MALIGNANT MESOTHELIOMA: FOCUS ON NEW THERAPEUTIC APPROACHES
Pemetrexed (Alimta), Cisplatin, Onconase, Bevacizumab (Avastin), Endostatin, and more
Malignant mesotheliomas (MMs) are aggressive neoplasms arising from the surface serosal cells of the pleural, peritoneal, and pericardial cavities. Asbestos exposure has been established as the primary cause of MMs; however, there is a long latency period of 30-45 years between exposure to asbestos and development of disease. Workers in the shipyard industry, insulation workers, construction workers, and asbestos miners and manufacturers seem to be at highest risk for developing the disease. The male to female ratio is about 4:1.
Mesothelioma is a relatively rare disease. In the United States, approximately 2200 new cases of mesothelioma occur annually. The incidence has been steadily rising over the last 40 years but is expected to decrease over the next 50-60 years as a result of legislation to reduce workplace exposure to asbestos. The incidence of mesothelioma in Western Europe is much higher, about 5000 cases per year, and it is expected to continue to rise until approximately 2020. Mesothelioma occurs in other areas of the world where occupational exposure to asbestos is high, although incidence data are less easy to obtain.
Malignant pleural mesothelioma (MPM) most commonly develops in the fifth to seventh decade of life, with a median age of 60 years at diagnosis. The most common symptoms at diagnosis are dyspnea and nonpleuritic chest pain.
Several prognostic factors have been identified in MM. Poor prognostic variables include: nonepithelial histology, older age (greater than 75 years), pleural primary, chest pain at presentation, poor performance status, and elevated platelet count (greater than 400,000/mcL). The median survival figures are reported in the range of 4-18 months. Current therapies have yielded disappointing results and include surgery, radiation therapy, chemotherapy, and multimodality therapy.
Although surgery and radiation therapy play a role in the treatment of MM, this review will focus on recent medical advances in the treatment of MPM, and specifically on some promising new therapies highlighted at the recent symposium.
Chemotherapy for Malignant Mesothelioma
A number of agents have been employed for the treatment of MPM, and their results will be briefly reviewed here. A breakdown of chemotherapy agents.
Several agents have demonstrated modest single-agent activity in the treatment of MPM. Doxorubicin, probably the most extensively studied agent, has a response rate in the 15% range. Other anthracyclines, such as detorubicin, pirarubicin, and epirubicin, have also been studied with similar results.
Cisplatin has been studied in a number of trials and seems to have an approximately 14% response rate. One small study of very high dose-intensity cisplatin (80 mg/m2/week) demonstrated a 36% response rate; however, the duration of response was short (2-8 months).
Other agents that have shown activity with a 10% to 20% response rate include carboplatin, mitomycin, cyclophosphamide, and ifosfamide. Early studies with high-dose methotrexate were reported in 1972 with response rates of 35% to 44%. However, no confirmatory studies have been published.
Combination Chemotherapy With Traditional Agents
Because of the lack of efficacy of single-agent chemotherapy regimes (response rates less than 20%), several combination regimens have been examined for the treatment of patients with MPM.
Doxorubicin has been combined with several agents, including cyclophosphamide and ifosfamide, but response rates were similar to single-agent doxorubicin. The combination of doxorubicin with cisplatin has shown marginal increases in response rate over single-agent therapy, but no survival advantage. A 44% response rate was seen with the 4-drug regimen of doxorubicin, cisplatin, mitoxantrone, and bleomycin, but this study has never been confirmed.
Despite many trials with numerous regimens, none of these combination chemotherapy regimens have consistently yielded response rates higher than those seen in single-agent studies. The development and testing of newer agents for the treatment of MPM are clearly needed.
Newer Chemotherapy Options
At the American Society of Clinical Oncology (ASCO) conference in 1998, Bischoff and colleagues, from Germany, reported a 31% response rate of single-agent gemcitabine in a small group of patients (n = 23) with MPM. An additional 40% of the patients were said to have experienced significant symptomatic improvement of their disease. The median and 1-year survival rates were not reported. It should be noted that the majority of the patient in this trial had epithelial histology (which confers a more favorable prognosis) and were in an early stage of disease.
Despite the impressive activity seen in this trial, published single-agent studies have failed to demonstrate any substantial antitumor activity of gemcitabine in mesothelioma. A Cancer and Leukemia Group B (CALGB) multicenter trial had no responders among the 17 patients studied. Another multicenter study conducted in Europe demonstrated a response rate of only 7%.
