Multimodal Therapy

Multimodal therapy, or multimodality therapy, is the combination of several cancer treatments (or modalities), including surgery, chemotherapy, and radiation. Multimodal therapy may also include certain experimental treatments. For mesothelioma patients, multimodal therapy has been clinically shown to possibly improve survival. While a single treatment may not be effective on its own, a combination of treatments may be more successful at destroying cancer cells. Multimodal treatment is considered one of the standard treatment options for stage II, III, and IV malignant mesothelioma and may be considered in stage I disease.

Treatment Components of Multimodal Therapy

Surgery

Surgery may be palliative or potentially curative, though options are limited for mesothelioma patients. Multimodality therapy including surgery has become a standard treatment of mesothelioma in patients with surgically removable tumors.

Radiation Therapy

Radiation is used in all stages of mesothelioma and can reduce symptoms and disease recurrence. As a multimodal therapy, intraoperative radiation is often used after a pleurectomy/decortication surgery.

Chemotherapy

The main chemotherapy treatment used in multimodal mesothelioma treatment is the combination of cisplatin and pemetrexed. Chemotherapy alone is only modestly effective in treating malignant pleural mesothelioma. However, adding a chemotherapeutic regimen to other treatment modalities, such as radiation therapy and surgery, improves survival.

Emerging and Experimental Treatments

There are a number of emerging and experimental treatments that are used in multimodal therapy. These are treatments that are currently being tested during clinical trials and include immunotherapy, gene therapy, photodynamic therapy, and more.

Trimodal Therapy

Malignant mesothelioma is difficult to completely remove with surgery alone. Because the tumor invades such sensitive structures as the diaphragm, esophagus, and heart, surgeons cannot remove a sufficient margin of healthy tissue around the tumor to make sure that all cancer cells have been removed. Therefore, additional cancer fighting treatments are needed.

Trimodal therapy for malignant pleural mesothelioma is the use of all three standard mesothelioma treatments—surgery, radiation therapy, chemotherapy—in some order. It is now widely accepted by oncologists and cancer researchers that more than one treatment modality is better than any single treatment for mesothelioma. A number of studies have shown that a trimodal approach provides the greatest benefit in terms of survival in select patients who can tolerate all three treatments. Indeed, most clinical practice guidelines for malignant pleural mesothelioma recommend trimodality therapy.

Given the relative rarity of malignant pleural mesothelioma, clinical practice guidelines also recommend that anyone undergoing trimodal therapy should be enrolled in a clinical trial whenever possible.

Choosing The Best Order of Treatment

While trimodal therapy is widely accepted as a standard treatment for malignant pleural mesothelioma, the order of treatments is a matter of debate.

Any of the treatment options can be what’s called the primary therapy, an adjuvant or a neoadjuvant therapy.

• Neoadjuvant Therapy — Any treatment given before primary therapy to improve results.
• Primary Therapy — Considered the most effective treatment option. This will most often be surgery.
• Adjuvant Therapy — Any treatment administered after primary therapy to alleviate symptoms and prevent cancer from returning.

In most cases, trimodal therapy will begin with chemotherapy followed by surgery (i.e., extrapleural pneumonectomy) and will finish with external beam, hemithoracic radiation therapy. Second most commonly, the patient first undergoes surgery followed by chemotherapy and radiation therapy. Less common approaches combine surgery with intracavitary chemotherapy followed later by radiation therapy. In some trimodal treatment combinations, hemithoracic radiation is replaced with intensity-modulated radiation therapy (IMRT).

Survival Rates

There is no clearly superior order of treatments in trimodality therapy. When surgery comes first, median survival ranges from 17 months to 28 months, and 39% to 81% of patients complete all three phases of treatment. When chemotherapy is administered before surgery, median survival ranges from 14 to 25.5 months and 32% to 69% of patients fully complete trimodal therapy.

Recent clinical trials have focused on pleurectomy with decortication in trimodality therapy. This surgical approach is associated with fewer complications than extrapleural pneumonectomy and, perhaps, better overall survival when incorporated in a trimodal therapy regimen. Moreover, 84% to 94% of patients were able to complete trimodal therapy when pleurectomy with decortication was used. One small clinical trial reported median survival of 30 months using this surgical approach. While the type of surgery used in trimodal therapy should be individualized to the patient’s circumstances, initial reports of a higher completion rate with pleurectomy and decortication are promising.

The course of therapy is different for each patient. A multidisciplinary team of cancer specialists decides on the best order of treatments based on patient preferences and circumstances.

Creating a Treatment Plan

Not everyone with malignant pleural mesothelioma is a candidate for multimodal therapy. Prior to this treatment, several diagnostic tests need to be run to determine a patient’s suitability for surgery, whether it is extrapleural pneumonectomy or pleurectomy with decortication. At a minimum, patients will undergo the following examinations:

• Physical examination – If other health problems are present, is the patient healthy enough to undergo major surgery?
• Pulmonary function testing – Will the patient have enough lung function in the remaining lobes of the lung after the diseased lung has been removed?
• Cardiac function testing – Does the patient have a strong enough heart to maintain blood pressure after some of the pulmonary blood vessels have been removed? Is the patient’s heart strong enough to undergo major surgery?
• Radiological studies – Radiological studies such as CT, MRI, and PET scans may be used to determine whether cancer cells have extended well beyond the affected lung to distant sites. If they have, trimodal therapy may not be successful.
• Histological examination – Patients do better if their mesothelioma is of the epithelial type rather than sarcomatoid. Because of the aggressive nature of sarcomatoid mesothelioma, doctors may decide not to use multimodal therapy. A third cancer cell type called biphasic mesothelioma has both epithelial and sarcomatoid cells. The prognosis for biphasic mesothelioma is not as good as epithelial mesothelioma, but multimodal therapy can still proceed with this cancer type.

Surgery for Mesothelioma After Radiation Therapy (SMART)

Surgery for Mesothelioma After Radiation Therapy or SMART is a multimodal treatment approach for malignant pleural mesothelioma.

Treatments Used in SMART

In SMART, the affected lung receives radiation (IMRT) just prior to an extrapleural pneumonectomy (EPP).

Intensity-modulated radiation therapy (IMRT)

The dose of radiation used in SMART is very high; the dose of ionizing radiation is high enough to be considered lethal for the lung and would be lethal for the patient if the lung was not removed soon after radiation treatment. Radiation is given on an accelerated schedule, where patients receive radiation treatment in five daily fractions over the period of one week. Lastly, radiation is directed at the largest portion of the tumor mass using IMRT, rather than hemithoracic external beam radiation. This targeted approach allows the patient to tolerate much higher doses of radiation.

Extrapleural Pneumonectomy (EPP)

One week after the last IMRT session, surgeons perform extrapleural pneumonectomy. If the disease has spread to the lymph nodes on the same side of the affected lung (but not the opposite side), chemotherapy is also administered after surgery.

Benefits of SMART

While the study included only a small number of patients, the initial results of SMART have been impressive. Sixty-five percent of people with epithelial mesothelioma treated with SMART had progression-free survival after three years and 84% survived overall. These reported survival rates are substantially better—about two times higher—than survival with other multimodality treatment approaches.