Trial Adds Gemcitabine to Pleural Mesothelioma HIOC Therapy

Results of a phase I clinical trial highlight how the addition of a drug to an existing treatment option appears safe and may improve outcomes in certain patients with malignant pleural mesothelioma (MPM).

The primary goal of the trial was to determine the maximum tolerated dose of gemcitabine added to cisplatin when these drugs are delivered together as heated intraoperative chemotherapy (HIOC) during surgery.

Researchers have studied cisplatin alone for HIOC. The addition of gemcitabine — a chemotherapy drug often used to treat pancreatic, ovarian and breast cancers — is new.

The Journal of Thoracic Oncology published the results May 9.

“We continue to advocate a personalized approach to surgery for MPM based on the surgeon’s assessment,” the authors wrote. “The results of our trial should be considered in the context of the variability in multimodality treatment programs for MPM at centers around the world.”

Dual Therapy for Malignant Pleural Mesothelioma

Standard treatment options for people diagnosed with malignant pleural mesothelioma include surgery, radiation therapy and chemotherapy.

One non-standard treatment option for pleural mesothelioma is the combination of macroscopic complete resection (MCR) and heated chemotherapy delivered directly into the area around the tumor:

• Macroscopic Complete Resection: This surgery completely removes all visible tumor.

• Heated Intraoperative Chemotherapy: This procedure places heated chemotherapy into the chest cavity during surgery, in direct contact with the cancer cells.

Trial Included EPP and P/D Surgeries

Based on each patient’s fitness and the possibility for MCR, the surgeon determined which surgery was most appropriate for each person. Patients were not randomized by surgery.

Surgical options included:

• Extrapleural Pneumonectomy (EPP): Removal of the affected lung, a portion of the diaphragm, nearby lymph nodes and the lining of the lungs and heart.

• Pleurectomy and Decortication (P/D): Surgery to remove the lining of the lung and all visible tumors while leaving the affected lung in place.

EPP is a more aggressive treatment, so only the healthiest patients were selected by their surgeon to receive this surgery.

This option typically is offered for patients with early stage pleural mesothelioma, when the cancer is confined to the chest cavity. This allows for the maximum amount of cancerous tissue to be removed.

An EPP usually helps ease breathing difficulties, which can improve quality of life.

Because EPP is an aggressive surgery and comes with higher risk of complications, some doctors prefer the P/D procedure on all mesothelioma patients, regardless of disease stage.

Ninety percent of patients undergoing P/D experience reduced symptoms after surgery.

Tolerated Dose of Gemcitabine

From 2007 to 2011, 141 patients were enrolled in the clinical trial and 104 completed treatment.

Fifty-nine patients underwent EPP and 41 received P/D surgery.

The maximum tolerated dose (MTD) for cisplatin — when combined with gemcitabine — was slightly lower than when cisplatin is given alone as HIOC.

When combined with cisplatin, the MTD for gemcitabine was 1,000 mg/m2.

All patients received cytoprotective treatment, which are medications to protect healthy cells. These drugs were administered during chemotherapy.

Two percent of patients died during surgery. The most common serious adverse events were acute respiratory distress syndrome (3.8 percent), atrial fibrillation (4.8 percent), shortness of breath (7.8 percent ) and deep venous thrombosis (2.9 percent).

The authors noted these are expected side effects in a small portion of patients and can be managed appropriately.

Kidney failure is associated with cisplatin therapy. This was the dose-limiting toxicity that led to the reduced cisplatin dose when combined with gemcitabine for HIOC.

Consider Survival Results Carefully

Compared with a previous clinical trial of cisplatin-only HIOC, patients in this study survived longer.

The authors cautioned more research is needed to draw firm conclusions on the risks and benefits of dual-drug HIOC.

“Whereas this is an encouraging result, these data should be interpreted with caution, however, as comparisons of these cohorts is likely confounded by group imbalances of patients with low risk profiles, who are most likely to respond favorably to HIOC,” the authors wrote.

This trial met the goal of determining safety and feasibility of using cisplatin and gemcitabine together for HIOC.

Investigators also strongly encouraged a personalized approach to surgery.

For some patients, more aggressive surgeries offer higher risk with little evidence of significant benefit compared to less aggressive options.

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