The Emerging Role of Antifolates In The Treatment of Malignant Pleural Mesothelioma
February, 2002
Karim Fizazi [MEDLINE LOOKUP]
William J. John [MEDLINE LOOKUP]
Nicholas J. Vogelzang [MEDLINE LOOKUP]
SECTIONS
Clinicians have long regarded malignant pleural mesothelioma as a
chemoresistant neoplasm and as a result no standard chemotherapy
regimen has emerged. Antifolates such as methotrexate are among the
most active compounds in mesothelioma, albeit based only on phase II
data. Recently two antifolate-based combinations with apparently higher
efficacy than older regimens have emergedthe pemetrexed/cisplatin
regimen and the raltitrexed/oxaliplatin regimen. In two phase I trials
with pemetrexed combined with either cisplatin or carboplatin responses
occurred in five of 11 and nine of 29 patients, respectively. In a
phase I trial of raltitrexed/oxaliplatin, six of 17 patients (35%) with
mesothelioma achieved a partial response. In a phase II trial of
raltitrexed/oxaliplatin, 14 objective responses were confirmed in 72
patients (25%) with malignant pleural mesothelioma. Indeed, responses
were seen in cisplatin-refractory patients. Based on the promising
results from these combination trials, two large phase III studies have
begun. The first study was a multicenter, multinational trial sponsored
by Eli Lilly and Company, which randomized more than 430 patients with
malignant pleural mesothelioma to cisplatin with or without pemetrexed.
That trial completed enrollment in February 2001 and is the largest
trial ever conducted in mesothelioma. The second trial is being
conducted by the European Organization for the Research and Treatment
of Cancer (EORTC) and compares cisplatin with or without raltitrexed
with planned accrual of 240 patients. In both trials, survival is the
main endpoint. These trials will help to define the role of these new
antifolates in malignant pleural mesothelioma.
Semin Oncol 2977-81. Copyright © 2002 by W.B. Saunders
Company.
SIGNIFICANT THERAPEUTIC interest has focused on malignant pleural mesothelioma in recent years due to the increasing incidence in Western countries and due to its dismal survival rate.1,2 Most patients with malignant pleural mesothelioma have locally advanced disease at presentation. Therefore, attempts at local control with surgery are restricted to a few candidates for pleurectomy or extrapleural pneumonectomy. Likewise, radiotherapy is rarely an option, although short-duration radiation therapy delivered to thoracoscopy scars prevents malignant seeding.3 Many systemic therapeutic options have been developed in the past, yet no standard therapy has emerged.4-6 Most agents have shown little activity but even "active" agents have only shown response rates of 15% to 20%, with median survivals of only 7 to 9 months.4-6 Response assessment has been a concern, since bidimensional measurements are difficult to obtain. In spite of these concerns, some phase II reports have suggested that patients can expect a 40% to 50% clinical benefit with some drugs.7-9 In the early 1990s, combining chemotherapy and immunotherapy yielded promising response rates, but the toxicity of this approach has precluded phase III development.10 Therefore, most research efforts have focused on assessing the efficacy of new agents and new combinations. Although most chemotherapeutics have limited activity, for example, paclitaxel and irinotecan,11-13 other agents including the antifolates have been more promising. This review discusses the design and results of trials with the older and newer antifolates.
HISTORICAL PERSPECTIVE OF ANTIMETABOLITES IN MESOTHELIOMA BEFORE THE MID-1990s
Although the role of antimetabolites (including the antifolates) has been assessed in mesothelioma, reliable data on monotherapy are scarce due to the relative rarity of the disease and the difficulties in assessing objective responses. For example, data on 5-azacytidine are available in only six patients treated in two trials,14,15 while data on 5-dihydro-azacytidine (DHAC) alone and in combination with cisplatin are more reliable and suggest activity, including rare complete remissions.16-18
The activity of another antimetabolite, 5-fluorouracil (5-FU), has also been poorly assessed in three very small trials containing a total of 25 patients.19-21 Although five patients (20%) achieved a response to therapy (including four complete responses), only one partial response out of 20 was reported in the largest prospective trial reported to date.21 There have been a number of case reports describing long-lasting responses with single-agent 5-FU or 5-FUbased combinations.22-25 A single-center phase II trial assessed the cisplatin/5-FU combination plus etoposide and mitomycin C with a promising response rate of 38%.26 However, that regimen induced myelosupression requiring colony-stimulating factors and the results require confirmation. Therefore, it is difficult to assess the efficacy of 5-FU (a thymidylate synthase [TS] inhibitor) in malignant pleural mesothelioma based on the available literature. A multicenter trial of the oral fluoropyrimidine, capecitabine, has been completed within the Cancer and Leukemia Group B (CALGB) and final results are pending.