While results of single-agent gemcitabine are discouraging, combination trials may prove to be more beneficial. Based on preclinical evidence that the combination of gemcitabine and cisplatin demonstrated additive antitumor activity, Byrne and colleagues, in Australia, initiated a phase 2 study examining the combination in patients with advanced MM. They studied 21 patients, 18 of whom had stage 3-4 disease.
The overall response rate was 47.6%, with a median duration of response of 25 weeks. The estimated 1-year survival was 41% and the treatment was well tolerated. The same group subsequently conducted a multi-institutional study that has been reported in abstract form. At the time of reporting, there were 53 eligible patients. Twelve of 46 assessable patients (26%) showed a partial response. The results of further trials, planned by the Southwest Oncology Group and the European Organization for the Research and Treatment of Cancer (EORTC)-Lung Cancer Cooperative Group are eagerly awaited.
Another interesting new chemotherapy agent that has been studied in MM is pemetrexed (multitargeted antifolate [MTA]). MTA is a novel chemotherapy agent that inhibits several folate-dependent enzymes, including thymidylate synthase (TS, the enzyme target of 5-flourouracil [5-FU] following its metabolic activation), dihydrofolate reductase (the enzyme target of methotrexate), and glycinamide ribonucleotide formyltransferase. MTA is a more potent inhibitor of TS than of the other enzymes. However, in vitro studies demonstrating activity of MTA against cancer cell lines resistant to 5-FU and raltitrexed because of TS amplification suggest that its cytotoxicity may be mediated through these enzymes as well. Several administration schedules of MTA have been studied in phase 1 trials: daily for 5 days, every 3 weeks; weekly for 4 weeks, every 6 weeks; and every 21 days. The maximum tolerated doses (MTDs) with these 3 schedules were 4 mg/m2/day, 40 mg/m2/week, and 600 mg/m2 every 3 weeks, respectively. The main dose-limiting toxicity (DLT) seen in these phase 1 studies was neutropenia.
Other toxicities included thrombocytopenia, mucositis, diarrhea, fatigue, anorexia, nausea, vomiting, skin rash, and liver enzyme elevations. Dexamethasone was given prophylactically to patients who developed skin rashes for 3 days prior to subsequent doses, and the rash was improved or prevented. The recommended dose for phase 2 studies was established at 600 mg/m2 every 21 days.
Pharmacokinetics parameters were examined in 20 patients at the 600 mg/m2 every 21 days dose level. The mean maximum concentration was 137 mcg/mL and the mean elimination half-life (t1/2) was 3.1 hours. The clearance and volume of distribution were 40 mL/min/m2 and 7 L/m2, respectively. The elimination of MTA is primarily renal, with greater than 80% of the dose recovered in the urine during the first 24 hours after dosing. The clearance of MTA correlated with the creatinine clearance, and, thus, it appeared to decrease with age.
MTA Single-Agent Studies
Single-agent phase 2 studies have demonstrated activity with MTA in nonsmall-cell lung cancer, advanced breast cancer, head and neck cancer, bladder cancer, colorectal cancer, and cervical cancer. The DLT of single-agent MTA in these phase 2 trials was neutropenia, with grade 3 or 4 toxicity occurring in about 50% of patients.
Grade 1-2 elevations in liver enzymes were common, occurring in 60% to 70% of patients, but were transient, returning to baseline values before the next cycle. Skin rashes were also common and sometimes severe, characterized by a diffuse erythematous maculopapular rash with a predominantly truncal distribution. This toxicity was ameliorated with the use of prophylactic corticosteroids prior to subsequent cycles.
Niyikiza and colleagues examined the relationship between nutritional status and toxicities with MTA in a multivariate statistical analysis of combined study data from 246 patients. The initial results were presented at the European Society for Medical Oncology meeting in 1998. They showed a correlation between elevated baseline plasma homocysteine levels (a marker for poor folate and B12 status) and development of life-threatening hematologic (neutropenia and thrombocytopenia) and nonhematologic (mucositis and diarrhea) toxicities.
An update of these data was presented at the ASCO conference in May 2001. An additional 78 patients were evaluated, and these patients received vitamin supplementation in the form of folic acid (350-1000 mcg per day) and vitamin B12 (1000 mcg intramuscularly every 9 weeks). The incidence of grade 3 and 4 toxicities was significantly reduced in the patients who received vitamin supplementation compared with control patients who did not. Drug-related deaths did not occur in the supplemented group.
At the mesothelioma symposium in April, Dr. Axel Hanauske briefly presented results from a recently completed phase 2 study in mesothelioma. In this study, 62 patients with advanced mesothelioma, the majority of which had epithelial histology and were stage 4, were treated with MTA. The preliminary overall response rate was 14.5%, with a median duration of response of 10.8+ months, median time to progression of 5.4 months, and median survival of 10.7 months.
