The medical journal Current Treatment Options in Oncology has recently published a number of articles on the biology, diagnosis and treatment of mesothelioma. In a report published last week, we covered their article, “Diagnosis, Staging, and Surgical Treatment of Malignant Pleural Mesothelioma,” which provided an overview of the diagnostic procedures used to identify the disease, the system that has been developed to analyze the disease’s stage in an individual patient and an introduction to the surgical procedures that are used to treat pleural mesothelioma. Surgical invention is one of the key elements in the multimodal treatment of the disease, but many patients are not eligible for radical surgery because their diagnosis only came after the disease had progressed to an advanced stage. For these patients, chemotherapy represents their best chance to extend survival. In recognition of its importance to overall mesothelioma treatment, Current Treatment Options has also published an article describing the current use of chemotherapy in the treatment of the disease.

“Systemic Treatments for Mesothelioma: Standard and Novel” provides an historical overview of the chemotherapy treatments deployed before the introduction of pemetrexed, as well as a description of the current use of pemetrexed and an overview of other avenues in contemporary mesothelioma research. The article closes with a discussion of novel therapeutic agents that have been proposed for mesothelioma treatment.

Cytotoxic Chemotherapy Before Pemetrexed

The article begins with reference to a report published in the Journal of Clinical Oncology from 1988 entitled “Malignant Mesothelioma, a disease unaffected by current therapeutic maneuvers,” which noted that chemotherapy, like every other then-current cancer treatment, was simply not effective for management of the disease. Since that time, however, much has changed for the better. Even though the disease is still without a cure, current treatments have definitely led to improvements in both median survival time and symptom management.

Before the introduction of pemetrexed in 2004 a number of different chemotherapy drugs had tried–and failed—to treat mesothelioma. Anthracyclines, such as doxorubicin, were once hailed as a promising new therapeutic avenue for the disease, but subsequent radiological analysis showed limited response rates to these agents. Even though a number of these drugs were also tried, they only offered limited value at disease control.

Along with the use of single-agent treatment regimens, combination therapies were also used, but they, too, demonstrated limited efficacy. A meta analysis was then conducted on the different chemotherapy clinical trials performed between 1965 and 2001 and this showed that the platinum agent cisplatin was the most active single drug for mesothelioma treatment. Because of this, cisplatin became the focus of a number of new treatment regimens. Along with it, other platinum agents, such as carboplatin and oxaliplatin, were also investigated for their efficacy in mesothelioma treatment.

The Antifolates

Antifolates are the most active class of chemotherapy agents that have been used to treat mesothelioma. These drugs inhibit the ability of cells to metabolize folate (folic acid), which is an essential ingredient in the process of DNA replication. Thus, an antifolate's fundamental mechanism of action is disrupting a tumor’s ability to continue to replicate. Methotrexate is one of the most common antifolates deployed for cancer treatment and studies that investigated its use for mesothelioma showed a higher response rate (37%) and a longer median survival (11 months) than many of the previous mesothelioma trials had shown. These results gave great hope to mesothelioma physicians, but it was with the introduction of pemetrexed that chemotherapy turned a corner in its effectiveness for mesothelioma treatment.

The FDA approved pemetrexed in 2004 after the largest clinical trial that had ever been conducted on a mesothelioma treatment showed clear advantages to combination therapy using pemetrexed and cisplatin than the use of cisplatin alone. Not only did this study achieve one of the highest response rates (41%) and the longest median survival time (12.1 months) when compared to other trials, study participants also reported significant increases in symptom control and quality of life issues. The combination of cisplatin and pemetrexed is now the world-wide chemotherapy standard of care for pleural mesothelioma and the investigations into its activity for peritoneal mesothelioma are also promising. In some cases, cisplatin may be replaced with carboplatin, which has demonstrated similar—though slightly less effective—response rates to cisplatin, but is associated with a less severe toxicity profile. Because of this, weak patients are sometimes given carboplatin in place of cisplatin.

Even as pemetrexed has achieved “standard of care” status, the article notes that a number of questions regarding its use remain unanswered. One of the most important of these questions has to do with onset of treatment: is it better to begin treatment at time of diagnosis, at the onset or progression of symptoms or at signs of radiological disease progression? For patients who are diagnosed in the disease’s later stages, this question is not applicable because symptoms have usually become quite difficult at that time, but for patients who are diagnosed in its early stages and with the epithelial subtype of the disease—which is associated with the best prognosis—this question is still opened. Physicians are waiting for the results of a large trial before they can answer this question with any certainty.

Another question the article brings up revolves around the optimum length of treatment: four to eight cycles of combination therapy are typically given to patients, but many people are not able to tolerate more cycles, so the question of the long-term management of the disease with chemotherapy remains open. There is some indication that pemetrexed can be given as a single agent after the full combination course has been completed, but, again, physicians are waiting for trial results before any definitive answers are given.

Another antifolate that has shown some activity in the treatment of mesothelioma is raltitrexed. It has not yet matched pemetrexed’s efficacy when combined with a platinum agent, but some research is still being conducted on this agent.

Other Active Cytotoxic Agents

Gemcitabine and vinorelbine are two other chemotherapy agents that have demonstrated some activity in the treatment of mesothelioma. Studies investigating gemcitabine in both single-agent regimens and in combination regimens with cisplatin, carboplatin and oxaliplatin have shown a wide variety of response rates. Prior studies on pemetrexed and gemcitabine have not found any synergistic effect in their combination, but they have shown increased toxicity profiles. However, investigations of this regimen do continue.

Vinorelbine is a chemotherapy drug in the class of drugs known as vinca alkaloid agents. While other vinca alkaloids have not shown much activity for mesothelioma, studies involving vinorelbine have shown some of the highest response rates besides pemetrexed. A number of recent studies have reported promising indications for its use in both first-line and second-line therapy and larger scale studies investigating its overall efficacy are currently being planned.

Novel Agents

Investigations into the biological substrates of mesothelioma genesis have identified a number of proteins that may be overexpressed by the disease. In identifying these elements, the studies opened up the possibility that highly targeted treatment agents could possibly be developed that would inhibit the growth of the malignancy at a cellular level. Some of the areas targeted for therapy include EGFR, PDGF and VEGF. Initial studies on agents targeted at these growth factors have not shown much clinical efficacy to the treatments under investigation, but the agents are still quite new and many physicians still believe that the more we understand the molecular composition of mesothelioma, the more effective our treatments of it will become.

A number of other agents besides the ones mentioned in this article are also under investigation, although definitive results for many of these studies will not be available for years. Even as the disease’s still-poor response rate to most treatments is frustrating when seen against the background of great successes that have been achieved in the management of other cancers, the number of studies under active investigation for mesothelioma is an indication that treatments are improving and that hope for the development of future treatments is well-placed.

Labels: chemotherapy, mesothelioma, treatments