Pemetrexed in Malignant Pleural Mesothelioma

Malignant pleural mesothelioma (MPM) is a rare, aggressive malignancy that has been linked with exposure to one or more types of asbestos fibers. Asbestos exposure is associated with 70% to 80% of all cases of mesothelioma; 60% of these cases are directly related to occupation and 20% are paraoccupational.[ 1] Because of the relationship to occupational exposure, mesothelioma is seen predominately in males (5:1), as they are more likely to be employed in occupations that have an increased exposure to asbestos. Asbestos fibers all have unique physical, chemical, and biological properties and are divided into two major groups. The serpentine group of asbestos fibers includes the crysotile fibers, and the amphibole group of fibers includes crocidolite, amosite, anthophyllite, and tremolite fibers.[2] The carcinogenic effects of asbestos appear to be related to its physical properties,[3] and crocidolite is the most oncogenic type of asbestos fiber.[ 2] The long needlelike amphibole fibers appear to lodge in the distal respiratory system more readily than short fibers[4]; after inhalation, fibers that remain tend to accumulate in the lower third of the lungs adjacent to the visceral pleura.[1] The latency period from time of asbestos exposure to onset of malignant mesothelioma is long, and may be 30 to 40 years.[5] In the United States, the first ban on the use of asbestos was in 1971. Because of the long latency period, incidence was expected to peak at 2,300 cases per year around 2000.[6] In Europe, where the elimination of the use of asbestos did not occur as quickly as in the United States, there will be an estimated 250,000 deaths from mesothelioma in the next 30 to 35 years,[7] and the peak incidence is expected to occur in 2020. There is some evidence that suggests that genetics, radiation, and viruses may interact with environmental carcinogens, such as asbestos, causing malignancy.[5] Malignant mesothelioma arises from the surface serosal cells of the pleural, peritoneal, and pericardial cavities.[8] Of the three morphologic types of pleural mesothelioma, epithelial is the most common morphologic type and is seen in 60% of cases, mixed or biphasic types occurs in 30% of cases and the sarcomatoid type occurs in 10% of cases. Sarcomatoid tumors have a poorer differentiation phenotype and are associated with a poorer prognosis than epithelial or mixed tumors.[5] The most common symptoms at presentation are dyspnea and/or chest pain. Patients commonly have large unilateral pleural effusions on chest x-ray, and over 50% of patients have pleural calcifications on computerized tomography (CT) scan and often coalescing nodules and plaques on visceral and parietal pleura are seen. Mesothelioma can involve the chest wall, pericardium, interlobar fissures and diaphragm, as well as the pleura. The prognosis for patients with mesothelioma is dismal due to limited therapeutic options; few drugs have demonstrated activity in this tumor. Numerous agents, as monotherapy and combination therapy, have been studied in patients with malignant pleural mesothelioma, with no drug or regimen emerging as the clear standard of care. In these studies, anthracyclines, platinum compounds, alkylating agents, topoisomerase agents, antimicrotubule agents, platinum agents, and antimetabolites have demonstrated activity in this tumor. Response rates in these studies were generally below 15%, with a few exceptions. The antimetabolites, as single agents, consistently produced response rates of 15% to 20%. Of all the antimetabolites, the antifolates have produced the highest response rates as single agents in the treatment of malignant mesothelioma. Numerous combination regimens have also been investigated. Combinations with a platinum agent and an antimetabolite have produced response rates of 16% to 45%.[9-15] The antifolates appear to be the most active class of agents investigated in the treatment of MPM to date. Trials investigating the efficacy of trimetrexate(Drug information on trimetrexate), edatrexate, raltitrexed (Tomudex) and methotrexate(Drug information on methotrexate) have demonstrated activity, with response rates up to 40%. Table 1 shows studies of antifolates in mesothelioma.[16-19] Several ongoing clinical trials are evaluating the activity of newer agents including gemcitabine(Drug information on gemcitabine) (Gemzar), pemetrexed(Drug information on pemetrexed) (Alimta), ranpirnase, raltitrexed/ oxaliplatin(Drug information on oxaliplatin) (Eloxatin) combination, and anti-EGFR agents such as gefitinib(Drug information on gefitinib) (Iressa) and erlotinib (OSI- 774, Tarceva). Of these, pemetrexed seems to be the most promising drug. In addition, data suggest that gemcitabine is active in patients with MPM. Pemetrexed has been studied in three trials in patients with MPM, and two phase I trials included patients with MPM. In a phase II trial, pemetrexed was studied as a single agent in patients with MPM. This study included more than 60 MPM patients; nearly 60% of patients in this trial received full vitamin supplementation and 30% of patients received partial or no vitamin supplementation.