A Review of Chemotherapy Trials for Malignant Mesothelioma

doi:10.1378/chest.113.1_Supplement.66S

Chest

Volume 113, Issue 1, Supplement, January 1998, Pages 66S-73S

https://doi.org/10.1378/chest.113.1_Supplement.66S Get rights and content

Treatment of malignant pleural mesothelioma continues to be frustrating regardless of the modality employed. Numerous trials of chemotherapeutic agents have been performed, but until recently, these studies were small and subject to inaccuracies of disease measurement. To our knowledge, no chemotherapeutic regimen has emerged as a standard of care. A review of the literature reveals that small activity against this disease has been shown by the anthracyclines, platinum compounds, and alkylating agents, whereas higher activity has been reported with the antimetabolites. The plant alkaloids have not demonstrated any activity against mesothelioma. Dose-escalated chemotherapeutic regimens may offer an advantage, whereas combination chemotherapy has not shown any benefit over single-agent therapy. Favorable responses have been reported with the administration of intrapleural biological response modifiers. Further trials and the investigation of new agents in the treatment of this disease are necessary.

Section snippets

Single-Agent Chemotherapy

Numerous single agents have been tested for activity against mesothelioma. In the past, many small studies reported relative success, but these may have represented a bias toward publishing positive results. Such favorable outcomes have usually not been confirmed by larger, follow-up series. Table 4 summarizes the larger single-agent chemotherapy trials that have included ≥15 patients.12, 13, 14^,17, 18, 19^,²²^,24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45

Combination Chemotherapy

Combination chemotherapy regimens have been evaluated in a number of studies, but have not shown any clear advantage over single-agent chemotherapy (Table 5).¹¹,¹⁵^,¹⁶^,²²^,⁶¹^,68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88 Most combination chemotherapy studies have included doxorubicin, cisplatin, or an alkylating agent, reflecting the popularity of these drugs based on their mild efficacy in single-agent trials.

Conclusion

Despite many investigations, no chemotherapeutic protocol has yet emerged as an effective treatment for malignant pleural mesothelioma. Previous studies have been hindered by small size, inability to accurately measure disease extent, absence of a precise staging system, and lack of knowledge regarding the natural history of the disease. Cohesive, multi-institutional studies have become necessary to approach this disease in an efficient manner.