Vitamin supplementation was added to the treatment protocol of some patients during the trial. Responses were 1/17 (6%) in those patients who did not receive vitamin supplementation, 3/5 (60%) in those who started vitamin supplementation part way through the trial, and 5/40 (13%) in those who received vitamin supplementation throughout the trial. The principle toxicity was neutropenia (grade 3-4 approximately 27%), which occurred with a lower incidence in patients receiving vitamin supplementation. Other toxicities included febrile neutropenia (4.8%), fatigue (grade 3, 8.7%), anorexia (5.9%), and nausea (4.8%).
MTA Combination Studies
A number of recent studies have examined the use of MTA in combination with other chemotherapy agents.
Adjei and colleagues, from the Mayo Clinic, studied the combination of MTA and gemcitabine in patients with advanced solid tumors and found the combination to be well tolerated and broadly active. Of the two patients with mesothelioma that were enrolled in this study, one had a partial response.
Thodtmann and colleagues, in Belgium, conducted a phase 1 study of MTA and cisplatin in patients with advanced solid tumors and found that an every-21-days schedule (both drugs on day 1) was well tolerated and clinically active. Of note, 11 patients with pleural mesothelioma were enrolled onto this study, and 5 of them had a partial response. Two phase 2 studies of this combination have been reported in previously untreated nonsmall-cell lung cancer patients. These studies showed promising activity with the MTA/cisplatin combination in that disease.
At the ASCO conference in May 2001, Hilary Calvert, from Newcastle upon Tyne, United Kingdom, presented preliminary phase 1 results of MTA in combination with carboplatin in patients with advanced solid tumors. Both agents were given every 21 days in a dose-escalating fashion. At the time of the report, 22 patients, all with MM, were enrolled. The MTD had not been reached. Grade 3 and 4 toxicities were mainly myelosuppression (neutropenia 69%, leukopenia 44%, and thrombocytopenia 38%). The overall response rate was 29% and clinical improvement was seen in 70% of patients. Vitamin supplementation was not used in this trial.
Prompted by the promising activity seen in MM phase 1 studies of the cisplatin/MTA combination, a large phase 3 trial has recently been conducted comparing cisplatin/MTA vs cisplatin alone. This trial, which is the largest randomized trial to date in this disease, enrolled 430 patients. Accrual was completed in April and interim results are expected to be available shortly.
Dr. Hanauske reported at the mesothelioma symposium that the initial 75 patients in each arm received MTA without vitamin supplementation; however, an unexpectedly high death on study rate (7%) was noted. This prompted the initiation of folic acid and B12 supplementation and the death on study rate dropped to less than 1%. The results of this study are eagerly awaited.
Other Chemotherapy Agents for the Treatment of Mesothelioma
A number of other newer combinations of chemotherapy, including oxaliplatin/raltitrexed
and cisplatin/irinotecan, have been examined in small trials with promising
activity. Whether confirmatory studies will establish a standard regimen
remains to be seen. Despite the promise of these newer chemotherapy agents,
chemotherapy has so far failed to affect the survival of this disease.
This has led to the development and testing of a number of additional
agents with novel mechanisms of action.
Novel Agents for the Treatment of Malignant Mesothelioma
Onconase (also know as P-30 protein) is a protein derived from the eggs and early embryos of the leopard frog (Rana pipens), which has shown activity against a wide range of human tumor cell lines. Dr. Taub, from Columbia University, presented a multicenter phase 2 study of onconase in 105 patients with advanced MM at the 1999 ASCO conference. Onconase was administered at a dose of 480 mcg/m2 intravenously (over 30 minutes) weekly. The estimated median survival time for the intent-to-treat group was 5.8+ months, with 1- and 2-year survivals of 34.3% and 20%, respectively. In patients with epithelial histology, the median survival time was 9.6 months, with 1- and 2-year survivals of 42% and 23.4%, respectively. The authors noted that these results compared favorably with those of control patients from previous CALGB studies.
Based on these encouraging results, a randomized phase 3 multicenter trial of onconase vs doxorubicin was conducted in patients with unresectable MM. Dr. Vogelzang, from the University of Chicago, presented preliminary results at the 2000 ASCO conference. The median survival times were similar in the 2 groups, 7.7 months vs 8.2 months in the onconase and doxorubicin groups, respectively. The 1-year (30.7% for onconase vs 32.3% for doxorubicin) and 2-year (17.8% for onconase vs 6.4% for doxorubicin) survival rates were also similar in the 2 groups.
