Pemetrexed/Cisplatin Increases Survival in Pleural Mesothelioma

ORLANDO—Pemetrexed (Alimta) plus cisplatin (Platinol) with folic acid/vitamin B12 supplementation should be considered standard front-line therapy for patients with malignant pleural mesothelioma, Nicholas J. Vogelzang, MD, said at the plenary session of the 38th Annual Meeting of the American Society of Clinical Oncology (abstract 5).

Dr. Vogelzang, Fred C. Buffett Professor and director, University of Chicago Cancer Research Center, reported results of an international phase III study, the largest ever in the disease, showing significantly improved survival and improved symptom control with the combination, compared with cisplatin alone.

Malignant pleural mesothelioma is an aggressive cancer of the lining of the lung for which there is no approved or effective chemotherapy. It is associated with exposure to asbestos and occurs from 20 to 40 years after exposure. Pemetrexed is an experimental antifolate that targets three key enzymes necessary for DNA and RNA synthesis.

The study involved 574 patients who were not candidates for curative surgery and had received no prior chemotherapy. Of these, 456 patients were randomized to receive pemetrexed 500 mg/m² IV over 10 minutes followed 30 minutes later by cisplatin 75 mg/m², both given on day 1 of a 3-week cycle, or cisplatin alone. All patients received dexamethasone prophylaxis for skin rash. A total of 448 patients were eligible for analysis.

Early on in the study, the protocol was changed due to a high rate of severe toxicity and drug-related death in the pemetrexed arm. This was linked to folic acid deficiency as reflected by elevated homocysteine levels. The remaining patients received oral folic acid 350 to 1,000 µg daily and vitamin B12 1,000 µg intramuscularly every 9 weeks in addition to their assigned treatment.

Vitamin supplementation reduced toxicity, allowing fewer treatment interruptions. "The median number of cycles in the combination arm increased from 2 in the never-supplemented patients to 6 in the supplemented patients," Dr. Vogelzang said. "Interestingly, similar results were seen in the cisplatin arm."

The drug-related death rate in the combination arm declined from 7% to 3% after supplementation was instituted. Neutropenia fell from 41% to 23%; febrile neutropenia from 5% to 1%, and vomiting from 21% to 11%.

Study Results

With a minimum follow-up of 9 months in all patients, median overall survival was 12.1 months in the pemetrexed arm vs 9.3 months in the cisplatin-alone arm (P = .02). Time to progressive disease was 5.7 months vs 3.9 months, respectively (P = .001). Response rates were 41% vs 17% (P < .001).

The combination was also more effective at reducing pain and shortness of breath, symptoms commonly experienced by patients with mesothelioma. "Lung function, as measured by vital capacity, began to improve in the second cycle and continued to improve, compared with cisplatin alone, at subsequent follow-up times," Dr. Vogelzang said. "These differences were highly significant." This improvement in lung function was paralleled by improvements in dyspnea.

Likewise, pain declined in the combination arm after two cycles of therapy and remained significantly less in the pemetrexed/cisplatin arm throughout the trial.

Relevance to General Practice

The discussant for the paper, Valerie W. Rusch, MD, chief of thoracic surgery, Memorial Sloan-Kettering Cancer Center, praised the study design and noted that the results are relevant to general oncology practice. "The patients were not a select group of individuals but, rather, represented a patient population that is typical of what we see in day-to-day practice," she said.

She agreed with Dr. Vogelzang that the trial establishes pemetrexed and cisplatin as a new standard in systemic therapy for mesothelioma.

"It supersedes single-agent therapy and probably supersedes the recently popular regimen of gemcitabine [Gemzar] and cisplatin, a regimen associated with response rates ranging from 9% to 45% in several phase II trials," she said.

Dr. Rusch pointed out that "it would be reasonable to move this treatment regimen into earlier-stage disease as induction therapy for patients who have potentially resectable tumors." Future studies, she said, should focus on the addition of either other cytotoxic agents or one of the several targeted therapies currently being tested in phase II trials in this disease.