Since the mid-1990s, a number of novel nonchemotherapy-based treatment approaches for mesothelioma have been studied. Discussed below are some of the new approaches currently being investigated.
Molecularly Targeted Therapy
Drugs that can specifically target cancer cells are currently being studied to evaluate their clinical activity in individuals with advanced mesothelioma. More clinical trials will be needed to ascertain the role of these treatment approaches in patient management.
- Epidermal growth factor receptor (EGFR) pathway – In majority of malignant mesothelioma cases, EGFR is overexpressed. In one phase II trial involving 43 patients who were administered gefitinib, two objective responses were recorded. In another phase II trial involving 63 previously untreated patients who were administered erlotinib, no objective responses were recorded. More on EGFR inhibitors.
Vascular endothelial growth factor (VEGF) pathway – Two separate approaches have been used in order to block the VEGF pathway:
- Sorafenib, which is a VEGF tyrosine kinase (TK) inhibitor, was used among 51 patients (31 previously treated, 20 chemotherapy naïve). 17 patients registered stable disease and 2 partial responses were recorded, with median overall survival being 6 months. Another VEGF TK inhibitor, Vatalanib, was assessed in 47 previously untreated patients diagnosed with pleural or peritoneal mesothelioma. An objective response was observed in 5 (11% RR) and SD in 30 (66%).
- Bevacizumab – This is a monoclonal antibody that binds VEGF, and has been used in combination with the gemcitabine plus cisplatin treatment regimen. In a randomized phase II study, it was observed that bevacizumab did not prolong overall survival in comparison to placebo.
Histone deacetylase inhibition – Vorinostat was assessed in 73 individuals with advanced cancer (13 of these were mesothelioma patients). There were 2 PRs among these 13 patients.
An anti-neoplastic ribonuclease extracted from frog eggs, Ranpirnase has demonstrated some evidence of clinical activity in a phase II trial. However, in another randomized trial involving 157 individuals with advanced disease, there was no evidence of a statistically significant benefit in survival.
In a larger phase III study, 428 individuals with unresectable mesothelioma were assigned randomly to the combination of doxorubicin plus ranpirnase or doxorubicin alone. Initial results, which were presented in 2009 at the American Society of Clinical Oncology (ASCO) meeting, demonstrated that the ranpirnase plus doxorubicin combination regimen did not significantly prolong overall survival in comparison to doxorubicin alone (the median survival being 11.1 months as opposed to 10.8 months; and hazard ratio being 1.03).
Immunotherapy and Gene Therapy
Immunotherapy involving systemically administered interleukin (IL)-2 has shown limited efficacy and considerable side effects. In a study involving 29 individuals with advanced mesothelioma who were administered recombinant IL-2 as a single agent, only 2 partial responses were recorded (the objective response rate being 8 percent). However, more studies on systemic IL-2 and the synthetic upregulation of endogenous IL-2 via gene transfer are currently underway. These are based on data sourced from murine models of mesothelioma.
Intrapleural or intratumoral administration of IL-2 has demonstrated more promising results.
Mesothelin is one of the primary targets for therapy because it is a tumor differentiation antigen which is overexpressed by epithelial mesotheliomas. Below are the three types of mesothelin-targeted agents that are currently in different stages of clinical development:
- CRS-207, which is a live-attenuated Listeria monocytogenes vector encoding human mesothelin
- MORAb-009, which is a chimeric anti-mesothelin monoclonal antibody
- SS1P (anti-mesothelin dsFv-PE38), which is a recombinant immunotoxin comprising an anti-mesothelin Fv fragment linked to a truncated Pseudomonas exotoxin
The justification for mesothelin being used as a tumor vaccine is based on the evidence that mesothelin elicits significant T-cell response among patients. Phase I studies involving SS1P and MORab-009 have been completed, and minor antitumor activity has been demonstrated with SS1P. Preclinical models indicate considerable synergy between the above mentioned agents and systemic chemotherapy. Trials involving combination therapies are currently underway.
Chemoimmunotherapy – This has been used only rarely since the clinical approval of pemetrexed. Interferon-alfa 2a and interferon-gamma 1b have been used in combination with a number of standard chemotherapies for mesothelioma. These trials have demonstrated variable response rates – 27-36% for interferon-alfa 2b plus cisplatin, 11% for interferon-alfa 2b with doxorubicin alone, and 29% for interferon-alfa 2b with cisplatin plus doxorubicin.
A group of 24 individuals with advanced mesothelioma was assigned to high-dose methotrexate in combination with interferon-alfa and interferon-gamma. Partial response was observed in seven patients (29%), with the one-year survival and two-year survival being 62% and 31% respectively. In a relatively small trial involving epirubicin plus IL-2, only a single partial response was observed among 25 individuals with advanced disease.
Peritoneal Mesothelioma Systemic Therapy
The progression of the disease within the peritoneal cavity is almost entirely responsible for morbidity and mortality. Aggressive localized therapy involving cytoreductive surgery (CRS) in combination with intraperitoneal chemotherapy has found increasing use for patients with peritoneal surface malignancies, including those with malignant peritoneal mesothelioma. In case of appropriately selected patients, certain centers have observed median survivals of up to five years when this specific approach was used.
In cases of individuals with advanced (recurrent or unresectable) disease, who may not be appropriate candidates for receiving aggressive localized treatment, palliative systemic chemotherapy can be similar to that described above for pleural-based disease. First-line treatment involving pemetrexed plus cisplatin is usually well tolerated and has demonstrated significant responses in specific patients.