Researchers with the largest Phase III trial to date for mesothelioma, an aggressive cancer affecting the lining of the lung, reported results showing that patients on a new chemotherapy drug regimen live longer and have less pain than those on an older drug. The findings were announced at the annual meeting of the American Society of Clinical Oncology meeting in Orlando, Fla., on May 20, 2002.
Pemetrexed (brand name Alimta™) is a novel antifolate, a class of drugs that targets the folic acid metabolic pathway, which effects availability of certain B complex vitamins. The results of the trial show that tumors shrank in 41 percent of patients on pemetrexed in combination with a more commonly used chemotherapy agent called cisplatin. Only 17 percent of patients receiving cisplatin alone experienced tumor shrinkage. Additionally, those on the pemetrexed combination lived nearly three months longer than those on cisplatin alone.
According to lead author, Nicholas J. Vogelzang, M.D., University of Chicago Cancer Research Center, “This is the largest clinical trial ever conducted in this disease and the 25 to 30 percent improvement in survival for patients on the combination therapy is the first time anyone has documented a significant improvement in patients treated for mesothelioma.”
Malignant pleural mesothelioma is associated with a history of asbestos exposure in about 70 to 80 percent of all cases and there is no approved or very effective chemotherapy for the disease. Researchers hypothesized that pemetrexed might prove effective in treating this disease because it targets key enzymes thought to play a role in allowing the rapid growth of this tumor.
Early Phase I trial results in 11 patients tested with pemetrexed and cisplatin were promising and a definitive randomized Phase III trial was developed. Since there are no established therapies for this condition, a standard chemotherapy agent called cisplatin that has shown efficacy in treating other diseases, was used as the control arm. The Phase III study initially planned to enroll 456 patients from April 1999 to March 2001. However, after enrolling 150 patients, a high rate of severe toxicity and death was associated with the pemetrexed and cisplatin arm of the trial. Elevated levels of homocysteine, a chemical byproduct that results when proteins are broken down in the blood, were found, which provided a basis for redesign of the trial to reduce the dangerous drug side effects.
Two hundred and eighty patients were enrolled to the revised protocol. Using a strategy to reduce drug side effects that has been successful in the past, this new protocol added folic acid to the regimen because pemetrexed as an antifolate agent reduces levels of this important vitamin. Folic acid was given prior to and during the trial, and vitamin B12 was given only during the trial. Both vitamins should boost folic acid levels, reduce homocysteine formation, and hence reduce toxicity to pemetrexed (alitma). “We now have a significantly less toxic regimen than the one we started with,” said Vogelzang.
Because of the presumed importance of the vitamins to the study, the researchers examined not only the combination therapy versus the single drug therapy, but also looked at the results of patients on the vitamin supplements versus those early enrollees who had not initially received vitamins.
Standard treatment for malignant mesothelioma has been surgery. Surgical treatment rarely results in cure and long-term survival is unusual. Use of radiation therapy and/or chemotherapy following surgery has not improved survival for patients but radiation treatments may alleviate some pain associated with the disease.
Note that Alimta is the correct brand name for pemetrexed. It is sometimes mispelled as Altima, Alitma, Amilta, and Atilma.
Feb 2007: Study: Combining Pemetrexed and Cisplatin Increases Patient Life Span
Mesothelioma patients were able to live nearly three months longer when treated with a combination of chemotherapy drugs, Cisplatin and Pemetrexed.
The large multi-center study involving 448 patients in Europe, Australia, Asia, and the Americas was published earlier this month.
Two groups were set up with the first receiving pemetrexed and cisplatin (with folic acid and b12 to counter some side effects) while the second received cisplatin alone. Members of the first group lived an average of 2.8 months longer while also reporting reductions in overall pain and side effects.
The study led by researchers at the Clatterbridge Center for Oncology in England, concluded that, “Pemetrexed used in combination with cisplatin significantly increases the length of survival, when compared with cisplatin alone.” They also stated that more information was needed before it becomes a treatment option for pleural mesothelioma patients.
Side effects included blood cell abnormalities, nausea and diarrhea, which decreased in both incidence and severity when the vitamins were added to the treatment.