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Journal of Clinical Oncology, Vol 25, No 29 (October 10), 2007: pp. 4587-4592 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.0592 Phase I Study of Oxaliplatin, Full-Dose Gemcitabine, and Concurrent Radiation Therapy in Pancreatic Cancer
From the Division of Hematology/Oncology, Department of Radiation Oncology, Department of Radiology, Department of Pathology, and Department of Surgery, University of Michigan, Ann Arbor, MI Address reprint requests to Mark M. Zalupski, MD, University of Michigan, 3-219 Cancer and Geriatrics Center, 1500 E Medical Center Dr, Ann Arbor, MI 48109-0934; e-mail: Zalupski{at}umich.edu
Purpose To determine a biweekly dose of oxaliplatin for combination with full-dose gemcitabine and concurrent radiation therapy (RT) in pancreatic cancer.
Patients and Methods Patients with previously untreated pancreatic cancer received gemcitabine days 1, 8, and 15, and oxaliplatin days 1 and 15, repeated at 28-day intervals. RT (27 Gy in 1.8-Gy fractions) was administered during cycle 1. Dose escalation was guided using the time-to-event continuous reassessment method. Dose levels 1 to 4 included gemcitabine 1 g/m2 intravenously (IV) during 30 minutes and oxaliplatin 40, 55, 70, or 85 mg/m2 IV during 90 minutes, respectively; for dose levels 5 and 6, oxaliplatin dose remained 85 mg/m2 but infusion time for gemcitabine 1 g/m2 was increased to 65 or 100 minutes, respectively. The trial objective was to determine the dose level associated with dose-limiting toxicity (DLT) through cycle 2 in Results Forty-four patients were enrolled (median age, 64 years; 27 men, 17 women) with resectable (n = 12), unresectable (n = 29), and metastatic (n = 3) pancreatic cancer. Ten DLTs occurred in nine patients, including grade 4 platelets (n = 4), decline in performance status (n = 2), GI bleeding (n = 2), and GI toxicity (n = 2). The estimated probability of DLT for dose level 3 was .21 (90% posterior probability interval [PI], .12 to .33); for dose level 4, the estimated probability was .24 (90% PI, .14 to .36). Conclusion The addition of oxaliplatin 85 mg/m2 days 1 and 15 to full-dose gemcitabine and radiation therapy was well tolerated. On the basis of these results, a multi-institutional neoadjuvant phase II study in resectable pancreatic cancer is planned.
Effective therapy for pancreatic cancer is limited by a combination of disease dissemination at diagnosis and resistance to systemic therapies. Gemcitabine (Gemzar; Eli Lilly, Indianapolis, IN) has demonstrated clinical benefit in patients with advanced pancreatic cancer and has largely supplanted fluorouracil as systemic therapy.1 Gemcitabine is also a potent radiation sensitizer in vitro and in vivo.2 To maximize local and systemic treatment effects, we have developed a combined-modality treatment (CMT) program that uses full doses of gemcitabine, 1,000 mg/m2 weekly for 3 weeks, concurrent with 15 fractions of radiation therapy (RT).3 Modification of radiation dose, fraction size, and volume was required to accommodate full-dose gemcitabine, as described previously.3,4 Emerging data suggest that, compared with single-agent gemcitabine, gemcitabine combinations improve efficacy in pancreatic cancer.5-8 To further develop gemcitabine-based RT, we were interested in evaluating three approaches. First, we wished to explore the addition of oxaliplatin (Eloxatin; Sanofi-aventis, Bridgewater, NJ). Oxaliplatin has activity in pancreas cancer and appears to be synergistic with RT in vivo.9,10 The incorporation of oxaliplatin into our full-dose gemcitabine-RT CMT might be expected to enhance local and systemic treatment effects. The second approach was to consider fixed dose rate infusion of gemcitabine. Preclinical studies in mice bearing pancreas xenografts have shown improved radiation sensitization with fixed dose rate infusion (unpublished data). The third approach is the use of neoadjuvant therapy in resectable patients. We previously reported a multi-institutional experience using full-dose gemcitabine and RT as neoadjuvant therapy in 20 patients with resectable pancreatic cancer.11 Despite positive surgical outcomes, a majority of patients developed metastasis, emphasizing the need for more effective systemic treatment. On the basis of these considerations, we performed a phase I study incorporating escalating doses of oxaliplatin into our gemcitabine-RT CMT program in patients with pancreatic cancer. The goal of this study was to define a dose of oxaliplatin to be added to gemcitabine and RT for subsequent investigation as a neoadjuvant approach in resectable disease. At the higher dose levels, we attempted to incorporate fixed dose rate gemcitabine infusion. This report emphasizes the initial 9 weeks of treatment, dose-limiting toxicity (DLT) observed, and the experience of surgically resected patients.