Analysis of prognostic factors revealed that there were significantly more patients with poor prognostic factors in the onconase group (38.1%) than the doxorubicin group (17%). When these patients were excluded from the analysis (along with 5 patients whose histology did not show MM), the results favored onconase.
The median survival times, 1-year, and 2-year survival rates were 11.3 months vs 9.1 months, 46.2% vs 34.5%, and 34.3% vs 10.7% for the onconase vs doxorubicin patients, respectively. The investigators concluded that onconase is at least as active as doxorubicin for the treatment of MM and may be more active in certain patient subsets.
A randomized, open-label, multicenter phase 3 study is now under way, comparing doxorubicin alone vs the combination doxorubicin/onconase in patients with MM. Patients will be stratified according to disease histology (epithelioid vs nonepithelioid) and CALGB prognostic groups 1-4.
Angiogenesis, the process of generating new blood vessels, is necessary for tumor growth. A number of factors are involved in the regulation of tumor angiogenesis, but the most important factors are thought to be vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2).
Mesothelioma patients have higher levels of VEGF than patients with any other solid tumors, and VEGF is an autocrine growth factor in MM. There are currently 2 inhibitors of VEGF in clinical trials, SU5416 and bevacizumab.
SU5416. SU5416 is a highly selective receptor tyrosine kinase inhibitor that targets the VEGF receptors Flt-1 and KDR/Flk-1. The KDR/Flk-1 receptor seems to be the major mediator of endothelial cell proliferation during angiogenesis and also mediates vascular permeability in tumor microvasculature.
A phase 1 study of SU5416 in patients with advanced malignances showed it to be well tolerated, with the principal toxicities being mild to moderate headache and nausea. Objective responses were observed in colorectal cancer, Kaposi's sarcoma, and metastatic basal cell cancer.
At the 2001 ASCO conference, Dr. Kindler, from the University of Chicago, reported preliminary results of a phase 2 multicenter trial of SU5416 in mesothelioma patients. SU5416 was given intravenously at a dose of 145 mg/m2 twice weekly with steroid premedication. The principle toxicities were hyperglycemia, headache, and fatigue. Only a few patients were evaluable, 36% had minor response and 28% stable disease.
This study will also examine biologic correlates such as microvessel density, proliferative and apoptotic indices on tumor biopsies, tumor perfusion via dynamic contrast magnetic resonance imaging, serum levels of VEGF, and vascular cell adhesion molecule.
Bevacizumab. Bevacizumab is a recombinant human monoclonal antibody against VEGF. A phase 1 study of bevacizumab examined dose levels from 0.1 mg/kg to 10 mg/kg administered intravenously over 90 minutes on days 0, 28, 35, and 42 in patients with advanced malignancies. There were no grade 3 or 4 toxicities observed. Grade 1 and 2 adverse events included asthenia, headache, and nausea. The infusions of bevacizumab were well tolerated. There were 3 episodes of tumor-related bleeding.
Another phase 1 study examined weekly bevacizumab in combination with 3 chemotherapy regimens. Patients received 3 mg/kg of bevacizumab in combination with doxorubicin, carboplatin/paclitaxel, or 5-FU/leucovorin. The combinations were well tolerated and the toxicities observed were those that would be expected with the chemotherapy regimens.
Bevacizumab is being studied in several malignancies, including colorectal cancer, renal cell carcinoma, breast cancer, ovarian cancer, nonsmall-cell lung cancer, and prostate cancer. A study presented at the 2001 ASCO conference showed acceptable toxicity and possible prolonged survival in patients with nonsquamous lung cancer.
At the recent mesothelioma symposium, Dr. Kindler outlined an upcoming multicenter trial that she will be conducting. This will be a randomized, placebo-controlled phase 2 trial comparing gemcitabine plus cisplatin with or without bevacizumab. The primary objective will be time to progression, with response and survival as secondary end points. A number of biologic correlates will also be examined.
Thalidomide. Thalidomide also has antiangiogenic properties, although the exact mechanism by which it acts is not clear. Thalidomide has been shown to have antitumor activity against multiple myeloma, and it is currently being studied in a number of other malignancies. Dr. Kindler reported that the EORTC has recently begun enrolling patients in a phase 2 study of thalidomide in MM.
Tumor Growth Factor Inhibition
Human tumors express high levels of growth factors and their receptors. Tyrosine kinases are proteins involved in both normal cell growth and malignant transformation. Among the best studied of the receptor tyrosine kinases is the epidermal growth factor receptor (EGFR) subfamily, compromised of 4 homologous receptors: ErbB1 (commonly referred to as EGFR), ErbB2 (HER2/neu), ErbB3 (HER3), and ErbB4 (HER4). Studies have identified that activation of the EGFR tyrosine kinase is a key initiating event for cell proliferation. A recent study at Washington University School of Medicine demonstrated that EGRF is overexpressed in MM.
