopenia (13 patients; 29%) and/or infections of the biliary tract, lung, or soft tissue (five patients; 11%), and asthenia/anorexia (four patients; 9%). The main reason for dose delay in arm B was neutropenia (three patients; 7%) with fever in two episodes, and pancreatitis in one patient. Dose reductions (> 10%) as a result of toxicity were reported for 12 patients (27%) in arm A and 11 patients (25%) in arm B, mostly as a result of neutropenia (eight patients [18%] in arm A and nine patients [20%] in arm B).
Chemotherapy with gemcitabine has become the standard treatment in advanced pancreatic cancer after it was shown to be more effective than FU in a randomized phase III trial.3 Nevertheless, the response rate with this agent was only 5.4%, and the survival advantage over FU was small (5.7 v 4.4 months).3 There is evidence from phase II trials that dose-intense infusion of gemcitabine increases its activity,18 and the preliminary results of a phase III trial indicate that gemcitabine in combination with the tyrosine kinase inhibitor erlotinib increases overall survival.19 Several other phase III trials have failed to identify any agent or combination chemotherapy that significantly improves survival over gemcitabine alone.4,7-9,20-23 To define an appropriate combination regimen for further development, we selected docetaxel, gemcitabine, and cisplatin on the basis of their proven clinical activity in pancreatic carcinoma, their apparent synergistic activity in preclinical models, and because they are not cross-resistant. Given the disappointing results of published large randomized phase III trials, a randomized phase II design was considered appropriate to identify the most promising of the chosen regimens for future investigation. The results of this multicenter trial demonstrate clinical activity with both combination treatments tested (docetaxel plus gemcitabine and docetaxel plus cisplatin). For both regimens, the response rate was approximately 20%, the disease control rate (ie, CR + PR + SD) was approximately 55%, and the median survival time was greater than 7 months. As far as we are aware, this is the first full published study to show that docetaxel plus cisplatin is active in pancreatic cancer and may warrant further investigation. We noted, however, that the proportion of patients surviving at 1 year was greater in arm A (28%) than in arm B (16%). Thus both regimens clearly met the predefined criteria for activity and toxicity to warrant further investigation, with a slight trend in favor of the docetaxel plus gemcitabine combination (arm A). Although encouraging, the results do not clearly exceed the ones observed in some trials of gemcitabine alone. However, they are supported by preclinical evidence for synergism of docetaxel and gemcitabine24 and by other phase II trials using different schedules of the two drugs: response rates ranged from 7% to 30% and median survival times ranged from 4.7 to 10.5 months,24-29 with a 1-year survival of 29% in the largest study including 55 patients.26 Whereas a biweekly schedule of docetaxel and gemcitabine was considered not worthy of further investigation based on the modest activity and significant toxicity,24 others reported response rates of 20% to 30% and median survival times greater than 8.1 months with weekly schedules.25,26 As expected, hematologic adverse events constituted the major toxicities.25 Although the optimum schedule remains to be defined, the results from our study and others suggest that docetaxel plus gemcitabine is worthy of further investigation in comparative trials. The main concern before starting this trial was the anticipated risk of severe myelosuppression. In fact, because neutropenia together with obstructive jaundice may potentially be deleterious, acute febrile hematotoxicity was incorporated as an additional primary end point. As expected, neutropenia grade 3 to 4 was the predominant side effect, experienced in arm A by 47% of patients and in arm B by 55% of patients. In contrast, the incidence of febrile leucopenia was lower than expected, with four episodes (9%) in arm A and seven episodes (16%) in arm B. Of note, the toxic death was not caused by biliary infection but rather pneumonia. This toxicity profile is tolerable and compares favorably with the experience of others using alternative schedules.24,29 We consider docetaxel plus gemcitabine more favorable because patients experienced somewhat less neutropenia or febrile neutropenia, and because hyperhydration is not needed to prevent nephrotoxicity. As noted before, this study aimed to select a regimen for future comparison in a phase III trial. Although there was no clear-cut difference between both investigational arms, the efficacy results and toxicity profiles seem to favor the combination of gemcitabine plus docetaxel. To determine the true efficacy of this combination regimen, comparison in a randomized phase III trial against a standard treatment (eg, gemcitabine, gemcitabine as fixed-dose–rate infusion18 or gemcitabine plus erlotinib,19 gemcitabine plus oxaliplatin,21 or other new combinations) is warranted. The combination of docetaxel plus cisplatin might be worthwhile for evaluation after pretreatment with gemcitabine.
