Mesothelioma is a rare malignancy arising from the mesothelial surfaces of the pleura, peritoneum, pericardium, or tunica vaginalis. There are roughly 2000 to 3000 new cases of mesothelioma annually in the United States.¹ Although the incidence of this disease peaked in the United States about a decade ago, its incidence in many other parts of the world continues to rise, particularly in regions without sufficient asbestos regulation.²

Even with aggressive multimodality therapy for seemingly localized disease, disease recurrence or progression occurs in the vast majority of cases. Effective systemic treatment options for mesothelioma are sorely needed. To date, there is only one agent—pemetrexed—that has received specific approval from the U.S. Food and Drug Administration (FDA) for the treatment of mesothelioma. The development of effective systemic therapies for patients with mesothelioma has faced several significant challenges.

The relatively low incidence of this cancer makes accrual to clinical trials—particularly large, randomized trials—challenging. In addition, the relative rarity of this cancer can dampen enthusiasm and limit funding from pharmaceutical companies and funding agencies. As a result, much of the clinical data in this disease consists of smaller, single-arm, investigator-initiated studies. Furthermore, comparisons of outcomes between these smaller studies are complicated by significant variability in staging systems among the trials, as well as by differences in the histologic composition of each trial, which consists of varying percentages of the three main histologic types of mesothelioma: epithelioid, sarcomatoid, and biphasic disease. Epithelioid histology consistently has been associated with a better prognosis. Therefore, differences in the histologic composition of each trial can confound useful comparisons between studies.

Another obstacle to determining treatment efficacy in mesothelioma is the assessment of tumor response: the applicability of standard Response Evaluation Criteria in Solid Tumors (RECIST) has been limited in mesothelioma, particularly with respect to serial assessments of the pleural rind. To address this problem, RECIST have been modified specifically for the assessment of mesothelioma (Table 117-1).³

Faced with these challenges and dissuaded by low response rates in early clinical trials of cytotoxic chemotherapy in mesothelioma, drug development in this disease had slowed. More recently, though, the clinical success of agents like pemetrexed and the preclinical activity of novel targeted agents have helped to spur a number of promising clinical trials and have offered a renewed sense of hope for patients suffering from this disease.

For patients with unresectable mesothelioma, combination with cisplatin plus pemetrexed is the standard first-line therapy and remains the only FDA-labeled treatment option in this disease. Though both cisplatin and antifolate agents were long known to have activity in this disease, the efficacy of this combination in mesothelioma was not demonstrated until 2003.

Cisplatin, an alkylating agent first described in 1845,⁴ is an integral component of combination chemotherapy regimens in many cancer types. A meta-analysis of clinical trials reported between 1965 and 2001 highlights the activity of cisplatin in mesothelioma.⁵ When used as a single agent, though, activity is modest. Experiences in other cancers had shown that cisplatin is best used in combination with other agents.

Antifolates were also long known to have some efficacy against mesothelioma. This class of agents was among the first chemotherapy agents to show activity in mesothelioma. Administration of high-dose methotrexate (3 g/m² every 10–21 days) with leucovorin rescue was associated with response in 22 of 60 patients evaluable for response (37%), with a median survival of 11 months.

The development of the multitargeted antifolate pemetrexed in the late 1990s and early 2000s would ultimately establish a new standard for systemic therapy in mesothelioma. This agent inhibits several key enzymes in purine and pyrimidine synthesis: thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. In a large phase III trial, patients with previously untreated mesothelioma were randomized to receive cisplatin plus pemetrexed or cisplatin alone.⁶ The addition of pemetrexed was associated with improvements in response (41.3% vs. 16.7%, p < 0.0001), median time to progression (TTP) (5.7 vs. 3.9 months, p = 0.001), and median overall survival (OS) (12.1 vs. 9.3 months, p = 0.02). The combination of cisplatin plus pemetrexed was generally well tolerated. Although there were three patient deaths in the combination therapy arm that were considered to be treatment-related, all occurred in patients who had not received supplementation with folic acid and vitamin B₁₂ . There were no deaths in the vitamin-supplemented group. The most common grade 3 or 4 toxicities in the fully supplemented group included neutropenia (23.2%), nausea (11.9%), vomiting (10.7%), and fatigue (10.1%).

