Drug combination extends survival in mesothelioma

First therapy to make a difference

July 14, 2003

Patients with cancer of the lining of the lung, known as pleural mesothelioma, live longer and have less pain and shortness of breath when treated with a combination of cisplatin plus a newer drug called pemetrexed than if they received cisplatin alone according to a Phase III study published in the July 15, 2003, issue of the Journal of Clinical Oncology.

This study--presented in part at a plenary session at last year's meeting of the American Society for Clinical Oncology (ASCO)--is the first to show a benefit for this type of cancer.

"For the first time we have a therapy for mesothelioma that makes a difference," said study director Nicholas J. Vogelzang, MD, Fred C. Buffett Professor of Medicine and director of the University of Chicago Cancer Research Center. "This is a real step forward. It should encourage patients to keep trying and inspire physicians to focus more attention on this frustrating disease."

"This trial establishes pemetrexed and cisplatin as a new standard in systemic therapy for mesothelioma," noted Valerie Rusch, MD, of Memorial Sloan-Kettering Cancer Center in New York, in an editorial in the Journal. "It is now reasonable to state that effective chemotherapy exists for MPM [malignant pleural mesothelioma], dispelling the profound sense of nihilism surrounding treatment of this disease."

Mesothelioma patients who were treated with pemetrexed (trade named Alimta®) plus the commonly used chemotherapy drug cisplatin lived for about a year after diagnosis, nearly three months longer than did patients who received only cisplatin. Consequently, one-year survival after diagnosis increased from 41.9 percent for patients receiving cisplatin to 56.5 percent for those receiving cisplatin plus pemetrexed.

The two-drug combination caused the cancer to shrink in 41 percent of patients, compared to 17 percent of patients who received only cisplatin, and was more effective at reducing pain and shortness of breath, symptoms commonly experienced by patients with pleural mesothelioma.

Pleural mesothelioma is a rare and lethal form of cancer that occurs in the mesothelium, a thin layer of specialized cells that lines the lungs. Most cases are caused by asbestos exposure. In the United States there are about 2,500 new cases a year. Because the disease is often advanced at the time of diagnosis, average survival for those with pleural mesothelioma has been significantly less than one year.

Pemetrexed is a cousin of one of the earliest chemotherapy drugs, methotrexate, used for the treatment of other types of cancer. While methotrexate blocks one enzyme necessary for cell division and tumor growth, pemetrexed blocks three such enzymes.

This Phase III randomized study was the largest mesothelioma trial ever conducted, involving 456 patients. Patients were selected at random to receive pemetrexed plus cisplatin or cisplatin alone.

In the course of the study, the researchers found that many of the patients were deficient in the vitamins folic acid and B12. The deficiencies, presumably caused by the cancer and a poor appetite, decreased the ability of normal cells to repair and produce new DNA. The vitamin-deficient patients who received pemetrexed were more likely to experience severe toxicity (such as very low white blood cell counts, severe diarrhea, and severe mouth ulcers) than patients who received only cisplatin.

Following this observation, all patients in the study received folic acid and vitamin B12 as a standard part of their treatment. This reduced the toxic side effects associated with pemetrexed, allowing more patients to benefit from the drug.

"Although the pemetrexed plus cisplatin chemotherapy regimen is a clear advance in the treatment of MPM," wrote Rusch, "it hardly represents a home run in this difficult disease." Future studies, she suggested, should focus on applying this regimen to patients with earlier stages of the disease and the addition of other anti-cancer agents or targeted therapies for patients with advanced disease.

Two such follow-up trials are already underway at the University of Chicago Hospitals. One is testing cisplatin plus pemetrexed, followed by surgery and radiation therapy, for patients whose disease has been diagnosed earlier and can potentially be cured by surgery and radiation alone. The addition of chemotherapy is designed to improve the cure rate, which currently hovers around 15percent with surgery and radiation. A second study combines pemetrexed with the chemotherapy agent gemcitabine, which replaces cisplatin.

This combination of pemetrexed and gemcitabine "is keeping me alive," reports Richard Shanas, a 55-year-old retired police officer from Chicago, diagnosed with mesothelioma in November of 2000. Shanas has an abdominal tumor, rather than lung disease. He entered a clinical trial of an investigational angiogenesis inhibitor but had to drop out when his tumor continued to grow. Since beginning treatment with pemetrexed and gemcitabine his tumor has shrunk by about one third.

The side effects of therapy are "moderate but unpredictable," said Shanas. He had a rash at the beginning but that went away. Now he tires easily, which has forced him to cut back on his work, and requires occasional blood transfusions, but reports that "on the whole, my quality of life is not bad."

The study was supported by a grant from Eli Lilly and Company, makers of Alimta.

The research team came from the University of Chicago Cancer Research Center; Eli Lilly and Company, Indianapolis, IN; US Oncology, Dallas, TX; Allgemeines Krankenhaus Harburg, Hamburg, Germany; Institut Gustave Roussy, Villejuif, France; Krankenhaus Großhansdorf, Großhansdorf, Germany; Royal Prince Alfred Hospital, Camperdown, Australia; Hacettepe University Medical Faculty, Ankara, Turkey; and Thoraxklinik-Rohrbach, Heidelberg, Germany.

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