Eligibility Patients with pathologic confirmation of pancreatic carcinoma with resectable, unresectable, or low-volume metastatic disease were eligible for this study. Resectability was determined based on a multidetector computed tomography (CT) scan using a biphasic technique and surgical consultation per National Comprehensive Cancer Network guidelines.12 Pretreatment evaluation included a complete history and physical examination, and baseline assessment of organ function. Eligibility criteria included life expectancy more than 12 weeks; Zubrod performance status of  2; and adequate hematologic, renal, and hepatic function. Biliary obstruction, if present, required stenting before treatment initiation. Patients with prior history of abdominal irradiation or chemotherapy for pancreatic cancer were ineligible. The Institutional Review Board of the University of Michigan Medical School (Ann Arbor, MI) approved the trial. Written informed consent was obtained from all patients before initiation of therapy.
Treatment Radiation and gemcitabine doses were held constant, whereas the dose of oxaliplatin and infusion time for gemcitabine was assigned based on the time-to-event continuous reassessment method (TITE-CRM) algorithm (described in Trial Design). RT consisted of 27 Gy administered daily in 1.8-Gy fractions, five times weekly, beginning on day 1 of the first cycle, with planning and volumes as described previously.3,4 Late in the trial, radiation dosing was amended to provide 30 Gy during the first cycle of chemotherapy to obtain prospective data for a subsequent neoadjuvant trial. The last seven patients entered were treated with 30 Gy. Gemcitabine 1,000 mg/m2 was administered as a 30-, 65-, or 100-minute infusion. Oxaliplatin was administered intravenously during 90 minutes after gemcitabine infusion. The dose levels for investigation are summarized in Table 1. After combination treatment with chemotherapy and RT, a second cycle of gemcitabine and oxaliplatin was administered without RT.
Within a cycle, on the day that treatment was due, for absolute neutrophil count (ANC)  1,000/µL and platelets 75,000/µL, full doses of gemcitabine and oxaliplatin were administered. Gemcitabine was reduced 50% when ANC was 500/µL and less than 1,000/µL, and/or platelets were 50,000/µL and less than 75,000/µL. Oxaliplatin was not dose reduced at these levels. All treatment (including RT, if administered) was delayed for ANC less than 500/µL, platelets less than 50,000/µL, or grade 3 nonhematologic toxicity. If treatment was withheld during CMT, patients were re-evaluated weekly and treatment was resumed when toxicity resolved to grade 2, with a 25% dose reduction of both agents. If chemotherapy was withheld during cycle 2, those doses were dropped and not made up. If treatment could not be resumed within 2 weeks because of toxicity, patients were removed from the protocol. To assess the impact of adding oxaliplatin to gemcitabine and radiation therapy, we calculated the percent of gemcitabine received compared with that intended by protocol during the first two cycles, as described previously.3 A multidetector CT scan was repeated during week 9. Response of the primary tumor was determined using Response Evaluation Criteria in Solid Tumors Group.13 Resectable patients underwent surgery. All histologic slides from resections were reviewed by a single pathologist (J.K.G.) and therapeutic response was assessed and graded using a system described previously.14 Patients had CA 19-9 measurements before treatment and after their second cycle of therapy.
