Research on Malignant Mesothelioma on Upswing

NEW YORK—"In 2002 there is a lot of activity in mesothelioma research," Nicholas J. Vogelzang, director, University of Chicago Cancer Research Center, said at a media briefing on malignant mesothelioma, sponsored by the American College of Preventive Medicine. "This was an orphan disease for many years." Roman Perez-Soler, MD, of Albert Einstein College of Medicine, added: "We’re moving from empiricism to rational therapies."

Said Dr. Vogelzang: "Many people did not believe that chemotherapy worked," Today, he said, new active drugs are having modest but real effects. 

The only potential cure remains extrapleural pneumonectomy. With this operation, which removes the lung, diaphragm, and pericardial sac, 5-year survival is about 15%, Dr. Perez-Soler said. Without it, no one survives, Dr. Vogelzang said. Most cases are advanced at diagnosis, he added, and not surgically treatable. "Radiation therapy can be used," he said, "but rarely eliminates the cancer. It can prevent the cancer from spreading outside the chest wall, and this is primarily what it’s used for."

Given the site of malignant mesothelioma in the pleura and visceral walls, one rational approach would be intra-cavity drug administration, Dr. Perez-Soler said. Several agents, including L-NDDP (a liposomal formulation of a cisplatin analog), developed in his laboratory, have been tried this way with good results. Most patients, however, he said, "are not eligible for this because when they present, the tumor is too thick, and the penetration of the drug from inside the cavity into the wall is suboptimal." The same is true for photodynamic therapy.

The most promising systemic chemotherapeutics, Dr. Perez-Soler said, are the antifolates, anthracyclines, and platinums. In trials of antifolates such as methotrexate, he noted, 18% of patients had significant tumor reductions. Dr. Perez-Soler called Eli Lilly’s investigational agent pemetrexed "a better methotrexate" because it targets three key enzymes in the cancer pathway rather than two.

Responses to the anthracycline doxorubicin averaged 12% and to cisplatin (Platinol), 13%. Taxanes and camptothecins have not proven effective, Dr. Perez-Soler said. With cisplatin-based combinations, the response rate is about 20%. An Australian trial of cisplatin-gemcitabine (Gemzar) using different criteria than in US studies recorded a 47% positive response rate, he noted, and a median survival of 9.5 months.

Dr. Vogelzang and his colleagues have defined six categories of the disease based on patient characteristics. In the group with the poorest prognosis, median survival is 1.4 months; in the group with the best prognosis, it is 13.9 months.

About 2,500 cases are diagnosed annually in the United States, Dr. Vogelzang said, and about 5,000 in western Europe. "There are hot pockets in Australia," he added. Rates will rise in India, Turkey, some Middle Eastern countries, and Eastern Europe, he predicted, because of increased asbestos importation. "The incidence peaked in about 2000 in the US and will peak in about 2018 in western Europe," he said, "if we believe that asbestos exposure is the only cause. That remains to be seen."

First described as a pathologic entity about 1870, malignant mesothelioma was not causally linked to asbestos exposure until the 1960s, Dr. Vogelzang noted. Onset occurs 20 to 40 years after asbestos exposure, he indicated, and median age at diagnosis is 60. The disease affects three times as many men as women, he added. "The current belief," he said, "is that about 80% of mesothelioma can be clearly ascribed to asbestos exposure."

A hint that some cases have a genetic basis comes from documentation of multigenerational cases in Turkey. Even after migration to Europe, nearly half of family descendants developed the disease. Another possibility is a viral link. The virus SV-40 binds p53 and causes rapid development of the disease in hamsters, he said. SV-40-like sequences are found in about 60% of human mesotheliomas.

This viral fingerprint may be useful in developing targeted drugs. Excitement is building, Dr. Perez-Soler said, about molecularly targeted agents such as anti-EGFR and anti-VEGF inhibitors. "We don’t believe one of these alone will do the trick," he said, "but maybe several of these together will be able to hit several targets at the same time and accomplish a significant response."