[20] Phase II Single-Agent Pemetrexed Trial in MPM Distribution of patient characteristics was well balanced between the two groups (supplemented and nonsupplemented patients); most patients had advanced disease, good performance status (Karnofsky performance status of 80 to 100), and an epithelial histologic subtype of MPM.[21] The response and survival data are shown in Table 2. Because it can be difficult to obtain objective tumor measurements in MPM, two determinations of best response were performed on each patient: one by the investigator and one by an external expert panel. The investigator-assessed response rate was as 14.1% in all patients. Supplemented patients had higher response rates than nonsupplemented patients-16.3% compared with 9.5%, respectively. Survival was longer in supplemented patients than nonsupplemented patients. Median survival was 13 and 8 months, median time to disease progression was 4.8 and 3 months, and 1-year survival was 54.2% and 34.2% in supplemented and nonsupplemented patients, respectively. For the entire patient population, the 1-year survival of 47.8% and median survival of 10.7 months seems promising, despite the fact that this was a phase II study. Randomized Phase III Study of Pemetrexed/Cisplatin vs Cisplatin(Drug information on cisplatin) A randomized phase III study of pemetrexed/cisplatin vs cisplatin was conducted in patients with MPM. Patients were randomly assigned to receive pemetrexed at 500 mg/m² followed by cisplatin at 75 mg/m² on day 1, every 21 days, or cisplatin at 75 mg/ m² on day 1, every 21 days. Patients were stratified according to pain level, analgesic consumption, and dyspnea at study entry, treatment center and country, degree of disease measurability, performance status, gender, histologic subtype, baseline white blood cell count, and baseline homocysteine levels. During the course of the study, three treatment- related deaths were noted in the first 43 patients. Other studies of pemetrexed demonstrated that severe toxicities may be linked to high levels of homocysteine and methymalonic acid. A large multivariate analysis suggested that such toxicity and possibly some deaths may be related to reduced folic acid(Drug information on folic acid) and vitamin B₁₂ pools. The protocol was amended in December 1999, requiring folic acid and vitamin B₁₂ supplementation for all patients receiving pemetrexed. As a result of this change, this study had three patient populations: patients who were enrolled in the study prior to the protocol amendment and never received vitamin supplementation; partially supplemented patients who were enrolled at the time this change was made and received vitamin supplementation after the protocol was amended; and fully supplemented patients who received vitamin supplementation from the time of study enrollment. The sample size of the study was increased to ensure adequate statistical power of the fully supplemented group of patients. Of the patients enrolled, 70 patients never received vitamin supplementation, 47 patients were partially supplemented, and 331 patients were fully supplemented. The primary objective of this trial was survival; secondary objectives included time to progressive disease, time to treatment failure, tumor response rate, duration of response, pulmonary function testing, lung density analysis, and quality-oflife outcomes. Patient Characteristics
Patient characteristics were well balanced between the two arms: pemetrexed/ cisplatin (n = 226) vs singleagent cisplatin (n = 222). Nearly 70% of patients had an epithelial tumor type, approximately 10% had the sarcomatoid type, and 16% of patients had a mixed type in both groups. In each arm the majority of patients, almost 80%, had stage III or IV disease. Over 80% of patients enrolled had a Karnofsky performance status of at least 80. The median number of cycles of therapy received depended on whether or not patients received vitamin supplementation. In patients who were never supplemented, a median of only two cycles of therapy could be administered. In fully supplemented patients, the median number of cycles of therapy increased to six in the combination arm and four in the cisplatin arm. Supplemented patient were well balanced between the arms: pemetrexed/cisplatin (n = 168) vs single- agent cisplatin (n = 163). Toxicity
