Walter Sall, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: November 12, 2003
Faculty Disclosure: Howard S. Hochster, M.D.
This presentation by Dr Hochster includes discussion on the use of pemetrexed in the treatment of colorectal cancer which has not been approved by the FDA
Presenter: Howard S. Hochster, M.D.
Affiliation: New York University
Pemetrexed is a multi-targeted anti-folate similar in structure to methotrexate. It inhibits thymidylate synthase, dihydrofolate reductase and GARFT (glycinamide ribonucleotide formyl transferase). Intra-cellular poly-glutamation leads to greatly increased in-vitro activity. Single agent activity for pemetrexed has been shown in mesothelioma, non-small cell lung cancer and colorectal cancer in addition to several other primary tumors. The primary toxicity is hematologic. Neutropenia can be greatly reduced by folate and B12 supplementation during pemetrexed therapy.
Two multi-center trials have shown a 15-17% response rate for pemetrexed as a single agent in advanced colorectal cancer. Pemetrexed has been combined with irinotecan in several small phase I and II trials in pretreated colorectal cancer patients. With vitamin supplementation, full doses of pemetrexed and irinotecan are well tolerated with some responses observed. More phase II/III data are required to determine response rates and the existence of possible survival benefits with this combination.
Pemetrexed and oxaliplatin combinations for pretreated colorectal cancer patients have also been tested in the phase I/II setting. Preliminary data have shown response rates up to 28% with lower than expected toxicity. As vitamin supplementation was included in these trials, it has been hypothesized that higher chemotherapy doses may be tolerated and lead to even better response rates.
Future studies include randomized studies of pemetrexed/oxaliplatin vs. FOLFOX-4 as well as FOLFIRI vs. pemetrexed/irinotecan.
In conclusion, the relatively high single agent activity of pemetrexed, its favorable toxicity profile and convenient q 3 week dosing schedule make it attractive in the treatment of advanced colorectal cancer. It has been shown that pemetrexed is well tolerated with full doses of conventional chemotherapy agents. Phase II/III studies will help determine exactly where pemetrexed fits in the colorectal cancer treatment algorithm.