Abstract
Background: Drug-induced pancreatitis is less common compared to other causes of acute pancreatitis; the incidence ranges from between 0.1% to 2% of acute pancreatitis cases. Among alkylating agents, oxaliplatin has not been reported to be associated with acute pancreatitis. Patients and Methods: This case study presents a series of six cases of acute pancreatitis presumably related to exposure to oxaliplatin which had different gastrointestinal malignancies and were being treated with oxaliplatin in combination with other chemotherapeutic drugs. All other related causes of acute pancreatitis were excluded before implicating oxaliplatin as a possible cause. Results: In all cases, oxaliplatin was stopped and patients had resolution of their signs and symptoms, along with a decrease in serum amylase and lipase levels. Conclusion: Knowledge regarding acute pancreatitis related to oxaliplatin is of paramount importance in order to diagnose cases early and institute effective treatment in patients who are undergoing chemotherapy with this drug.
Oxaliplatin is a third-generation platinum-based alkylating agent. Cisplatin and carboplatin are other platinum-based alkylating agents. The chemical structure of oxaliplatin consists of a square planar platinum center. In comparison to cisplatin and carboplatin, it contains a bidentate ligand 1,2 diaminocyclohexane in place of the two monodentate ammine ligands. It also has a bidentate oxalate group.
The cytotoxicity of oxaliplatin is thought to result from the formation of DNA adducts and inhibition of DNA synthesis in cancer cells. It is used in combination with 5-flourouracil (5-FU) and leucovorin (LV) as FOLFOX chemotherapy, primarily for adjuvant chemotherapeutic treatment of stage III, Dukes' C colorectal cancer. Oxaliplatin received approval from the U.S. Food and Drug Administration for the treatment of stage III advanced colorectal cancer in 2002 (1). It has also shown promising results in other gastrointestinal malignancies, namely, esophagogastric, gall bladder and pancreatic cancer (2-5).
The reported side-effects of oxaliplatin include peripheral neuropathy (both acute, reversible and chronic, irreversible), fatigue, stomatitis, nausea, vomiting, diarrhea, neutropenia, thrombocytopenia, increase in transaminases and alkaline phosphatase, ototoxicity, nephrotoxicity, allergic (hypersensitivity) reaction and local damage to connective tissue if the infusion leaks through the vein. Pancreatitis associated with platinum-alkylating agents is rare; however, there are a few published case reports of cisplatin-induced pancreatitis (6, 7). To date, there has not been any reported case of oxaliplatin causing acute pancreatitis. This study reports a series of six cases of acute pancreatitis presumably caused by oxaliplatin.
Patients and Methods
Subjects. All patients were affected with various gastrointestinal malignancies and were receiving chemotherapeutic treatment at the Yale Cancer Center from July 2008 to July 2010.
Pancreatitis diagnosis. Acute pancreatitis was diagnosed as having any two of the following three features: (i) abdominal pain characteristic of acute pancreatitis, (ii) serum amylase and/or lipase ≥3 times the upper limit of normal and (iii) characteristic findings of acute pancreatitis on a computerized tomography (CT) scan of the abdomen.
Laboratory measurements. Normal levels of serum amylase at the Yale Cancer Center was 28-100 U/l, and for serum lipase they were <60 U/l.
All other causes of acute pancreatitis, including alcohol, gallstones and other drugs were excluded before patients were suspected of having oxaliplatin-induced pancreatitis.
Demographic, laboratory/radiological findings and treatment outcomes.
Results
Patient characteristics, laboratory/radiological findings and treatment outcomes are described in Table I.
Discussion
Oxaliplatin was approved by the FDA to be used in combination with other chemotherapeutic drugs as adjuvant treatment in patients with stage III colon cancer who have had surgery for cancer removal. It was also approved to treat advanced (stage IV) colorectal cancer and in patients whose cancer has recurred after earlier chemotherapy. Oxaliplatin is also commonly used in combination with gemcitabine or 5-FU in pancreatic cancer.
Earlier clinical trials for advanced colorectal cancer by de Gramont et al. showed that adding oxaliplatin to the combination of 5-FU and LV led to significant improvement in disease-free survival than the traditional 5-FU/LV regimens (8). This was subsequently supported by Kuebler et al. (9). Moreover, the MOSAIC trial by Andre et al. showed that the combination oxaliplatin/5-FU/LV (FOLFOX) improved not only disease-free survival but also overall survival in stage II or III colorectal cancer (10). Recent meta-analysis of six randomized controlled trials performed by Cao et al. showed that there is no statistically significant difference in overall survival, progression-free survival and overall response rate between capecitabine plus oxaliplatin vs. 5-FU plus oxaliplatin regimen as first-line treatment for advanced colorectal cancer (11).
The combination of 5-FU and cisplatin used to be the standard adjuvant chemotherapy for previously untreated advanced esophagogastric cancer. However, recently Cunningham et al. showed that the combination of oxaliplatin and capecitabine is as effective (2). Recently, Zhao et al. also showed that a modified FOLFOX regimen is active and well-tolerated as first-line chemotherapeutic treatment in advanced gastric cancer for patients over the age of 65 years (3).
With regards to gallbladder and biliary tract cancer, one study showed that gemcitabine and oxaliplatin have good activity in non-gall bladder cancer but poor activity in gallbladder cancer (12), whereas triple therapy as GEMFOX (gemcitabine, oxaliplatin and 5-FU) showed comparable results for response and survival for both advanced bile duct and gall bladder carcinoma but with more toxicity (4).
The management of pancreatic cancer is quite challenging and revolves around gemcitabine as a standard therapy with combinations such as GEMFOX (gemcitabine plus oxaliplatin). This regimen shows some benefit in patients with advanced pancreatic cancer after their disease progressed, following standard gemcitabine treatment (5).
There have been some case reports mentioning cisplatin causing acute pancreatitis (6, 7); however, to date there has been no report of oxaliplatin-induced acute pancreatitis. The reported cases of this study are, therefore, the first ones highlighting the fact that patients undergoing treatment with oxaliplatin need to be warned about the possible side-effect of developing acute pancreatitis. This recognition is of high importance and in such situations oxaliplatin needs to be discontinued in order to avoid the potentially fatal complications of pancreatitis. Further studies are necessary to elucidate whether factors such as certain characteristics of the individuals, the chemical structure of the drug itself or the nature and stage of certain malignancies predispose patients to develop pancreatitis at increased risk.
- Received October 13, 2010.
- Revision received November 12, 2010.
- Accepted November 15, 2010.
- Copyright© 2010 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
