According to the National Cancer Institute, pancreatic cancer affects 44,030 Americans annually. Treatment for patients with locally advanced or metastatic disease depends on the stage of the cancer. Surgical treatment for cancer of the head of the pancreas is performed with the Whipple procedure, while distal pancreatectomy is preferred for cancer of the tail of the pancreas. Adjuvant single-agent chemotherapy with gemcitabine is used as a treatment of metastatic pancreatic cancer. Expression of the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) in pancreatic tumors has led to the development of agents such as erlotinib, an EGFR tyrosine kinase inhibitor. Considering that the response rates with single-agent therapy are low, trials of combination second-line therapy for metastatic pancreatic cancer are being conducted.
One such study assessed the efficacy and toxicity of combination therapy involving 5-fluorouracil (5-FU) and leucovorin in combination with irinotecan plus oxaliplatin (FOLFIRINOX) as second-line therapy in metastatic pancreatic adenocarcinoma (MPA).
Irinotecan, a topoisomerase I inhibitor, is used against colorectal cancer in patients refractory to 5-FU treatment, and the combination of docetaxel and irinotecan is an active treatment for advanced pancreatic cancer. 5-FU is an antimetabolite pyrimidine analog that functions as an irreversible inhibitor of thymidylate synthase. Leucovorin, a folic acid analog, protects against the harmful effects of methotrexate. Intravenous oxaliplatin is an antineoplastic alkylating agent approved by the FDA for use with 5-FU and leucovorin to treat stage III colon cancer after surgery.
A retrospective analysis of 27 MPA patients treated with FOLFIRINOX as second-line therapy after progressing on first-line chemotherapy with gemcitabine (mean of 6 treatment cycles per patient) was recently published in Oncology. The dosage cycle was as follows:
1. Oxaliplatin 85 mg/m2 on day 1
2. Irinotecan 180 mg/m2 on day 1
3. Leucovorin 400 mg/m2 on day 1
4. 5-FU 400 mg/m2 as a bolus on day 1 and 2400 mg/m2 as 46-hour continuous infusion biweekly
Treatment tolerance was acceptable, with the relative dose density delivered per patient 92.8% for oxaliplatin, 89.1% for irinotecan, and 96.4% for 5-FU. Grade 3/4 neutropenia was seen in 55.6% of patients. As evaluated by WHO and RECIST criteria, the overall survival was 8.5 months, with median time to progression 5.4 months and median event-free survival 3 months. Overall disease control rate was 63%, and a clinical benefit was seen in 55% of patients.
An ESMO Symposium on Metastases to be held in Zurich, Switzerland, on November 10-11, 2011, will focus on the basic science and clinical impact of lymph node, hematopoietic, brain, lung, liver, and bone metastases, as well as biological rationales for new drugs in development, the use of biomarkers, and prevention of metastases. For more information:http://www.esmo.org/events/esmo-symposium-metastases-2011/program.html.
Suggested reading:
1. Assaf E, Verlinde-Carvalho M, Delbaldo C, et al. 5-fluorouracil/leucovorin combined with irinotecan and oxaliplatin (FOLFIRINOX) as second-line chemotherapy in patients with metastatic pancreatic adenocarcinoma. Oncology. 2011;80:301-306.
2. Howlader N, Noone AM, Krapcho M, et al, eds. SEER Cancer Statistics Review 1975-2008. National Cancer Institute. Bethesda, MD. http://seer.cancer.gov/csr/1975_2008/.
3. Ychou M, Conroy T, Seitz JF, et al. An open phase I study assessing the feasibility of the triple combination: oxaliplatin plus irinotecan plus leucovorin/5-fluorouracil every 2 weeks in patients with advanced solid tumors. Ann Oncol. 2003;14:481-489.
4. Ducreux M, Mitry E, Ould-Kaci M, et al. Randomized phase II study evaluating oxaliplatin alone, oxaliplatin combined with infusional 5-FU, and infusional 5-FU alone in advanced pancreatic carcinoma patients. Ann Oncol. 2004;15:467-473.
5. DeCaprio JA, Mayer RJ, Gonin R, Arbuck SG. Fluorouracil and high-dose leucovorin in previously untreated patients with advanced adenocarcinoma of the pancreas: results of a phase II trial. J Clin Oncol. 1991;9:2128-2133.
6. Van Rijswijk RE, Jeziorski K, Wagener DJ, et al. Weekly high-dose 5-fluorouracil and folinic acid in metastatic pancreatic carcinoma: a phase II study of the EORTC Gastrointestinal Tract Cancer Cooperative Group. Eur J Cancer. 2004;40:2077-2081.
7. Rothenberg ML, Moore MJ, Cripps MC, et al. A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer. Ann Oncol. 1996;7:347-353.
8. Burris HA 3rd, 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. 1997;15:2403-2413.
9. Itakura J, Ishiwata T, Shen B, et al. Concomitant over-expression of vascular endothelial growth factor and its receptors in pancreatic cancer. Int J Cancer. 2000;85:27-34.
10. Berlin JD, Catalano P, Thomas JP, et al. Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297. J Clin Oncol. 2002;20:3270-3275.
11. Palmer KR, Kerr M, Knowles G, et al. Chemotherapy prolongs survival in inoperable pancreatic carcinoma. Br J Surg. 1994;81:882-885.