From these results, the combination of cisplatin plus pemetrexed has become the standard first-line therapy in mesothelioma. The agents are delivered intravenously once every 21 days: cisplatin 75 mg/m² and pemetrexed 500 mg/m². Patients should receive supplementation with vitamin B₁₂ (1000 mcg intramuscularly starting 1 week before cycle 1 and then given every 9 weeks thereafter) and folic acid (400 mcg by mouth daily). In addition, patients also typically receive dexamethasone premedication (4 mg PO BID on the day before, day of, and day after chemotherapy) in order to prevent pemetrexed-associated rash. They also receive aggressive antiemetic therapy in light of the emetogenic potential of cisplatin. Restaging scans are recommended after every two to three cycles of treatment to monitor for progression. In the Vogelzang study, patients who tolerated therapy well and who achieved ongoing response or stable disease were continued on treatment. The median number of cycles of combination therapy received in that study was six (range 1–12), with only 7% of fully supplemented patients continuing on eight or more cycles of combination therapy.⁶ In practice, the optimum length of therapy has not been established, though extrapolation from other tumor types such as non–small-cell lung cancer has led many investigators to stop combination treatment after four to six cycles.

For those patients whose age, overall condition, and/or medical comorbidities preclude the use of combination therapy with cisplatin plus pemetrexed, treatment with pemetrexed plus carboplatin or with pemetrexed monotherapy could be considered. Although there has been no trial that directly compares pemetrexed-based combinations with cisplatin versus carboplatin, useful data are available from phase II trials as well as from the International Extended Access Program. In a phase II trial of carboplatin plus pemetrexed, 19 out of 102 patients achieved a response (18.6%, 95% CI 11.6%–27.5%), with 48 patients (47%) achieving stable disease.⁷ Median TTP was 6.5 months and median OS was 12.7 months, both comparable to the results seen with cisplatin plus pemetrexed in the Vogelzang study. In the Expanded Access Program, patients received carboplatin plus pemetrexed had a response rate of 21.7%, TTP of 6.9 months, and a 1-year survival of 64%.⁸

For those patients for whom combination chemotherapy with a platinum-based agent is deemed intolerable, pemetrexed monotherapy can be considered. A phase II study of pemetrexed monotherapy as well as data from the pemetrexed Expanded Access Program have provided insights into the activity of single-agent activity in mesothelioma. As a single agent, pemetrexed achieves response rates of about 10% to 12%, with median survivals of 10.7 to 14.1 months.^9,10

Pemetrexed Maintenance or Reinitiation

Just as the optimal duration of first-line therapy is not well established, the role of pemetrexed maintenance therapy is also an area of ongoing investigation. A small phase II study followed 27 patients with nonprogressing disease after six cycles of first-line therapy with a pemetrexed-containing combination. In this study, 13 patients received pemetrexed maintenance versus 14 who did not. Both TTP (8.5 vs. 3.4 months) and OS (17.9 vs. 6.0 months) favored those patients receiving pemetrexed maintenance. Furthermore, treatment was generally well tolerated, with fatigue (15%) as the only non-hematological grade 3 toxicity encountered. A randomized study of the role of maintenance therapy is currently ongoing.

For patients who had received a first-line regimen that did not contain pemetrexed, consideration should be given to pemetrexed as a second-line agent at the time of progression.^11,12 For patients whose disease recurs well after completing first-line therapy with a pemetrexed-containing combination and who had never progressed while on that therapy, physicians can consider reinitiating pemetrexed-based therapy. Though there is no specific trial exploring this indication, it is not unreasonable to return to pemetrexed, given the proven activity of the agent, the existing data for its use in the maintenance setting (see previous), and the general paucity of other commercially available systemic options in mesothelioma.

Other Cytotoxic Chemotherapeutics with Activity in Mesothelioma

Although there are no agents besides pemetrexed that have been specifically FDA-approved for the treatment of mesothelioma, there are existing, commercially available therapies with known activity in this tumor type. The two most commonly considered agents in patients who have progressed on pemetrexed-based therapy are vinorelbine and gemcitabine.

Vinorelbine

Vinorelbine, a semisynthetic vinca alkaloid, also has demonstrated activity against mesothelioma, alone or in combination. In a randomized trial, vinorelbine monotherapy had a response rate of 16% and demonstrated a trend toward improved median OS (9.5 months) compared with active symptom control alone (7.6 months) in previously untreated mesothelioma patients (HR 0.80, 95% CI 0.63%–1.02%; p = 0.08).¹³ Had the trial not suffered from poor accrual, it might have ultimately attained sufficient power to show a statistically significant benefit for vinorelbine over active symptom control alone. Other phase II trials of vinorelbine monotherapy in mesothelioma have shown similar response rates (16%–24%) and median OSs (9.6–10.6months).^14,15

Gemcitabine