Three trials have assessed the activity of the oldest antifolate, methotrexate, in mesothelioma with response rates of 2/6, 4/9, and 22/60 (37%), respectively.27-29 This apparent efficacy of high-dose methotrexate plus leucovorin rescue did not lead to widespread use in malignant pleural mesothelioma. This technique is difficult to handle in adult patients whose median age is typically 70 years and in patients where pleural and peritoneal effusions complicate methotrexate pharmacokinetics.
Therefore, methotrexate analogs were developed and tested against mesothelioma. Dideazafolic acid (CB3717), a quinazoline antifolate which inhibits TS, was assessed in 17 patients with only one partial response.30 Further trials of this compound were suspended due to unpredictable nephrotoxicity.
The CALGB has followed up this promising lead by performing a series of clinical trials using various antifolates in mesothelioma. Trimetrexate was the first agent administered in 52 patients, treated sequentially at two doses (6 mg/m2 × 5 and 10 mg/m2 × 3 days every 21 days). It resulted in a low (but definite) response rate (12%) and a reasonable 2-year survival rate of 18%.31 The Food and Drug Administration (FDA) approved trimetrexate to treat Pneumoncystis carinii pneumonia. Surprisingly, further studies with trimetrexate in mesothelioma have not been initiated.
Edatrexate monotherapy (80 mg/m2 intravenously weekly) yielded five responders in 20 patients (25%). However, this regimen was associated with a high incidence of serious side effects, including two lethal neutropenic fevers. The combination of edatrexate with leucovorin was better tolerated, although the response rate was only 16%, thus raising the question of an adverse role of leucovorin on the efficacy of edatrexate.32 Since edatrexate is unlikely to be FDA-approved, newer antifolates and TS inhibitors continue to be developed.
Recently, reproducible efficacy has been reported by several groups using the combination of new-generation TS inhibitors (either pemetrexed or raltitrexed) and platinating agents (oxaliplatin, cisplatin, or carboplatin).
Pemetrexed/cisplatin
Pemetrexed (Alimta, LY231514, Eli Lilly and Company, Indianapolis, IN), a recently developed antifolate/antimetabolite,33 has shown promising activity in malignant pleural mesothelioma alone or in combination with cisplatin or carboplatin. Pemetrexed is an antifolate that inhibits several folate-dependent enzymes including TS, dihydrofolate reductase (DHFR), and GAR formyl transferase (GARFT). Given at a dose of 500 mg/m2 intravenously every 3 weeks, pemetrexed has a broad range of antineoplastic activity in lung, colon, pancreas, and breast cancers.34-36
In a phase I trial of pemetrexed combined with cisplatin, five of 11 patients (45%) with malignant pleural mesothelioma had a confirmed response.37 Based on these results, a randomized phase III trial of cisplatin (75 mg/m2) plus pemetrexed (500 mg/m2) every 3 weeks was compared to cisplatin monotherapy. This trial (called EMPHACISEvaluation of Mesothelioma in a Phase III Study of Alimta with Cisplatin) has reached the accrual goal of 430. This trial, the largest phase III trial ever conducted in malignant pleural mesothelioma, is currently undergoing analysis.
