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Journal of Clinical Oncology, Vol 26, No 18 (June 20), 2008: pp. 3100-a-3101 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.17.0985
In ReplyDepartment of Radiation Oncology, The Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL
Department of Medicine, Section of Oncology, Vanderbilt-Ingram Cancer Center, Nashville, TN
Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA
Department Radiation Oncology, University of Michigan Medical Center, Ann Arbor, MI
Department of Surgery, Robert H. Lurie Comprehensive Cancer Center, Evanston, IL
Division of Hematology Oncology, Robert H. Lurie Comprehensive Cancer Center, Chicago, IL
Department Radiation Oncology, Vanderbilt-Ingram Cancer Center, Nashville, TN
Department of Internal Medicine, University of Michigan Medical Center. Ann Arbor, MI
Department of Hematology and Oncology, Karmanos Cancer Institute, Detroit, MI
Department Radiation Oncology, University Hospitals Case Medical Center, Cleveland, OH
Division of Surgical Oncology, Vanderbilt University Medical Center, Nashville, TN
Department of Surgery, Fox Chase Cancer Center, Philadelphia, PA
Division of Hematology Oncology, Robert H. Lurie Comprehensive Cancer Center, Chicago, IL
Department Radiation Oncology, Maine Medical Center, Portland, ME We believe that a number of issues brought up by Drs Kleeff and Friess regarding our recent publication of phase II results for full-dose gemcitabine and radiotherapy in nonmetastatic pancreatic1 cancer deserve comment. First, the statement that local control is of little relevance is simply not true. Cure, although infrequent, can never be achieved without local control. In fact, it can be argued that if we can improve systemic control, local control becomes more important. In addition to its impact on survival, local progression of disease can also have devastating quality-of-life implications leading to duodenal and biliary obstruction, bleeding, and pain. Drs Kleeff and Friess also state that there is no solid evidence that neoadjuvant therapy is of any benefit (or at least not harmful) in pancreatic cancer. Neoadjuvant strategies have proven efficacious in other malignancies, including rectal2 and esophageal3 cancers, and there is no reason to believe pancreatic cancer would be any different. Given the need to deliver effective systemic therapy, our regimen provides a platform for up-front full-dose gemcitabine with modified radiotherapy (36 Gy/3 weeks). This allows all patients to receive adjuvant therapy and provides a test of time to avoid potentially morbid unnecessary surgery. Drs Kleeff and Friess quote their own article,4 stating that the vast majority of surgical resections are not curative. The margin-negative rate for resected patients in our phase II trial was 94%,5 certainly suggesting that this regimen is active in patients who are to undergo resection, and is worthy of additional consideration. Attempting to go straight to a randomized trial with such a unique neoadjuvant strategy seems incongruous with normal trial development and necessitates a multicenter phase II trial. The criticism of Drs Kleeff and Friess that this trial is simply another phase I/II neoadjuvant trial seems to miss the uniqueness and the potential toxicity of a regimen that combines full-dose gemcitabine and radiotherapy, which has not previously been accomplished in a multi-institutional setting. The authors further criticize the use of this platform with the combination of bevacizumab. The bevacuzumab trial was developed as our multicenter trial was completing and maturing. The trial rationale included evidence of efficacy for the combination of gemcitabine and bevacizumab,6 and evidence for radiosensitization with the use of angiogenesis inhibition and radiotherapy.7 Early results of the bevacizumab trial were presented this year, demonstrating a 33% complete pathologic response in resected patients.8 Adding biologic agents to combined chemotherapy and radiotherapy is a logical attempt to improve outcomes. In conclusion, pancreatic cancer is a devastating disease that would benefit from a therapeutic approach that demonstrates an obvious improvement in outcomes. Our unique approach, which combined full-dose systemic therapy with modified radiotherapy (36 Gy/3 weeks), produced a high margin negative resection rate, low toxicity, and encouraging efficacy. We share the desire of Drs Kleef and Freiss for a randomized study; however, it is neither ethical nor economically feasible to embark on an appropriately powered randomized study before establishing feasibility and safety in a multi-institutional setting. Unique phase II trials should be encouraged, but only those that demonstrate a true significant advance in pancreatic cancer should be considered for a large randomized study. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST 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: Al B. Benson III, Eli Lilly, Genentech Stock Ownership: None Honoraria: None Research Funding: William Small Jr, Eli Lilly; Al B. Benson III, Eli Lilly, Genentech Expert Testimony: None Other Remuneration: None REFERENCES
1. Small W Jr, Berlin J, Freedman GM, et al: Full-dose gemcitabine with concurrent radiation therapy: A multicenter phase II trial. J Clin Oncol 26:942-947, 2008 2. Sauer R, Becker H, Hohenberger W, et al: Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731-1740, 2004 3. Tepper J, Krasna MJ, Niedzwiecki D, et al: Phase III trial of trimodality with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781. J Clin Oncol 26:1086-1092, 2008 4. Esposito I, Kleef J, Bergmann F, et al: Most pancreatic cancer resections are R1 resections. Ann Surg Oncol 15:1651-1660 5. Talamonti M, Small W Jr, Mulchay 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 6. Kindler HL, Friberg G, Singh D, et al: Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 23:8033-8040, 2005 7. Li J, Huang S, Armstrong EA, et al: Angiogenesis and radiation response modulation after vascular endothelial growth factor receptor-2 (VEGFR-2) blockade. Int J Radiat Oncol Biol Phys 62:1477-1485, 2005[CrossRef][Medline] 8. Small W Jr, Mulcahy MF, Benson AB, et al: A phase II trial of weekly gemcitabine and bevacizumab in combination with abdominal radiation therapy in patients with localized pancreatic cancer. Proc 2008 Gastrointestinal Cancers Symposium, Orlando, FL, January 25-27, 2008 (abstr 131) Related Correspondence
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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