Among the chemotherapy agents that have been

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Vaccination with epigenetically treated mesothelioma cells induces immunisation and blocks tumour growth
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Citation Excerpt :
Indeed, the incidence and mortality rates of this aggressive cancer are continuously increasing worldwide [1] and conventional therapies have failed to prevent their progression. Favourable responses to treatment barely exceed 20% with single-agent therapy [2] and reach only 41% with the reference combination chemotherapy [3]. Thus, even small benefits provided by new anticancer drugs and/or new antitumour strategies are urgently needed.
Malignant mesothelioma (MM) is an aggressive tumour associated with poor outcome in patients. Current treatments for MM are of limited efficacy. Our recent findings suggest that epigenetic drugs may induce both cytotoxicity and an immune response against MM cells. Thus, we used a mouse model of MM (AK7) to analyse how epigenetic drugs could modulate MM development in vivo. The treatment of tumour-bearing mice with an epigenetic drug already tested in clinical MM treatments (SAHA/Vorinostat) reduced the tumour mass and induced a moderate lymphocytic infiltration. However, the treatment did not stop tumour development. In order to show the potential effect of this epigenetic drug on tumour immunogenicity, in addition to cell cytotoxicity, we immunised mice either with AK7 cells pre-treated with SAHA, or with one of two cytotoxic drugs (curcumin or selenite), prior to transplantation of live AK7 cells. A specific immune response was observed only in mice immunised with AK7 cells pre-treated with the epigenetic drug (SAHA) and the tumour growth was arrested. An increase in the proportion of CD3+ CD8+ lymphocytes occurred in the peritoneal cavity. We also observed large conglomerates of immune cells in the omentum with clusters of CD8+ T cells, together with lymphocytes directed against residual AK7 cells in the interlobular connective tissue of the pancreas. Our data demonstrate that epigenetic drugs, such as SAHA, can stimulate tumour immunogenicity and improve the recognition of aggressive MM cells by the immune system in vivo.
Malignant pleural mesothelioma: Medical treatment update
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Malignant pleural mesothelioma (MPM) is a disease usually unaffected by current therapeutic strategies, but for the majority of patients, the use of systemic chemotherapeutic drugs remains the only therapeutic option available. During the past 15-20 years, many phase II and a few phase III clinical trials have studied a large variety of drugs such as anthracyclines, alkylating agents, platinum compounds, taxanes, vinka alkaloids, and antifolates as single agents and in combination, with the aim to increase responses and survival. The combination of pemetrexed and cisplatin tested in the largest phase III randomized trial of malignant pleural mesothelioma ever conducted has become the current standard of care. New targeted therapeutic approaches with a variety of anti–growth factor drugs are currently undergoing investigation worldwide.
Enhanced effect of connexin 43 on cisplatin-induced cytotoxicity in mesothelioma cells
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The expression levels of connexin (Cx) proteins, which are gap junction (GJ) components, are often decreased in many cancers, and restoring their levels has been shown to have antitumor effects. Previously, dysfunctional gap junctional intercellular communication (GJIC) has been observed in several malignant mesotheliomas (MMs), and among the many Cx proteins, Cx43 is prominently expressed in nontumorigenic mesothelial tissues. Therefore, we investigated whether Cx43 upregulation has an antitumor effect on an MM cell line (H28 cell), especially with regard to drug resistance. After treatment with the chemotherapeutic agent cisplatin (CDDP), MM cell viability significantly decreased, and apoptosis induction was observed in Cx43-transfected clones. A specific GJIC inhibitor could not abrogate this effect. On the other hand, the Src protein is known to phosphorylate Cx43, which results in GJIC inhibition. This suggests that Src activity might also be regulated by the hyperexpression of Cx43. In fact, the Src protein level was decreased in Cx43-transfected clones. Moreover, Src inhibition reinforced CDDP cytotoxicity in parental H28 cells. These data suggest that Cx43 could improve the resistance to CDDP in a GJIC-independent manner, which may be partly mediated by the suppression of Src activity.
Response to the methylation inhibitor dihydro-5-azacytidine in mesothelioma is not associated with methylation of p16<sup>INK4a</sup>: Results of cancer and leukemia group B 159904
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The molecular mechanisms of oncogenesis in mesothelioma involve the loss of negative regulators of cell growth including p16^INK4a. Absence of expression of the p16^INK4a gene product is exhibited in virtually all mesothelioma tumors and cell lines examined to date. Loss of p16^INK4a expression has also been frequently observed in more common neoplasms such as lung cancer as well. In a wide variety of these malignancies, including lung cancer, p16^INK4a expression is known to be inactivated by hypermethylation of the first exon. This project (CALGB 159904) intended to test the hypothesis that in mesothelioma loss of p16^INK4a via methylation would correlate with response to the cytidine analog and methylation inhibitor dihydro-5-azacytidine (DHAC).
Using tissue samples from CALGB 8833 and 9031, two clinical studies which used DHAC based therapy in mesothelioma, this study tested the hypothesis that tumors possessing methylation of p16^INK4a would have a better response and survival following DHAC treatment than their nonmethylated counterparts.
Methylation of p16^INK4a was identified in 4 of the 20 specimens. Although there was a trend towards improved survival the result was not statistically significant.
There was no significant correlation between the presence of p16^INK4a methylation and response to DHAC therapy or overall survival.
A retrospective analysis of malignant pleural mesothelioma patients treated either with chemotherapy or best supportive care between 1990 and 2005. A single institution experience
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Citation Excerpt :
Therefore, further investigations of various therapeutic modalities should be tested for their effectiveness in mesothelioma, for which therapeutic success is still unsatisfactory [9,32,33]. Just a few years ago, although almost every chemotherapeutic agent had been tested against DMPM both as single agents and in combination chemotherapy regimens, rates of objective tumor regression were reported under 30% with no significant improving on median survival [8–11,13–15]. Therefore, DMPM was considered relatively resistant to chemotherapy and no regimen was accepted as standard for treatment of DMPM.
The aim of this study was to investigate the efficacy and safety profile of chemotherapy (CT) compared to best supportive care (BSC) in patients with histopathologically confirmed diffuse malignant pleural mesothelioma (DMPM). A total of 161 patients between 1990 and 2004 treated either with CT (109 patients) or BSC (52 patients) depending on patients choice were evaluated in this analyses. Chemotherapy protocols included a combination of cisplatin, mitomycin C and recombinant interferon alpha 2a (CM-In), or cisplatin, mitomycin C and ifosfamide (CMI), or cisplatin and gemcitabine (CG).
We found a significant difference in the median survivals of the patients with CT compared to BSC, 11.3 months versus 8.0. Objective response rate was 28/109 (25.7%) with 3.7% of complete response rate. Stable disease rate was 39/109 (35.8%). There was a significant difference between median survivals of patients with objective response (17 months) and median survivals of patients with progressive diseases (6 months) and also with stable diseases (16 months). There was a significant difference between the stable disease and the progressive disease. Stages 3 and 4 patients of epithelial cell type having received chemotherapy live longer than those not having received chemotherapy (12 months versus 4). There was no significant difference between the survivals of the different chemotherapy regimens. The toxicity with CT regimens were mild and well-tolerated.
We conclude that CT prolongs survival compared to BSC in patients with DMPM. Survivals of patients with objective response prolong considerably with CT compared BSC. We observed that stages 3 and 4 patients with epithelial cell type got benefit from CT. Especially, of epithelial cell type stages 1 and 2 should receive multimodal treatment.

