This document posted Recommendations and Reasons October 2008 Committee to Evaluate Drugs (CED)

Oxaliplatin (for metastatic )

Product: Highlights of Recommendation: has not been conducted by the (Eloxatin®) manufacturer to assess value for money ♦ Oxaliplatin (Eloxatin) is a in the second-line setting. Class of drugs: agent used in the treatment of ♦ Overall, the Committee noted that, in Antineoplastic colorectal cancer (colon cancer and the first-line treatment of metastatic rectal cancer). colorectal cancer, the FOLFOX regimen Indication: ♦ This particular review considered the is similar in efficacy as the FOLFIRI regimen but is much more expensive. Treatment of metastatic colorectal funding of oxaliplatin (Eloxatin) in a Therefore, the Committee cancer combination regimen, called the FOLFOX regimen, for the treatment of recommended that the FOLFOX regimen

metastatic colorectal cancer, which is be funded for first-line treatment only in Manufacturer: cancer that has advanced and spread patients who have a contraindication or sanofi aventis Canada Inc. beyond the colon and rectum. intolerance to the FOLFIRI regimen. ♦ The FOLFOX regimen is a combination The Committee recommended that the CED Recommendation containing oxaliplatin (Eloxatin) and two FOLFOX regimen not be funded in the other chemotherapy drugs: 5- second-line treatment of metastatic For the initial or first-line treatment of and leucovorin. colorectal cancer because value for metastatic colorectal cancer, the CED ♦ An alternative combination treatment money has not been demonstrated. recommended that oxaliplatin (Eloxatin) for metastatic colorectal cancer is the be funded only in patients who have a FOLFIRI regimen. The FOLFIRI contraindication or intolerance to the regimen combines three chemotherapy Background: FOLFIRI regimen, on the basis that drugs: , 5-fluorouracil and oxaliplatin (Eloxatin) is similar in leucovorin. Colorectal cancer refers to cancer of the efficacy as this comparator regimen but ♦ In the initial or first-line treatment of colon (large bowel) and cancer of the is significantly more expensive. metastatic colorectal cancer, evidence rectum. Metastatic colorectal cancer is supports that the FOLFOX regimen and cancer that has spread to other parts of For the subsequent or second-line the FOLFIRI regimen provide similar the body, such as the liver and lung. efficacy. treatment of metastatic colorectal ♦ However, the two treatment regimens Treatment of metastatic colorectal cancer cancer in patients who have failed first- differ in their side effects. The FOLFIRI usually consists of combination line therapy, the CED recommended regimen is associated with a higher risk chemotherapy. For patients unable to that oxaliplatin (Eloxatin) not be of low blood cell count and diarrhea. tolerate combination therapy, standalone funded, on the basis that value for The FOLFOX regimen is associated with treatments are also available. money has not been demonstrated in a high risk of peripheral neuropathy this setting. (pain, numbness, tingling, swelling and Two standard combination regimens for muscle weakness in various parts of the metastatic colorectal cancer are the body). FOLFIRI regimen (irinotecan, 5- Executive Officer Decision ♦ Because the two regimens have similar fluorouracil and leucovorin) and the efficacy, the difference in side effect FOLFOX regimen (oxaliplatin, 5- Following the CED's recommendation profile usually determines which fluorouracil and leucovorin). Standard and based on a subsequent pricing treatment a physician may choose for a practice in North America is to choose one agreement with the manufacturer, the particular patient. of these two regimens as the initial or Executive Officer decided to fund ♦ The FOLFOX regimen is approximately first-line treatment. If the FOLFIRI oxaliplatin (Eloxatin) for both first- and three times more expensive than the regimen is chosen as the first-line second-line treatment of metastatic FOLFIRI regimen ($1,492 per treatment treatment and it fails, the patient can be cycle versus $582 per treatment cycle). colorectal cancer. switched to the FOLFOX regimen as their The Committee indicated that the price second-line treatment. Likewise, if the

premium is not justified. FOLFOX regimen fails as first-line

♦ In the subsequent or second-line treatment, the patient can be switched to treatment of metastatic colorectal the FOLFIRI regimen as their second-line