Definition of DLT
Trial Design
Between July 2004 and March 2006, 44 patients were registered onto the study. The median age of study participants was 64 years (range, 35 to 81 years); there were 27 men and 17 women. Baseline performance status was 0, 1, and 2 in 14, 28, and two patients, respectively. Baseline CA 19-9 was elevated in 35 patients (median value in all 44 patients, 500 U/mL; range, 2 to 410,840 U/mL). Twelve patients were enrolled as resectable, 29 patients were enrolled as unresectable, and three patients were enrolled with low-volume metastatic disease. Four patients were not assessable for DLT, the primary study end point. Two patients elected to discontinue treatment before completing two cycles (days 3 and 28, respectively), one patient suffered a myocardial infarction on day 11, and one patient died on day 2 of treatment as a result of cholangitis and sepsis. It was determined by the supervising Data Safety and Monitoring Board that these decisions and events were unlikely or not related to protocol treatment.
DLT
The number of patients experiencing DLT and the probabilities of DLT estimated by means of the dose-toxicity model used to conduct the trial are listed for each treatment level in Table 2. The primary goal of the trial was to determine a treatment level associated with a probability (P) of DLT closest to .20. Levels 2 and 3 have estimated P (DLT) within .01 of that value, whereas levels 1 and 4 have estimated P (DLT) within .04 of that value. Levels 5 and 6 are almost certainly too toxic to be of additional interest. The trial recruited 40 assessable patients in 20.4 months. Of the 40 assessable patients, 17 were treated at doses with P (DLT) estimated to be within .01 of the target rate. There were no pauses in the trial. Other serious adverse events occurring in the first 9 weeks of treatment not considered to be DLTs included seven patients with cholangitis, two patients with cardiac events, two patients with pulmonary emboli, one Clostridium difficile infection, and one patient with amaurosis fugax. Patients with cholangitis generally presented with a short history of nausea, emesis, and fever. No patient was neutropenic at the time of the event and each had preexisting biliary stent and an acute elevation of bilirubin. Hematologic toxicity included uncomplicated grade 3 neutropenia in nine patients and grade 4 neutropenia in one patient of less than 7 days duration, and grade 3 thrombocytopenia in seven patients. Grade 3/4 adverse events occurring in all patients during the first two cycles are summarized in Table 4.
Considering all 44 patients, 41 patients completed the 3 weeks of RT during cycle 1 and 38 patients completed two cycles of chemotherapy. Two patients did not complete two cycles due to DLT during cycle 1; one patient was removed from study and the other patient elected to stop treatment. The median dose-intensity of gemcitabine received by the 38 patients who completed two cycles of therapy was 86% (range, 39% to 102%) of that intended by protocol. All 38 patients who completed two cycles of therapy had baseline and follow-up CT scans for response assessment by Response Evaluation Criteria in Solid Tumors Group. One patient had no mass seen on baseline CT scan and therefore was not assessable for response. Of the remaining 37 patients, five patients had a partial response (13.5%; 95% CI, 4.5% to 28.8%), 29 patients had stable disease (78.4%; 95% CI, 61.8% to 90.2%) and three patients had progression of disease (8.1%; 95% CI, 1.7% to 21.9%). Of the 29 patients with stable disease, nearly half (48%) had more than 10% but less than 30% reduction in tumor longest diameter. Thirty-five patients had an elevated baseline CA 19-9, of whom 30 completed two cycles of therapy and were assessable for CA 19-9 response. Seventeen patients (57%) had more than 50% decline in CA 19-9 and 12 patients had stable CA 19-9 (50% to 150% of baseline value), whereas only one patient had an increase in CA 19-9 more than 150% of baseline. Twelve patients were enrolled as resectable; each completed two cycles of therapy and 11 underwent surgical exploration. One patient experienced local progression and was deemed unresectable. Of the 11 patients undergoing laparotomy, three were found to have arterial involvement precluding resection and one had hepatic metastasis. Of the seven resected patients, one had grade 4 pathologic complete response and another patient had grade 3 response with less than 10% viable appearing tumor cells. All seven resected patients had negative margins and only two had positive lymph nodes. Average length of stay was 10 days (range, 8 to 12 days). No patient was readmitted in the 60 days after surgery. There were no perioperative deaths. Patients were observed for this report until February 2007. All seven resected patients remain alive; three patients are disease free at 20.8, 25.0, and 25.9 months, and four patients have experienced disease recurrence at 6.1, 18.1, 19.4, and 20.8 months, respectively. Twenty-eight patients have died. Median survival in all registered patients is 12.5 months (95% CI, 8.9 to 18.6 months). For those 32 patients entered with unresectable (n = 29) or metastatic disease (n = 3), median survival is 9.1 months (95% CI, 5.2 to 12.5 months). A survival curve for all 44 patients is shown in Figure 1.