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Chest

A Review of Chemotherapy Trials for Malignant Mesothelioma

Section snippets

Single-Agent Chemotherapy

Combination Chemotherapy

Conclusion

Chest

Chest

Ann Oncol

Ann Oncol

Cancer Treat Rev

Eur J Cancer

Lung Cancer

Ann Oncol

Ann Oncol

Eur J Cancer

Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province

Br J Ind Med

Relation between exposure to asbestos and mesothelioma

N Engl J Med

Asbestos-related diseases

N Engl J Med

Benign and malignant mesothelioma

A proposed new international TNM staging system for malignant pleural mesothelioma

Chest

Chrysotile, tremolite and mesothelioma in man

Chest

Cytotoxicity of long and short crocidolite asbestos fibers in vitro and in vivo

Cancer Res

Malignant mesothelioma: diagnostic and management strategies for 1992

Semin Oncol

Use of photodynamic therapy for the management of pleural malignancies

Semin Surg Oncol

Randomized phase II trial of cisplatin with mitomycin or doxorubicin for malignant mesothelioma by the Cancer and Leukemia Group B

J Clin Oncol

Carboplatin in malignant mesothelioma: a phase II study of the Cancer and Leukemia Group B

Cancer Chemother Pharmacol

Dihydro-5-azacytidine (DHAC) in malignant mesothelioma (Meso) using serum hyaluronic acid (SHA) as a tumor marker: a phase II trial of the CALGB [abstract 1248]

Proc Am Soc Clin Oncol

Trimetrexate in malignant mesothelioma: a CALGB phase II study

J Clin Oncol

Dihydro-5-azacytidine (DHAC) and cisplatin (DDP) in mesothelioma (CALGB 9031) [abstract 1371]

Proc Am Soc Clin Oncol

Dihydro-5-azacytidine (DHAC) and cisplatin (DDP) in mesothelioma [abstract 1470]

Proc Am Soc Clin Oncol

Edatrexate for malignant mesothelioma: a phase II study of the Cancer and Leukemia Group B, 9131 [abstract 1087]

Proc Am Soc Clin Oncol

Edatrexate with oral leucovorin rescue for malignant mesothelioma: a phase II study of the Cancer and Leukemia Group B-CALGB 9131 [abstract 1068]

Proc Am Soc Clin Oncol

Paclitaxel (Taxol) for malignant mesothelioma (MM): a phase II study of the Cancer and Leukemia Group B (CALGB 9234) [abstract 1382]

Proc Am Soc Clin Oncol

Factors predictive of survival among 337 patients (PTS) with mesothelioma treated between 1984 and 1994 by the Cancer and Leukemia Group B (CALGB)

Chest

Pathology of malignant mesothelioma

Chemotherapy in malignant pleural mesothelioma: a review

J Clin Oncol

Chemotherapy in malignant mesothelioma: a review

Cancer Chemother Pharmacol

Randomized trial of doxorubicin versus cyclophosphamide in diffuse malignant pleural mesothelioma

Cancer Treat Rep

Malignant mesothelioma, the Eastern Cooperative Oncology Group (ECOG) experience

Cancer

A prospective study of detorubicin in malignant mesothelioma

Cancer

A phase II study of pirarubicin in malignant pleural mesothelioma

Cancer

Activity and toxicity of 4′-o-tetrahydropyranyladriamycin (pirarubicin) in malignant mesothelioma [abstract 1225]

Proc Am Soc Clin Oncol

Epirubicin in malignant mesothelioma: a phase II study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group

J Clin Oncol

Epirubicin in the treatment of malignant mesothelioma: a phase II cooperative study

Tumori

Phase II study of mitoxantrone in patients with mesothelioma: a National Cancer Institute of Canada Clinical Trials Group study

Cancer Treat Rep

Mitoxantrone in malignant pleural mesothelioma: a study by the EORTC Lung Cancer Cooperative Group

Eur J Cancer

Menogaril in treatment of malignant mesothelioma: a phase II study

Invest New Drugs

A phase II study of M-AMSA in patients with malignant mesothelioma

Cancer Chemother Pharmacol