Recent Innovations:
Despite overall improvement in survival with multimodality therapy, a cure is still elusive. Novel treatment strategies being developed for this locally aggressive tumor include intracavitary chemotherapy, photodynamic therapy, immunotherapy, gene therapy, brachytherapy and alternative medicine.
Alimta
Intracavitary Chemotherapy
Photodynamic Therapy
Immunotherapy
Brachytherapy
Intensity-Modulated Radiation Therapy (IMRT)
Alternative Medicine
In February 2004, the U.S. Food and Drug Administration (FDA) approved a new drug called Alimta® that offers new hope for victims of mesothelioma. Doctors have found that patients using Alimta® along with the anti-cancer drug cisplatin experienced measurable improvement in their symptoms, including less pain and shortness of breath. Trials also indicate that patients who use this treatment may live up to 30% longer. Alimta can provide a new hope for patients with advanced mesothelioma where surgery is not an option.
Alimta must be administered with vitamin B-12 and folic acid supplementation to decrease the incidence and severity of adverse effects.
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Chemotherapy, radiation or surgery alone is generally ineffective in treating mesothelioma. Combination approaches (multimodality therapy) utilizing these three treatments have shown promise in extending survival of some patients with early disease. However, the tumor occasionally recurs in the same area it was removed and/or in the abdomen.
Intracavitary chemotherapy is a novel chemotherapeutic approach that has been well studied in both thoracic and abdominal cancers. Chemotherapeutic agents (cisplatin) administered directly into the body cavities (chest and/or abdomen) can be administered at much higher doses than if administered systemically (through the bloodstream). The agent may directly enter the tumor cells by diffusion without the toxic effects of high dose systemic intravenous chemotherapy. Heating the chemotherapy (hyperthermia) seems to increase the killing effect of the chemotherapy.
The strategy of intracavitary, heated chemotherapy is one of surgery to the remove the tumor to the microscopic level, then, while still in the operating room under anesthesia (intraoperatively), administer chemotherapy into the chest and abdominal cavity, directly contacting any surfaces that harbor any tumor cells left behind and killing these cells. To protect healthy cells, a ‘cytoprotective’ agent is administered intravenously while the patients is still in the operating room.
Earlier Phase I studies at the Brigham and Women’s Hospital have demonstrated that it is feasible to administer intraoperative, intracavitary, heated cisplatin with a cytoprotective agent and to deliver high doses of cisplatin in this manner. Although these early studies were not designed to evaluate efficacy, the results for patient survival and time to relapse were very encouraging. Phase II evaluation of this therapy has been completed.
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Photodynamic therapy (PDT) uses a combination of a photoactive drug (a drug that is activated by light) and light from a laser. Both work by targeting and destroying cancer cells while limiting damage to surrounding healthy tissue. Light therapy starts with an injection of a non-toxic photosensitizer drug. The drug goes into all cells of the body, but normal cells excrete it in about two days. Timing is crucial, because the tumor cells need to be exposed to the laser light after the drug has left the healthy cells but before the drug has left the mesothelioma cells. The laser light will activate the drug present within those cells and destroy them.
The role, if any, for PDT in the treatment of mesothelioma has yet to be established. Because of the limited depth of the absorption of the light, treatment via PDT is limited to superficial areas but may be ideally suited to the treatment of mesothelioma following surgical resection. Limited centers have applied PDT intraoperatively after surgical resection; however, the number of patients treated in the different trials is small, and no definitive conclusions can be drawn. Most reports are Phase I and II studies. The final outcome of these studies with respect to survival is of limited value. The only phase III study, which was performed with an earlier generation photosensitizer, reported no advantage to the use of PDT in combination with surgery and immunochemotherapy.
To date, the most that can be said is that intraoperative PDT with newer generation photosensitizers can be performed safely in experienced centers, and that there are some encouraging results, especially in patients with stages I and II MPM.
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Immunotherapy, also called biological therapy, biotherapy, or biological response modifier (BRM) therapy, .is a treatment that is designed to stimulate the body’s own natural immune defenses to halt the spread of cancer. Research has found that the immune system is capable of recognizing and eliminating cancer cells under some circumstances. The problem with cancers like mesothelioma is that the body does not recognize these tumor cells as abnormal.
Immunotherapy uses BRMs to improve the body's natural ability to fight disease. BRMs, include interferons, interleukins, tumor necrosis factors, monoclonal antibodies and cancer vaccines. Some BRMs occur naturally in the human body, and others can be produced synthetically in the lab. They appear to alter the relationship that the body has with mesothelioma cells, causing the body to recognize them as hostile. The result is an ‘immune response’ where the body will now attack the mesothelioma cells and suppress the processes that allow the cancer to grow. Immunotherapy is also aimed at blocking the process that mesothelioma uses to change a normal cell into a cancer cell; this may even reverse the process. It is also hoped that BRMs can stop the spread of mesothelioma to other sites in the body, preventing its further growth.