The purpose of this study was to determine a dose of oxaliplatin that could be added to full-dose gemcitabine and radiation therapy in patients with pancreas cancer, and to make an initial assessment of efficacy. We were also interested in evaluating fixed dose rate gemcitabine infusion in this combination treatment. Given that we designed the trial with dose escalation of oxaliplatin first, we were unable to increase gemcitabine infusion time, and noted grade 4 thrombocytopenia in three of six assessable patients treated at dose level 5. Generally, however, oxaliplatin at biweekly doses up to 85 mg/m2 was well tolerated, and more than 85% of patients completed 9 weeks of therapy, comparing favorably with previous reports.17-19 The TITE-CRM design allowed us to recruit patients continually, without pauses for observation. The study was designed with a DLT target rate of 20%; nine of 40 patients (22.5%) actually experienced DLT, indicating that TITE-CRM did not expose patients to significant excess toxicity. Although the study obtained significant information and achieved its accrual goal, the relatively low proportion of DLTs observed at level 4 indicates significant additional information would have been gained had the trial remained open to explore levels 3 and 4. Because TITE-CRM is a Bayesian design, a post hoc decision to increase the sample size would not invalidate the interpretation of the results, and a more data-driven paradigm to determine if a trial should be closed or extended is now a subject of our research. The radiation treatment used in this protocol was not conventional, as dictated by concomitant use of full-dose gemcitabine.3,20-22 The radiation dose chosen for this study was lower than previously reported, principally to emphasize and accommodate full systemic doses of gemcitabine and oxaliplatin.3,4,11 An underlying hypothesis central to this work is that chemotherapy sensitization to a modest dose of radiation will provide enhanced local treatment effects. In the neoadjuvant setting, we anticipate this approach will translate to margin-negative resections and significant pathologic response, as was observed in this trial. In reported series of patients undergoing initial surgery for pancreas cancer, R1 resections generally occur in more than 20% and the prognosis for these patients is significantly worse than for those with negative margins.23-25 These data argue for wider application of neoadjuvant treatment and emphasize the importance of accurate margin assessment at the time of operation. In the 12 patients entered onto this trial as resectable, none experienced DLT, all completed therapy, and seven underwent resection with negative margins. This result compares favorably with the study by Mornex et al19 using fluorouracil-based CMT in which margins were involved in 20% of patients (five of 26). The current study and previous reports of gemcitabine-based RT suggest that pathologic response and margin-negative resection may be more frequent than with fluoropyrimidine-based RT.11,26 Not unexpectedly, although a majority of patients had clinical, radiologic, or CA 19-9 improvements during the initial 2 months of treatment, no patient entered as unresectable became resectable after CMT. It is appropriate to consider the best direction for improving systemic disease control in resectable patients. In advanced disease trials, a gemcitabine-platinum–containing doublet has consistently demonstrated improved response rates, progression-free survival, and clinical benefit compared with gemcitabine alone.7,27,28 In a meta-analysis of these trials, survival was also improved.6 We believe that these results from multiple studies outweigh the results of Eastern Cooperative Oncology Group trial 6201, which did not find improved survival,29 and we note that the single positive study that added erlotinib to gemcitabine for patients with advanced disease led to an increase in median survival of only about 15 days.8 Thus, with accumulating information regarding the benefit of systemic adjuvant chemotherapy in pancreas cancer, and an evolving role for neoadjuvant treatment, we