ZD1839, an anilinoquinazoline, is an orally active, potent, and selective inhibitor of the EGFR-tyrosine kinase. In preclinical studies, ZD1839 produced reversible growth inhibition and growth delay in a wide range of tumor cell lines. These effects seemed to be enhanced when ZD1839 was coadministered with cytotoxic agents. Phase 1 pharmacokinetic studies in normal volunteers and cancer patients revealed a half-life of 27-49 hours, supporting once daily administration. Additionally, phase 1 studies in patients with advanced cancer have shown that long-term daily administration of ZD1839 is well tolerated with minimal toxicities. ZD1839 is being studied in combination with cytotoxic agents in a number of malignancies including NSCLC, renal cell carcinoma, glioblastoma, head and neck cancer, and ovarian cancer.
ZD1839 will also be studied in MM. Dr. Kindler reported that the CALGB is initiating a study of ZD1839 in 40 previously untreated patients. The primary end point of the trial will be the time to progression. Biologic correlates will also be examined.
Immunotherapy for Malignant Mesothelioma
Nonspecific immunotherapy approaches, such as systemic or intrapleural administrations of interferons or interleukins, have shown limited clinical benefit in the treatment of patients with MM.
Single-agent studies of systemic interferon-alpha (IFN-alpha) produced response rates of about 12%. A number of trials have examined the use of systemic IFN-alpha in combination with various chemotherapy agents. Despite encouraging initial studies that showed impressive response rates of 36% and 27% with a 12-month median survival, most combination trials have produced response rates similar to those seen with single-agent chemotherapy, generally with added toxicity.
Intrapleural administration of interleukin-2 (IL-2) has yielded high response rates in patients with early-stage disease. Astoul and colleagues, in France, administered intrapleural IL-2 to 23 patients with MPM. The response rate was 55% (11 partial responses and 1 complete response), and the therapy was well tolerated. The median survival time was 18 months. The majority of the patients in this trial had stage 2 or less disease. A recently published trial examined intrapleural IL-2 followed by low-dose systemic IL-2 and demonstrated a response rate of 22%. Unfortunately, despite the promising response rates, the applicability of this therapy is limited to the few patients who have early-stage disease at diagnosis.
Many of the presentations at the recent mesothelioma symposium were focused on the role of the SV40 virus in the etiology of mesothelioma and possible applications for treatment. A detailed discussion of this topic is beyond the scope of this review article, but it is mentioned here as a possible direction for the immunotherapy of mesothelioma. SV40 (or Simian virus 40) is a DNA tumor virus, which is endogenous to the rhesus monkey. It is thought that the virus infected the human population through contaminated polio and adenovaccines in the late 1950s and early 1960s. Transmission among humans is similar to that of other papovaviruses. SV40 was linked to tumor development in animal studies in the 1960s. In the 1990s, researchers found a potential link between SV40 and mesothelioma: 60% of hamsters injected with SV40 intracardially developed MM. When the virus was injected into intrapleural spaces, 100% of the experimental animals developed MM.
These discoveries led to the testing of human mesothelioma samples for the presence of SV40. The incidence of SV40 DNA in mesothelioma samples has ranged from 0 to 83%, with huge geographic differences. The ability of SV40 to transform human cells has been established in in vitro studies and many investigators believe that SV40 may be involved in the etiology of mesothelioma.
Dr. Michael Imperiale, from the University of Michigan, discussed the possibility of a therapeutic SV40 vaccine for the treatment of mesothelioma. An extensive amount of preclinical work has been done in this area, and plans to begin phase 2 testing of a recombinant virus vaccine are underway.
Summary and Conclusions
MM is a relatively rare disease in the United States; however, its incidence has been rising. It has been clearly linked to asbestos exposure, and recent evidence suggests an association with SV40, although an etiologic link is not proven. Currently there is no standard therapy for the treatment of MPM. However, despite the rarity of this tumor, much research has been focused on finding improved therapies.
Newer chemotherapy regimens offer improved response rates compared with historical regimens, but none of these agents has been able to prolong survival, yet, and it is clear that single-agent chemotherapy will not be the answer.
Novel agents such as the angiogenesis inhibitors and EGFR-tyrosine kinase
inhibitors have been studied in a number of malignancies and show some
promise. Studies examining these agents in combination with chemotherapy
for MPM are currently underway. The results of studies are eagerly awaited
and will hopefully define the role of these novel therapies in the treatment
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