Julia Draznin Maltzman, M.D
The Abramson Cancer Center of the University of Pennsylvania
Ultima Vez Modificado: 8 de febrero del 2003
On February 5th, 2004, the US Food and Drug Administration (FDA) approved a new drug called pemetrexed disodium (Alimta, Eli Lilly) for the treatment of a rare cancer called mesothelioma.
Mesothelioma is a cancer of the mesothelium, a thin membrane that covers and protects most of the body's internal organs. The most common site for this disease is in the mesothelium that surrounds the lungs (most commonly called the pleura). However, abdominal mesotheliomas are not uncommon and arise from the mesothelial tissue that covers most of the organs in the abdominal cavity. This type of cancer is usually associated with a history of asbestos exposure and afflicts about 2,000 people every year. Unfortunately, by the time symptoms appear, the disease is usually very advanced and cure is not ordinarily possible. Diagnosing mesothelioma is often difficult because the symptoms are so non-specific. Diagnosis is usually made by a physical exam, x-rays or a CT scan, and a biopsy.
Treatment for mesothelioma depends, to a large extent, on its location and the patients' general health and well being. Generally, surgical removal of the tumor is the first option if it can be safely removed. During surgery, the doctor may remove part of the mesothelium. In the case of lung mesothelioma, at times, lung tissue may need to be removed during the operation. Other options may include radiation therapy and chemotherapy. Up until recently, cisplatin was the chemotherapy drug of choice.
Chemotherapy has not had tremendous success in the treatment of mesothelioma. Many clinical trials using single agent chemotherapeutics reported short-term regression and symptomatic improvement in 15-20 percent of patients. Median survival remained nine months. In a 2003 meta-analysis of almost all phase II chemotherapy trials for this disease, proved cisplatin to be the "best" single agent. Recent reports noted that many anti-folate chemotherapeutics had good response rates, but the toxicity was too great. For example, methotrexate had a 37% response rate. However, 58% grade 4 toxicities were noted including one treatment related death.
Anti-folate chemotherapy works by interfering with normal cellular metabolic pathways including those necessary for making new DNA. Recently, newer anti-folates have received more attention in mesothelioma. Pemetrexed was approved for use in combination with cisplatin. In clinical trials, patients given the combination of these two drugs had a prolongation of survival by three months over those who took cisplatin alone.
In a phase III, blinded trial, dubbed the EMPHACIS trial, 456 patients were randomly assigned to cisplatin with either pemetrexed or saline placebo once every three weeks. The median survival was significantly better for combined therapy – 12.1 versus 9.3 months. Time to tumor progression also favored the combination arm – 5.7 versus 3.9 months. Most impressively, the objective response rate was 41% for the combination therapy and 17% for cisplatin alone. All these differences were most pronounced in patients taking folic acid and vitamin B12 supplementations during the course of chemotherapy. Treatment related toxicity was significantly less if supplementation was given, and more cycles of chemotherapy could be administered.
In addition to showing a survival benefit, the combination of pemetrexed and cisplatin was also associated with an improvement in the quality of life. In a report analyzing these secondary endpoints, the differences between the two groups was obvious by the first three cycles and was statistically significant by week 15 of treatments. All aspects analyzed were better in the combination arm – pain, shortness of breath, fatigue, anorexia, cough, and global quality of life.Imprima English
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