Another phase I study has combined pemetrexed with carboplatin in malignant pleural mesothelioma. The maximum tolerated dose of pemetrexed was 500 mg/m2 with a carboplatin area under the curve (AUC) of 5.0. Among 29 enrolled patients, nine (31%) achieved a partial response and symptomatic improvement was documented in 14 (48%). The median survival duration was 13.6 months.38 Finally, a phase II trial of single-agent pemetrexed (500 mg/m2) has recently completed accrual of 62 patients. Nine responses (14.5%) were observed and the median survival was 10.7 months.39
Because of sporadic and unpredictable episodes of neutropenia, diarrhea, stomatitis, and thrombocytopenia seen in early pemetrexed trials, Niyikiza et al analyzed toxicity as a function of baseline homocysteine levels.40They reasoned that the toxicity could be related to low baseline folate levels (a hypothesis which could be tested since homocysteine levels, reflecting folate, were measured in most patients on the phase II trials). Multivariate analysis found that high homocysteine levels (reflecting low folic acid levels/intake) and low albumin levels were most predictive of toxicity.40 B12 and folate supplementation was then added to subsequent pemetrexed trials and found to significantly reduce pemetrexed toxicity.41
Raltitrexed/oxaliplatin
TS catalyses the conversion of uracil monophosphate to thymidylate and is the only source of thymidylate for DNA replication. Several folate analogs, including the first antifolate TS inhibitor, CB3717, have been developed as TS inhibitors.42 The Cancer Research Campaign Center for Cancer Therapeutics modified CB3717, leading to raltitrexed.43 Raltitrexed is now approved in Australia, Canada, and Europe for the treatment of metastatic colorectal cancer.44
From 1997 to 1999, the Institut Gustave Roussy conducted a phase I trial of raltitrexed and oxaliplatin in advanced solid neoplasms.45 This study was intended to develop an alternative to 5-FU/oxaliplatin in colorectal cancer, with 5-FU being replaced by raltitrexed, a TS inhibitor given on a once-every-3-week schedule. Patients with orphan neoplasms, including those with refractory mesothelioma, were enrolled into the study. After the first two patients with cisplatin-refractory mesothelioma obtained a partial response and significant clinical benefit, the trial was opened to patients with chemonaive malignant pleural mesothelioma.10 Overall, six of 17 (35%) patients with mesothelioma achieved a partial response (35%), including four cisplatin-pretreated patients, whereas four other patients had a short-lived response that was not confirmed by a computed tomography scan 4 weeks later. Responses were reviewed by an independent radiologist. The median survival duration was 13 months and 17 months since inclusion in the study and since diagnosis, respectively. This outpatient combination was well tolerated with no alopecia and no significant hematologic toxicity.
Based on these encouraging results, a large phase II trial was initiated in France in malignant mesothelioma. The schedule was the same as that of the phase I trialraltitrexed (3 mg/m2) was given first as a 15-minute infusion and 45 minutes later oxaliplatin (130 mg/m2) as a 2-hour infusion, every 3 weeks in the outpatient clinic. Responses were also reviewed by an independent radiologist. Accrual to this study was completed in 1999 and the raltitrexed/oxaliplatin regimen induced responses in 14 of 72 patients (response rate, 25%; 95% confidence interval [CI], 14% to 8%). Currently, the median survival from trial entry and from diagnosis is 6.5 months (95% CI, 5.4 to 7.7) and 12 months (95% CI, 10.1 to 15.3), respectively.46,47 The final results, including an assessment of clinical benefit, are expected soon.
The promising efficacy of the raltitrexed/oxaliplatin combination has prompted the European Organization for Research and Treatment of Cancer (EORTC) to initiate a phase III randomized trial of cisplatin with or without raltitrexed. This study is ongoing with an accrual goal of 240 patients to detect a 50% increase in the median survival of patients treated with the combination regimen.
Recent results using the raltitrexed/oxaliplatin and pemetrexed/cisplatin or carboplatin regimens as chemotherapy for malignant pleural mesothelioma appear promising. These two regimens have in common the combination of a "third-generation" antifolate TS inhibitor and a platinum compound. Hopefully, the results of the two phase III trials comparing cisplatin alone versus cisplatin plus either raltitrexed (the EORTC trial) or pemetrexed (the EMPHACIS trial) will further define the role of these combinations in malignant pleural mesothelioma.
The molecular/cellular basis for the consistent activity of the antifolates in malignant pleural mesothelioma is unknown. However, recently, Bueno et al discovered that the human alpha folate receptor was consistently overexpressed in this disease. Using differential display analysis on freshly frozen RNA obtained from 61 normal lung, pleura, and mesothelioma specimens,48 they found that 44 (72%) of the mesothelioma patients had between two- and fourfold higher mRNA expression of the folate receptor compared to normal tissues. There was no correlation with histologic subtype. This finding suggests that folate receptor antagonist therapy in malignant pleural mesothelioma could benefit the majority of these patients.
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*** POSTED MAY 16, 2002 ***