Althoguh all authors completed the disclosure declaration, 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. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) <$10,000 (B) $10,000-99,999 (C)
We thank Benoit Baron for statistical advice and Philippe Rougier for advice during the design of the trial and for patient inclusion. In particular, we thank Liliana Baila and Paul O'Grady for proofreading and editing the manuscript.
Supported by an unrestricted educational grant to the European Organisation for Research and Treatment of Cancer Gastrointestinal Group by Aventis and by Grants No. 5U10 CA11488-29 through 5U10 CA11488-34 from the National Cancer Institute, Bethesda, MD. Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, May 18-21, 2002, Orlando, FL. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Li D, Xie K, Wolff R, et al: Pancreatic cancer. Lancet 363:1049-1057, 2004[CrossRef][Medline] 2. Neoptolemos JP, Stocken DD, Friess H, et al: A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 350:1200-1210, 2004 3. 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 4. Van Cutsem E, VandeVelde H, Karasek P, et al: Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 22:1430-1438, 2004 5. Huang P, Chubb S, Hertel LW, et al: Action of 2',2'-difluorodeoxycytidine on DNA synthesis. Cancer Res 51:6110-6117, 1991 6. Storniolo AM, Enas NH, Brown CA, et al: An investigational new drug treatment program for patients with gemcitabine: Results for over 3000 patients with pancreatic carcinoma. Cancer 85:1261-1268, 1999[CrossRef][Medline] 7. Bramhall SR, Schulz J, Nemunaitis J, et al: A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br J Cancer 87:161-167, 2002[CrossRef][Medline] 8. Moore MJ, Hamm J, Dancey J, et al: Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced or metastatic adenocarcinoma of the pancreas: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 21:3296-3302, 2003 9. Rocha Lima CM, Green MR, Rotche R, et al: 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. J Clin Oncol 22:3776-3783, 2004 10. Dumontet C, Sikic BI: Mechanisms of action of and resistance to antitubulin agents: Microtubule dynamics, drug transport, and cell death. J Clin Oncol 17:1061-1070, 1999 11. Rougier P, Adenis A, Ducreux M, et al: A phase II study: Docetaxel as first-line chemotherapy for advanced pancreatic adenocarcinoma. Eur J Cancer 36:1016-1025, 2000[CrossRef][Medline] 12. Androulakis N, Kourousis C, Dimopoulos MA, et al: Treatment of pancreatic cancer with docetaxel and granulocyte colony-stimulating factor: A multicenter phase II study. J Clin Oncol 17:1779-1785, 1999 13. Jensen PB, Holm B, Sorensen M, et al: In vitro cross-resistance and collateral sensitivity in seven resistant small-cell lung cancer cell lines: Preclinical identification of suitable drug partners to taxotere, taxol, topotecan and gemcitabine. Br J Cancer 75:869-877, 1997[Medline] 14. Schloesser NJJ, Richel DJ, Van Zandwijk N, et al: Phase I study of docetaxel and gemcitabine combination chemotherapy in chemotherapy naive patients with advanced or metastatic non small cell lung cancer. Proc Am Soc Clin Oncol 17:499a, 1998 (abstr 1924) 15. Engblom P, Rantanen V, Kulmala J, et al: Additive and supra-additive cytotoxicity of cisplatin-taxane combinations in ovarian carcinoma cell lines. Br J Cancer 79:286-292, 