Mesothelioma is an asbestos-caused cancer of the lining that surrounds many of the body’s vital organs. Pleural mesothelioma is the most common form of the disease and is diagnosed in 2000-3000 people every year. Peritoneal mesothelioma is the next most common form of the disease, but it is relatively rare and is diagnosed in only a few hundred cases per year. Because of this situation, detailed clinical trials and other treatment-related studies are difficult to perform and no standard of care yet exists for peritoneal mesothelioma.

Chemotherapy with pemetrexed is the standard of care for the treatment of pleural mesothelioma and many of the studies investigating effective therapies for peritoneal mesothelioma have incorporated pemetrexed into their treatment plans as well. An article was recently published in the Journal of Clinical Oncology that describes an open-label, multicenter study of the use pemetrexed in combination with gemcitabine for the treatment of peritoneal mesothelioma. This was the first study to investigate combination chemotherapy using these two chemo agents and the initial results, while limited, do show some efficacy for the treatment of peritoneal mesothelioma.

Overview of the Study

In order to evaluate the therapeutic efficacy of pemetrexed in combination with gemcitabine, the researchers enrolled 20 patients with histologically-proven peritoneal mesothelioma into their study. As is the case with most diagnoses of mesothelioma, the majority of patients were Caucasian men and epithelial mesothelioma was the most common histological sub-type of the disease. Enrollment criteria included good performance status (0-2), adequate organ function, and a malignancy not currently eligible for curative surgery. While some patients had previously undergone some form of cytoreductive surgery, patients were excluded from the study if they received prior systemic chemotherapy or radiotherapy to the target area, or they presented with evidence or suspicion of metastatic spread to the brain.

The study design indicated at least six chemotherapy cycles, with each cycle defined in 21-day increments. On Day 1 of the cycle, 1250mg/m² of gemcitabine would be delivered intravenously for 30 minutes. On Day 8, 500mg/m² of pemetrexed would be delivered over IV for 10 minutes, immediately followed by another IV administration of gemcitabine at the same dose as before. Because of previously reported toxicities related to pemetrexed delivery, a number of supplements were also given to patients. Folic acid was orally administered a week or two prior to beginning pemetrexed and was then given daily for the remainder of the patient’s enrollment in the study. Vitamin B12 was delivered by injection 1 or 2 weeks prior to beginning the first cycle and then subsequently delivered every 9 weeks the patient stayed enrolled. Dexamethasone was given one day before pemetrexed and was continued for three days per cycle.

Adjustments to the study design in terms of dose reductions and/or cycle delays could be made in response to individual patient treatment effects, but patients who received dose reductions would not be eligible for subsequent dose escalations and any patients whose cycle delay exceeded the cycle-length of 21 days were removed from the study. Physicians were able to add additional cycles if patients could tolerate them, or were able to remove patients from the study for other treatment effects as well. Any patient who demonstrated progressive disease during intracycle assessment was also removed from the study.

The principal endpoint of the study was determining tumor response rate, with secondary end points identified as disease control rate, overall survival, time to progression and response duration.

Results

10 patients completed the treatment course, while 10 others did not complete the study. 1 patient died in response to the chemotherapy, 5 were removed due to severe toxicity-related treatment effects, 3 patients experienced progressive disease during treatment and 1 patient dropped out of the study for “personal reasons.” 15 patients (75%) completed four chemotherapy cycles, while 12 patients (60%) completed at least six cycles.

The primary endpoint of the study was the determination of overall tumor response and even though not every patient completed the treatment plan, all were included in the determination of overall response rate. No patient experienced a complete response to the treatment, while 3 experienced a partial response and 7 others achieved stable disease (for a time). This leaves a tumor response rate of 15%. Disease control rate, a summation of all patients who achieved a partial response or stable disease, was a much higher 50%. 5 patients could not be fully evaluated for tumor response, either because of early removal from the study or because response data could not be independently-validated, so when these patients were excluded from the results, tumor response rate rose to 20% and disease control rate rose to 67%.

Median survival for the patient cohort was 26.8 months, with a one-year survival rate of 67.5% and a median time to progression of 10.4 months. The two-year survival figure was reported at 50%.

Treatment-related side effects were experienced by a number of patients, with neutropenia and fatigue the most commonly experienced effects. Neutropenia is a serious condition where the body has an abnormally low level of neutrophils, which are a type of blood white cell responsible for fighting infections in the body. 12 patients experienced grade 3 neutropenia and eight experienced grade 4 neutropenia. These figures are significantly higher than some of the earlier studies featuring pemetrexed and cisplatin, which reported neutropenia rates at under 5%.

Conclusion

The authors conclude their article by stating that the combination of pemetrexed and gemcitabine shows clear activity in the treatment of peritoneal mesothelioma and they call for more research into the use of this therapy for patients with peritoneal disease. While objective response rate was low, their statistics demonstrated an overall survival time of 26.8 months, which is longer than some of the figures reported in studies of pemetrexed and cisplatin combination therapy. However, they also state that treatment-related side effects were higher in this patient cohort than in previously-reported on cohorts, and they suggest that future studies should look to a reduction in gemcitabine dosage levels to counter these toxic events.

Studies of peritoneal mesothelioma are few and far between, so this article represents an important addition our knowledge of this rare form of mesothelioma. For patients who are diagnosed with peritoneal mesothelioma and who are not eligible for multimodal treatment plans involving significant cytoreductive surgery, combination chemotherapy using pemetrexed and gemcitabine may be an important new avenue of treatment.

Labels: mesothelioma, peritonealmesothelioma, treatments