Preliminary studies have shown significant shrinkage of mesothelioma tumors at very early stages of the disease. Much more research, however, is necessary to determine its efficacy as a treatment for malignant mesothelioma. A combined immunotherapeutic and chemotherapeutic approach has been evaluated in Phase I and Phase II trials in mesothelioma patients but has failed to demonstrate any convincing effect on survival or relapse rate.
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Brachytherapy is the use of radioactive substances to deliver radiation treatments. The term "brachy" comes from the Greek word for short range. This therapy is contrasted to that given as external beam radiation over a long range.
Since the radioactive substances that are used in these treatments are only effective in the short range, they need to be placed in or very near the target. Hence, for mesothelioma, brachytherapy can be used as an "Intraoperative Radiation Therapy" (IORT). The team of Thoracic Surgeon and Radiation Oncologist are able to measure regions of the chest cavity that have not been able to undergo a full oncologic removal of the mesothelioma with at least one centimeter clear margin. A customized radioactive implant can be made by weaving radioactive seeds into a flexible absorbable mesh. This can then be stitched into place. With coordination, this does not add to the overall operative time. The radiation from a radioactive iodine seed implant is delivered over about three months with some residual radioactivity present for about a year. At present there are no prospective data to support this. A few centers are reviewing their clinical experience retrospectively. More data will be available within the following year.
Memorial Sloan Kettering Cancer Center reported the use of High Dose Rate IORT for patients undergoing either an extrapleural pneumonectomy or pleurectomy decortication for mesothelioma on a prospective study. This study was closed early when it was found that the extra time needed to complete this intraoperative therapy, often in excess of two hours, was correlated with a high level of complications
The current practice at the Brigham and Women’s Hospital is to consider all patients for IORT brachytherapy with an Iodine radioactive implant. Intraoperatively, the margins are assessed by frozen section and if positive or unclear, an implant is given. Various centers in the USA and Europe continue to use IORT with a portable electron beam linear accelerator for various tumors including mesothelioma.
CT scan based dosimetry The mesh in stitched over
evaluation shows isodose the affected area.
lines for the implant to allow
the Radiation Oncologist to
assess success of implant.
Front and back view of the Radioactive iodine seeds in
surgical clips hold the suture vicryl suture are stitched
in place. into vicryl mesh cut and
marked out for the correct
size of implant.
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Gene Therapy is a technique for correcting defective genes responsible for disease development. It involves replacing, removing, inserting, or altering genes in order to prevent or treat a disease. This can occur in several ways. Researchers can correct defective genes by adding normal genes to the genome (the total set of genes carried by the cell), replacing abnormal genes, selectively mutating abnormal genes, or by altering the degree to which a gene is turned ‘on’ or ‘off.’
A carrier called a ‘vector’ is used to deliver the therapeutic gene. The most common ‘vectors’ are viruses (there are also non-viral vectors), because they already have the unique ability to get into the cell. Viral vectors are altered so they do not create new viruses in the cell, but just deliver their cargo, the new gene. Viruses are very effective at targeting specific cells.
For several years now, scientists in many labs in several countries have been looking for ‘suicide genes’ that would attack cancer cells, leaving normal cells untouched. A viral vector would introduce cells to a ‘suicide’ gene to rapidly dividing cells to raise intracellular protein levels associated with this gene. An inactive drug would then be administered to the cancer patient. The protein created by the suicide gene would convert the drug to its active form, which in turn would kill the cell. Since only tumor cells expressed the gene/protein, only tumor cells would be targeted and killed. Gene therapy is a relatively new treatment approach, very much in the experimental stages, and requires participation in a clinical trial to access.
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Intensity-modulated radiation therapy (IMRT) is a novel breakthrough in radiation oncology. It allows treatment of areas that were previously out of the reach of conventional radiation. IMRT for mesothelioma is available @ BWH one of the few sites in the country where this technique has been perfected. It requires a treatment team composed of radiation oncologist physicists and radiation therapists to deliver. The state of the art machinery available here @ BWH represents the top-of the line in radiation delivery equipment. Preliminary data indicates significant improvements in local recurrences for mesothelioma patients undergoing this treatment.
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Alternative medicine is defined as therapeutic practices, which are not currently considered an integral part of conventional medical practice. Therapies are termed as Complementary when used in addition to conventional treatments and as Alternative when used instead of conventional treatment. Alternative therapies include, but are not limited to the following disciplines: folk medicine, herbal medicine, diet fads, homeopathy, faith healing, new age healing, chiropractic, acupuncture, naturopathy, massage, and music therapy.
Some treatments that are considered alternative can help alleviate some of the symptoms of mesothelioma. Many cancer patients, including those who suffer from mesothelioma, find alternative methods soothing, as they focus not only on the physical ailment, but also on the spiritual, emotional and mental aspects of the disease. Many mesothelioma patients choose these remedies as a complement to their more conventional medical treatment. Many patients find the focus on the ‘well-being’ of the body as comforting.
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