Differences in hematologic toxicity were significant between the two arms of the study. Patients who received pemetrexed/cisplatin experienced more anemia, leukopenia, neutropenia, and thrombocytopenia than did patients who received single- agent cisplatin. The incidence of febrile neutropenia was l.8% in the pemetrexed/cisplatin arm, and no febrile neutropenia was reported in the single-agent cisplatin arm. Among nonhematologic toxicities, nausea, vomiting, fatigue, diarrhea, dehydration, and stomatitis were significantly higher in the pemetrexed/cisplatin arm than in the single-agent cisplatin arm. Comparing the toxicities seen in patients who received pemetrexed/cisplatin with and without vitamin supplementation revealed that patients who received vitamin supplementation from the start of the study experienced less toxicity than those who received partial or no vitamin supplementation. The incidence of grades 3/4 neutropenia decreased from 38% to 23%, anemia 9% to 4%, and thrombocytopenia 9% to 5%, respectively, in nonsupplemented and fully supplemented patients. Efficacy
Figure 1 illustrates a CT scan of a study patient prior to treatment with pemetrexed/cisplatin and at visit 4. These graphically illustrate a clear response associated with pemetrexed/ cisplatin. Overall, the tumor response rate was significantly higher on the pemetrexed/cisplatin arm (41.3%) than in the patients who received cisplatin (16.7%). Differences in response rates were also significant between fully supplemented patients who received pemetrexed/cisplatin compared with those who received cisplatin (45.5% vs 19.6%, respectively). Table 3 contains efficacy data for all patients and for fully supplemented patients. Survival between the pemetrexed/ cisplatin and cisplatin arms was also statistically significant, 12.1 vs 9.3 months, respectively. Time to disease progression was 5.7 months in patients who received pemetrexed/ cisplatin vs 3.9 months in patients who received cisplatin monotherapy. This difference was also statistically significant.[ 22] An analysis of this phase III study was conducted by Symanowsi et al,[23] on prognostic variables affecting survival. Vitamin supplementation, good Karnofsky performance ptatus, early-stage disease, and epithelial subtype were associated with improved survival. This analysis demonstrated that Karnofsky status, disease stage, and histology were powerful predictors of survival in patients with MPM.[23] Another analysis of this trial included evaluation of lung function and its correlation to tumor response.[24] Patients who experienced a tumor response had consistently better pulmonary function tests than did patients with stable disease; patients with stable disease had better pulmonary function tests than those with progressive disease. Figure 2 shows changes in forced vital capacity of patients on the pemetrexed/cisplatin and cisplatin single-agent arms of the study over six cycles of therapy. Quality-of-life data in this study demonstrated an advantage for the combination of pemetrexed/cisplatin over single-agent cisplatin.[25] Using the LCSS-Meso instrument, global quality of life, pain, dyspnea, fatigue, anorexia, and cough were compared between the two arms. The majority of these parameters reached statistical significance between the two arms by week 15, in favor of the pemetrexed/cisplatin arm (Figure 3). Manegold and colleagues identified the incidence of post study chemotherapy among patients in this trial and determined that 38% of patients who received pemetrexed/cisplatin received post study chemotherapy compared with 48% of patients who received cisplatin monotherapy. The most commonly identified second-line therapy was gemcitabine followed by vinorelbine and doxorubicin(Drug information on doxorubicin).[26] A phase III trial of pemetrexed plus best supportive care (BSC) vs BSC as second- line therapy in patients with MPM is ongoing. Discussion Many agents have been investigated in the treatment of MPM with no clear standard of care emerging. The antifolate class of agents shows the most promise of the agents investigated in the treatment of this aggressive disease. Recent data have demonstrated that pemetrexed, as a single agent and in combination with cisplatin, is an active agent with manageable toxicity when folic acid and vitamin B₁₂ supplementation is administered concurrently. Pemetrexed has demonstrated efficacy with toxicity that is manageable with the addition of vitamin supplementation. The combination of pemetrexed/cisplatin significantly improved the survival in comparison to cisplatin alone. Other analyses demonstrated significantly improved lung function and quality of life in patients who received pemetrexed/cisplatin compared with patients who received cisplatin monotherapy. Supplementation with vitamins demonstrated an improvement in toxicity and efficacy.