Although a number of studies have shown that multimodal approaches to the treatment of mesothelioma have achieved some measure of local disease control, there is still controversy surrounding a number of issues, including which protocols are the most effective, which patients are the most likely to benefit from therapy and just how effective any of these treatments are when it comes to overall survivability. The relative rarity of pleural mesothelioma and peritoneal mesothelioma in the general population has slowed the development of new treatment protocols because the small sample sizes of many mesothelioma research programs often limit the scope of the conclusions that can reasonably be drawn from the results. Thankfully, though, research into innovative therapies continues to be conducted and slowly, but surely, physicians are learning more about the disease’s behavior patterns and the various ways in which it responds to treatments.

Of the various multimodal treatments that have been proposed, trimodality therapy—where some form of radical surgery is combined with adjuvant or neoadjuvant chemotherapy and radiation—has been shown in a number of studies to be the most effective protocol in local control of disease spread. However, questions have been raised regarding its true effectiveness in sustaining survival. To answer this question, physicians from a number of hospitals in Istanbul, Turkey conducted a study on the efficacy of trimodality treatments and recently published their results in the Journal of Thoracic Oncology. The study definitively found a survival benefit to the treatment, for some patients at least, and in the article the authors describe the patient profile for those who may respond well to therapy and for those who are unlikely to demonstrate a signifcant response.

Overview of the Study

The authors treated 37 patients for mesothelioma between 2003 and 2007. All patients were examined using chest and upper abdomen CT, thoracic MRI and those treated after 2004 also received PET scans. Cardiac and pulmonary function tests were routinely performed. For those selected for the study, the surgical protocol stipulated extrapleural pneumonectomy (EPP) with the pleura, lung, diaphragm and pericardium totally removed. Tissue samples from the EPP were then examined at 20 different sites for evidence of malignancy. If each site examined was negative for malignant tissue beyond the identified surgical margins, the surgery was deemed a microscopic complete resection. Otherwise, it was considered a macroscopic complete resection with microscopic positive margins.

Four to six weeks after surgery, the treatment protocol stipulated adjuvant radiation of the affected hemithorax, i.e., the side of the chest in which the surgery was performed, as well as for the incision points and the sites of the chest drain. The radiation was delivered in 1.8 Gy fractions until a total dose of 54 Gy was received. Some patients with residual disease received an extra 9 Gy of radiation.

The final section of the protocol stipulated adjuvant chemotherapy using a cisplatin-based treatment regimen. This was to be delivered four to six weeks after the cessation of radiation. For patients treated between 2003 and 2005, cisplatin was used along with gemcitabine. For those patients who were treated after 2005, pemetrexed (see Alimta Therapy) replaced gemcitabine.

Results

Of the 37 patients treated for mesothelioma, 20 were selected for inclusion into the authors’ trimodality treatment study. There were 12 males and 8 females, with 11 patients presenting with right-side disease and 9 patients presenting with left-side disease. Histological analysis revealed 17 patients with the epithelial subtype of the disease, two patients with the biphasic subtype and one with sarcomatous mesothelioma. The median age for the cohort was 56 years-old.

Of the 20 patients selected, 16 received the EPP, with four disqualied due to more extreme tumor invasion or lung weakness. Of these sixteen patients, 8 received a right-sided EPP and 8 a left-sided EPP. One patient died in the hospital and eleven others suffered some treatment morbidity. Only 12 of the 16 patients who received an EPP received the radiation and chemotherapy portions of the protocol. The radiation was well-tolerated overall, as was the chemotherapy portion. With the chemotherapy regimen, a number of patients experienced significant nausea and vomiting at the beginning of treatment, but this was eventually controlled through the use of ondansetron, an antiemetric agent used for control of these symptoms.

The authors report an overall median survival figure of 17.2 months. For the 16 patients who underwent an EPP, this figure rose to 19.6 months and to 23.9 months for the 12 who completed the full trimodal protocol. When the authors examined their findings for patients who demonstrated extrapleural lymph node involvement, they found that 8 were positive for it and their median survival figure dropped to 13.3 months. The 13 patients without extrapleural nodal involvement demonstrated a median survival figure of 23.9 months. These patients had a three year survival figure of 56%.

Conclusion

The authors conclude their article by stating that trimodality therapy is definitely an effective treatment protocol for pleural mesothelioma patients who present without extrapleural lymph node involvement, but its use for these latter patients is still questionable. To better make this differentiation, they call for the development of more effective staging methods. The protocol can be difficult to tolerate and it does take a significant time to complete, but for those who can benefit from it and who can tolerate it, trimodal therapy seems to represent a real breakthrough in the effectiveness of mesothelioma treatments.

Labels: mesothelioma