believe that this well-tolerated treatment protocol of gemcitabine-oxaliplatin and RT is appropriate for additional study.17,19,26,30,31 On the basis of this phase I trial, a multi-institutional phase II trial limited to patients with resectable disease has been initiated. Neoadjuvant treatment consists of oxaliplatin 85 mg/m2 days 1 and 15, with gemcitabine 1,000 mg/m2 days 1, 8, and 15, for two cycles, with 30-Gy RT during cycle 1. End points for this trial include resectability rate, pathologic effects of CMT, and 2-year disease-free survival. We anticipate a simultaneous emphasis on local therapy with neoadjuvant radiation and full systemic doses of chemotherapy will have a favorable impact on resectability and disease control in patients with resectable pancreas cancer.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Edgar Ben-Josef, Sanofi-aventis; Daniel P. Normolle, Sanofi-aventis; Mark M. Zalupski, Sanofi-aventis Expert Testimony: None Other Remuneration: None
Conception and design: Edgar Ben-Josef, Daniel P. Normolle, Theodore S. Lawrence, Mark M. Zalupski Provision of study materials or patients: Sameer P. Desai, Edgar Ben-Josef, Diane M. Simeone, Alfred E. Chang, Lisa M. Colletti, Theodore S. Lawrence, Mark M. Zalupski Collection and assembly of data: Sameer P. Desai, Edgar Ben-Josef, Daniel P. Normolle, Isaac R. Francis, Joel K. Greenson, Mark M. Zalupski Data analysis and interpretation: Sameer P. Desai, Edgar Ben-Josef, Daniel P. Normolle, Isaac R. Francis, Joel K. Greenson, Mark M. Zalupski Manuscript writing: Sameer P. Desai, Edgar Ben-Josef, Daniel P. Normolle, Isaac R. Francis, Joel K. Greenson, Diane M. Simeone, Theodore S. Lawrence, Mark M. Zalupski Final approval of manuscript: Sameer P. Desai, Edgar Ben-Josef, Daniel P. Normolle, Isaac R. Francis, Joel K. Greenson, Diane M. Simeone, Alfred E. Chang, Lisa M. Colletti, Theodore S. Lawrence, Mark M. Zalupski
We thank Gwen Hejna, Janet Hampton, and Leah Olson for assistance in patient care, Monika Benedict-Blue for data management support, and Julie Wietzke for study administration.
Supported in part by Sanofi-aventis. Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA, and at the American Society of Clinical Oncology GI Symposium, January 26-28, 2006. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article
1. Burris HA III, 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 2. Lawrence TS, Chang EY, Hahn TM, et al: Radiosensitization of pancreatic cancer cells by 2',2'-difluoro-2'-deoxycytidine. Int J Radiat Oncol Biol Phys 34:867-872, 1996[CrossRef][Medline] 3. McGinn CJ, Zalupski MM, Shureiqi I, et al: Phase I trial of radiation dose escalation with concurrent weekly full-dose gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 19:4202-4208, 2001 4. Muler JH, McGinn CJ, Normolle D, et al: Phase I trial using a time-to-event continual reassessment strategy for dose escalation of cisplatin combined with gemcitabine and radiation therapy in pancreatic cancer. J Clin Oncol 22:238-243, 2004 5. Cunningham D, Chau I, Stocken D, et al: PS11 Best of ECCO 13 Phase III randomised comparison of gemcitabine (GEM) versus gemcitabine plus capecitabine (GEM-CAP) in patients with advanced pancreatic cancer. Eur J Cancer 3:12, 2005 (suppl; abstr PS 11) 6. Louvet C, Hincke A, Labianca R, et al: Increased survival using platinum analog combined with gemcitabine as compared to gemcitabine single agent in advanced pancreatic cancer (APC): Pooled analysis of two randomised trials, the GERCOR/GISCAD Intergroup Study and a German Multicenter Study. J Clin Oncol 24:179s, 2006 (suppl; abstr 4003) 7. 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 8. Moore MJ, Goldstein D, Hamm J, 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 25:1960-1966, 2007 9. Gérard JP, Chapet O, Nemoz C, et al: Preoperative concurrent chemoradiotherapy in locally advanced rectal cancer with high-dose radiation and oxaliplatin-containing regimen: The Lyon R0-04 phase II trial. J Clin Oncol 21:1119-1124, 2003 10. Khushalani NI, Leichman CG, Proulx G, et al: Oxaliplatin in combination with protracted-infusion fluorouracil and radiation: Report of a clinical trial for patients with esophageal cancer. J Clin Oncol 20:2844-2850, 2002 11. Talamonti MS, Small W Jr, Mulcahy MF, et al: A multi-institutional phase II trial of preoperative full-dose gemcitabine and concurrent radiation for patients with potentially resectable pancreatic carcinoma. Ann Surg Oncol 13:150-158, 2006 12. National Comprehensive Cancer Network: http://www.nccn.org 13. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000 14. Evans DB, Rich TA, Byrd DR, et al: Preoperative chemoradiation and pancreaticoduodenectomy for adenocarcinoma of the pancreas. Arch Surg 127:1335-1339, 1992 15. Cheung YK, Chappell R: Sequential designs for phase I clinical trials with late-onset toxicities. Biometrics 56:1177-1182, 2000[CrossRef][Medline] 16. Normolle D, Lawrence T: Designing dose-escalation trials with late-onset toxicities using the time-to-event continual reassessment method. J Clin Oncol 24:4426-4433, 2006 17. Hoffman JP, Lipsitz S, Pisansky T, et al: Phase II trial of preoperative radiation therapy and chemotherapy for patients with localized, resectable adenocarcinoma of the pancreas: An Eastern Cooperative Oncology Group Study. J Clin Oncol 16:317-323, 1998 18. Magnino A, Gatti M, Massucco P, et al: Phase II trial of primary radiation therapy and concurrent chemotherapy for patients with locally advanced pancreatic cancer. Oncology 68:493-499, 2005[CrossRef][Medline] 19. Mornex F, Girard N, Scoazec JY, et al: Feasibility of preoperative combined radiation therapy and chemotherapy with 5-fluorouracil and cisplatin in potentially resectable pancreatic adenocarcinoma: The French SFRO-FFCD 97-04 phase II trial. Int J Radiat Oncol Biol Phys 65:1471-1478, 2006[CrossRef][Medline] 20. Hoffman JP, McGinn CJ, Szarka C, et al: A phase I study of preoperative gemcitabine (GEM) with radiation therapy (RT) followed by postoperative GEM for patients with localized, resectable pancreatic adenocarcinoma (PaC). Proc Am Soc Clin Oncol 17:283, 1998 (abstr 1090) 21. McGinn CJ, Zalupski MM: Radiation therapy with once-weekly gemcitabine in pancreatic cancer: Current status of clinical trials. Int J Radiat Oncol Biol Phys 56:10-15, 2003[CrossRef][Medline] 22. Wolff RA, Evans DB, Gravel DM, et al: Phase I trial of gemcitabine combined with radiation for the treatment of locally advanced pancreatic adenocarcinoma. Clin Cancer Res 7:2246-2253, 2001 23. Massucco P, Capussotti L, Magnino A, et al: Pancreatic resections after chemoradiotherapy for locally advanced ductal adenocarcinoma: Analysis of perioperative outcome and survival. Ann Surg Oncol 13:1201-1208, 2006 24. Neoptolemos JP, Stocken DD, Dunn JA, et al: Influence of resection margins on survival for patients with pancreatic cancer treated by adjuvant chemoradiation and/or chemotherapy in the ESPAC-1 randomized controlled trial. Ann Surg 234:758-768, 2001[CrossRef][Medline] 25. Winter JM, Cameron JL, Campbell KA, et al: 1423 Pancreaticoduodenectomies for pancreatic cancer: A single-institution experience. J Gastrointest Surg 10:1199-1210, 2006[CrossRef][Medline] 26. Crane CH, Varadhachary G, Wolff RA, et al: The argument for pre-operative chemoradiation for localized, radiographically resectable pancreatic cancer.Best Pract Res Clin Gastroenterol 20:365-382, 2006[CrossRef][Medline] 27. Colucci G, Giuliani F, Gebbia V, et al: 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 94:902-910, 2002[CrossRef][Medline] 28. Heinemann V, Quietzsch D, Gieseler F, et al: Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J Clin Oncol 24:3946-3952, 2006 29. Poplin E, Levy DE, Berlin J, et al: Phase III trial of gemcitabine (30-minute infusion) versus gemcitabine (fixed-dose-rate infusion[FDR]) versus gemcitabine + oxaliplatin (GEMOX) in patients with advanced pancreatic cancer (E6201). J Clin Oncol 24:180s, 2006 (suppl; abstr LBA4004) 30. 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 31. Oettle H, Post S, Neuhaus P, et al: Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: A randomized controlled trial. JAMA 297:267-277, 2007 Submitted April 5, 2007; accepted July 19, 2007.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
