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Researchers are studying whether chemotherapy before surgery and radiation can deter tumor recurrence in patients with mesothelioma, a rare cancer of the lining of the chest caused by asbestos exposure.

The study builds on the success of a previous clinical trial at M. D. Anderson that included surgery called extra pleural pneumonectomy (EPP), which involves removal of the affected lung and lining of the chest, followed by a highly specialized form of radiation therapy known as Intensity Modulated Radiotherapy (IMRT).

The new multi-center study, which will recruit 77 patients nationwide, will involve EPP, post-operative IMRT and the chemotherapy drugs pemetrexed (Alimta®) and cisplatin, says Katherine Pisters, M.D., principal investigator on the study at M. D. Anderson and associate professor in the Department of Thoracic/Head and Neck Medical Oncology.

The other trial locations are:

Memorial Sloan-Kettering Cancer Center, New York
University of Chicago, Chicago
Johns Hopkins Hospital, Baltimore
Barbara Ann Karmanos Cancer Institute, Detroit
University of Pennsylvania, Philadelphia
Brigham and Women's University, Boston
Many of the sites already have begun studying the use of chemotherapy prior to surgery and radiation. The chemotherapy combination of pemetrexed and cisplatin was approved by the Food and Drug Administration (FDA) for treatment of mesothelioma after the drugs were shown to prolong survival.

Answering questions about both studies are Pisters, Craig Stevens, M.D., Ph.D., principal investigator on the previous M. D. Anderson trial and associate professor in the Division of Radiation Oncology; and David Rice, M.D., surgical principal investigator on the new study and assistant professor in the Department of Thoracic and Cardiovascular Surgery.

What is unique about this study?

Pisters: This is the first mesothelioma trial to explore the use of chemotherapy before surgery and radiation.

How does the new trial build on the previous study?

Stevens: Our previous trial involving extrapleural pneumonectomy and IMRT was more than 90% effective in preventing a local recurrence (return of the cancer to its original site). However, 50% of those patients experienced recurrence in a different location, usually the other lung, abdomen or another part of the body. M. D. Anderson will be the only center employing IMRT rather than conventional radiation therapy.

Pisters: We are now adding chemotherapy before surgery and radiation to decrease the possibility of distant cancer metastasis (spread to an area away from the original site). We are using pemetrexed and cisplatin because they already have been shown to be effective in metastatic disease.

How has this chemotherapy been found effective?

Stevens: Pemetrexed and cisplatin were shown to prolong survival by three months in mesothelioma patients with advanced disease (when the drugs were taken together, compared to if cisplatin was taken alone).

What does each component of the trial involve?

Stevens:

Pemetrexed (Alimta®) and cisplatin - Chemotherapy drugs given before surgery.

Extrapleural pneumonectomy (EPP) - Surgery to remove the lung, lining of the chest, diaphragm and pericardium, which is the sac that contains the heart. The diaphragm and pericardium are reconstructed with prosthetic material.

Intensity Modulated Radiotherapy (IMRT) - High-precision radiation that delivers multiple beams of radiation to tumors or areas within a tumor. This technique can deliver radiation to very irregularly-shaped targets, like those found after EPP. Other centers involved in this study will use more conventional forms of radiation.

What are the benefits of this surgery?

Rice: The only thing that has ever been shown to lead to any long-term survival has been extrapleural pneumonectomy followed by some form of post-operative treatment, usually radiation alone or a combination of chemotherapy and radiation.

Why is it necessary to remove the lung and other organs?

Rice: Mesothelioma starts in the parietal pleura (the lining of the inner chest wall and lining that covers the diaphragm) and grows into the visceral pleura (lining that covers the lung). It is almost impossible to separate the visceral pleura from the lung in order to remove the cancer, so the lung must be removed. In addition, mesothelioma frequently invades the lung tissue, so for complete removal of the tumor, the lung must be removed.

The tumor usually abuts the diaphragm and pericardium, so to completely remove all of the cancer we have to remove those structures. Then we reconstruct the diaphragm and the pericardium. It is a big operation and takes anywhere from four to six hours. Patients undergo the operation only after careful pre-operative evaluation that involves surgical staging (minor surgical procedures to determine the extent of the disease), as well as careful testing of lung and heart function. The staging done in the first trial was important because it eliminated 12% of the patients who were ineligible for surgery due to advanced disease.

Stevens: The other reason to remove the lung and diaphragm is to prevent breathing motion of the radiation targets. Accounting for such motion is very difficult. Accounting for the motion incorrectly will lead to more tumor recurrence.

What is life like for people with one lung?

Rice: It is very difficult to predict. Most people have a mild to moderate degree of shortness of breath (also one of the symptoms of the disease before surgery.) Because the surgery involves a very large incision and we occasionally have to take portions of the ribs out, many patients have a fair amount of pain immediately after surgery. But we are usually able to control it well with pain medication.

Sometimes, particularly with patients who have excruciating pain related to the tumor growing through the chest wall, if we can get that tumor out, the pain does improve. Paradoxically, some patients seem to breathe even better after we remove their affected lung. The reason for this is probably relief of tumor compression on the lung and the associated restriction of chest wall movement.

What was the survival rate in the previous trial?

Stevens: Out of 55 patients, we had only one infield failure (cancer returning within an area that received radiation). Most of our patients are more than two years out from treatment. In comparison, most patients without radiation have an 80% fail rate within nine months. With more "conventional" radiation approaches, about one of three patients fail in the irradiated regions.

How was IMRT able to be as precise as it was in the previous trial?

Stevens: During EPP, the surgeon implants titanium clips in the chest to mark the areas where mesothelioma tumors are located. We can see the clips on X-ray and can then pinpoint where the cancer was and irradiate that area with IMRT. The clips are critical, and the way the diaphragm is reconstructed is really important. The diaphragm is reconstructed with Gore-Tex®, a material that we can see on X-ray that allows us to better tailor the radiation beam to that patient. During surgery the (reconstructed) diaphragm is pulled tight so that the abdominal contents are pushed as far out of the radiation field as possible.

How many cases of mesothelioma will be treated in the United States this year?

Rice: There are expected to be approximately 3,500 cases, but that number will increase and peak in the next several years because of asbestos controls in the 1970s and the 20- to 40-year period between the time asbestos exposure begins and mesothelioma develops. It also is not clear how large amounts of asbestos released during the World Trade Center disaster will impact future mesothelioma incidences.

Although we have an estimation of the number of people who will be diagnosed with mesothelioma, it is not known exactly how many of those patients will be actually treated because there is probably a large number of patients with mesothelioma who are misdiagnosed as having metastatic adenocarcinoma (another form of cancer).

In addition, there is generally a nihilistic attitude about this disease in the medical community, and it is likely that many patients are not referred to centers where potentially curative treatment may be given.

Although we are far from having a cure for all patients with mesothelioma, the recent development of more effective chemotherapeutic agents, radical surgery and advanced radiotherapeutic modalities now at least offers a glimmer of hope to patients suffering from this devastating disease.

For more information about the new mesothelioma study at M. D. Anderson involving pemetrexed and cisplatin, EPP and IMRT, contact research nurses Li Ling Hwang or Jean Riddle in the Department of Thoracic/Head and Neck Medical Oncology at (713) 792-6363.

Courtesy of Cancer Wise