Initial experience combining cyclooxygenase-2 inhibition with chemoradiation for locally advanced pancreatic cancer.
Pancreatic cancer is a lethal disease that is resistant to chemotherapy and radiotherapy. Gemcitabine has recently been shown to be an improvement over 5-fluorouracil in patients with advanced disease. It is also a potent radiosensitizer, which has led to the investigation of gemcitabine with concurrent radiotherapy. However, preliminary results indicate that there are significant limitations to this approach in this challenging disease. Pancreatic cancer cells have alterations in many molecular signaling pathways that may be responsible for their resistance to cytotoxic therapy and aggressive behavior. Cyclooxygenase-2 (COX-2) is commonly overexpressed in pancreatic tumors, and preclinical evidence indicates that selective COX-2 inhibition enhances both chemotherapy and radiotherapy response, without affecting normal tissue damage. We have initiated preclinical studies as well as a phase I clinical protocol evaluating the combination of gemcitabine and celecoxib (Celebrex) with radiotherapy. In preclinical studies, celecelecoxib strongly enhanced the antitumor efficacy of chemoradiation. However, preliminary observations from both the preclinical experiments as well as the clinical protocol have revealed more toxicity with this combination than with gemcitabine and radiotherapy alone. These observations require further study, but are cause for concern when combining gemcitabine, radiotherapy, and celecoxib.
Crane
Christopher H
CH
Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA. ccrane@mdanderson.org
Mason
Kathy
K
Janjan
Nora A
NA
Milas
Luka
L
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068579:Celecoxib; D017321:Clinical Trials, Phase I as Topic; D003131:Combined Modality Therapy; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008565:Membrane Proteins; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011720:Pyrazoles; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*; D000093542:Gemcitabine
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D011720:Pyrazoles; D011838:Radiation-Sensitizing Agents; D013449:Sulfonamides; D003841:Deoxycytidine; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D000068579:Celecoxib; D000093542:Gemcitabine