Status cancer in patients who have failed first- treatment. line treatment, data from one study reported that the FOLFOX regimen Funding available through Cancer Care provided superior efficacy compared to Ontario’s New Drug Funding Program. oxaliplatin (Eloxatin) alone and 5- fluorouracil and leucovorin alone. continued... However, a proper economic evaluation Detailed Discussion: Cancer Care Ontario (CCO) Information: ♦ In the first-line treatment of metastatic line treatment, and vice versa, for colorectal cancer, data from three maximal survival benefits. The meta- Information on CCO regimens for colorectal randomized controlled studies (Goldberg analysis included results from seven cancer may be found at: et al. J Clin Oncol 2004. Colucci et al. J randomized controlled trials and found a http://www.cancercare.on.ca/ Clin Oncol 2005. Tournigand et al. J Clin 3.5 month increase in median survival in index_chemoRegimensbyDisease.htm Oncol 2004.) support that the FOLFOX patients who received a first-line regimen and the FOLFIRI regimen combination therapy with either The colorectal Disease Site Group Program provide similar efficacy in measures of oxaliplatin or irinotecan, as compared in Evidence-Based Care Guideline for overall response rate and median with patients who received oxaliplatin (Eloxatin) in colorectal cancer is survival. monotherapy. available at: ♦ In the Goldberg trial, a median time to ♦ The FOLFOX regimen and the FOLFIRI http://www.cancercare.on.ca/english/ progression of 8.7 months, response regimen have different side effect toolbox/qualityguidelines/diseasesite/ rate of 45%, and median survival time profiles. The FOLFIRI regimen is gastro-ebs/1 of 19.5 months were observed with the associated with higher risks of diarrhea FOLFOX regimen. These results were and neutropenia, while the FOLFOX superior to those observed with the IFL regimen is associated with a high risk of regimen for all endpoints (6.9 months, peripheral neuropathy. 31%, and 15.0 months, respectively). ♦ In addition to peripheral neuropathy, The IFL is a regimen similar to FOLFIRI. other common side effects with the With the FOLFIRI regimen, 5-fluorouracil FOLFOX regimen include neutropenia is given by infusion; whereas with IFL, (low white blood cell count), 5-fluorouracil is given by bolus injection. thrombocytopenia (low platelet count), Evidence has shown that infusional 5- anemia, nausea, diarrhea, vomiting, fluorouracil is superior to bolus 5- fatigue, and stomatitis (mouth sores). fluorouracil in terms of toxicity and ♦ In terms of costs, the FOLFOX regimen tumor response rate. is three times more expensive than the

♦ In the Colucci trial, no significant FOLFIRI regimen. The FOLFOX regimen

difference was observed between costs $1,492 per treatment cycle and the

patients treated with the FOLFOX and FOLFIRI regimen costs $582 per the FOLFIRI regimen with respect to treatment cycle. Value for money for overall response rate, median time to the FOLFOX regimen has not been progression and overall survival. The demonstrated. overall response rates were 31% in the ♦ Overall, the Committee agreed that FOLFIRI group versus 34% in FOLFOX available evidence supports the clinical group. In both treatment groups, the efficacy of the FOLFOX regimen. median time to progression was 7 However, the FOLFOX regimen is months. The overall survival was 14 significantly more expensive than the months versus 15 months, for FOLFIRI FOLFIRI regimen. In the absence of and FOLFOX respectively. evidence to demonstrate cost- ♦ The Tournigand trial demonstrated effectiveness, the Committee similar median survival (21.5 months recommended that the FOLFOX regimen versus 20.6 months) and overall be funded only for the first-line response rate (56% versus 54%) treatment of metastatic colorectal cancer between the FOLFOX and FOLFIRI in patients who have a contraindication

regimen. or intolerance to the FOLFIRI regimen.

♦ In the second-line treatment of ♦ The CED worked jointly with a metastatic colorectal cancer, results subcommittee involving cancer experts from one study (Rothenberg et al. J Clin to review this cancer drug, as is done for Oncol 2003) demonstrated that the all other cancer drug treatments. Ministry of FOLFOX regimen provided superior Health and Long-Term Care efficacy compared to oxaliplatin Ontario Public Drug Programs (Eloxatin) alone and 5-fluorouracil and leucovorin alone in terms of response rate, time to progression, and symptom For more information, please contact:

control. Ministry of Health and Long-Term Care ♦ A meta-analysis (Grothey et al. J Clin Ontario Public Drug Programs Oncol 2004) found that patients on first- line combination therapy containing Hepburn Block, 9th Floor

oxaliplatin (e.g. the FOLFOX regimen) 80 Grosvenor Street, Queen’s Park should subsequently be offered Toronto, Ontario M7A 1R3 combination therapy with irinotecan (e.g. the FOLFIRI regimen) as second- or click: (http://www.health.gov.on.ca/english/ providers/program/drugs/ced_rec_table.html)