1999[CrossRef][Medline] 16. Millward MJ, Zalcberg J, Bishop JF, et al: Phase I trial of docetaxel and cisplatin in previously untreated patients with advanced non-small-cell lung cancer. J Clin Oncol 15:750-758, 1997 17. Bryant J, Day R: Incorporating toxicity considerations into the design of two-stage phase II clinical trials. Biometrics 51:1372-1383, 1995[CrossRef][Medline] 18. Tempero M, Plunkett W, Ruiz Van Haperen V, et al: Randomized phase II comparison of dose-intense gemcitabine: Thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma. J Clin Oncol 18:3402-3408, 2003 19. Moore MJ, Goldstein D, Hamm, J et al: Erlotinib plus gemcitabine compared to gemcitabine alone in patients with advanced pancreatic cancer. J Clin Oncol 23:1s, 2005 (suppl; abstr 1)[CrossRef][Medline] 20. Heinemann V, Quietzsch F, Gieseler F et al: A phase III trial comparing gemcitabine plus cisplatin vs. gemcitabine alone in advanced pancreatic carcinoma. Proc Am Soc Clin Oncol 22:250, 2003 (abstr 1003) 21. Louvet C, Labianca R, Hammel P, 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 23:3509-3516, 2005 22. Richards DA, Kindler HM, Oettle H, et al: A randomized phase III study comparing gemcitabine + pemetrexed versus gemcitabine in patients with locally advanced and metastatic pancreas cancer. J Clin Oncol 22:315s, 2004 (abstr 4007) 23. O'Reilly EM, Abou-Alfa GK, Letourneau R, et al: A randomized phase III trial of DX-8951f (exatecan mesylate; DX) and gemcitabine (GEM) vs. gemcitabine alone in advanced pancreatic cancer (APC). J Clin Oncol 22:315s, 2004 (abstr 4006) 24. Shepard RC, Levy DE, Berlin JD, et al: Phase II study of gemcitabine in combination with docetaxel in patients with advanced pancreatic carcinoma (E1298): A trial of the Eastern Cooperative Oncology Group. Oncology 66:303-309, 2004[CrossRef][Medline] 25. Jacobs AD, Otero H, Picozzi VJ Jr, et al: Gemcitabine combined with docetaxel for the treatment of unresectable pancreatic carcinoma. Cancer Invest 22:505-514, 2004[CrossRef][Medline] 26. Fahlke J, Ridwelski K, Schmidt C, et al: Combination chemotherapy with docetaxel and gemcitabine in patients with metastatic or locally advanced pancreatic carcinoma: Results of a multicenter phase ll study. J Clin Oncol 22:338s, 2004 (abstr 4101) 27. Stathopoulos GP, Mavroudis D, Tsavaris N, et al: Treatment of pancreatic cancer with a combination of docetaxel, gemcitabine and granulocyte colony-stimulating factor: A phase II study of the Greek Cooperative Group for Pancreatic Cancer. Ann Oncol 12:101-103, 2001 28. Schneider BP, Ganjoo KN, Seitz DE, et al: Phase II study of gemcitabine plus docetaxel in advanced pancreatic cancer: A Hoosier Oncology Group study. Oncology 65:218-223, 2003[CrossRef][Medline] 29. Ryan DP, Kulke MH, Fuchs CS, et al: A phase II study of gemcitabine and docetaxel in patients with metastatic pancreatic carcinoma. Cancer 94:97-103, 2002[CrossRef][Medline] Submitted March 31, 2005; accepted September 29, 2005.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
25% was considered sufficient to warrant further investigation, whereas a response rate of 5% and severe acute toxicity rate of 45% was considered unacceptable. The size of the type I and II errors, 
and ß, was taken to be .10. Stage 1 of the study required 16 patients to be enrolled in each arm; if no response or 
