Systemic treatments for mesothelioma: standard and novel

Our plain-English summary of Systemic treatments for mesothelioma: standard and novel, by H.L. Kindler (Current Treatment Options in Oncology, 2008).

The study

• Author: H.L. Kindler
• Journal: Current Treatment Options in Oncology
• Published: 2008;9(2-3):171-9
• Type of article: Review
• Cited by: 55 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Systemic therapy is the only treatment option for the majority of mesothelioma patients, for whom age, co-morbid medical illnesses, non-epithelial histology, and locally advanced disease often preclude surgery. For many years, chemotherapy had a minimal impact on the natural history of this cancer, engendering considerable nihilism. Countless drugs were evaluated, most of which achieved response rates below 20% and median survival of <1 year. Several factors have hampered the evaluation of systemic regimens in patients with mesothelioma. The disease is uncommon, affecting only about 2500 Americans annually. Thus, most clinical trials are small, and randomized studies are challenging to accrue. There is significant heterogeneity within the patient populations of these small trials, for several reasons. Since all of the staging systems for mesothelioma are surgically based, it is almost impossible to accurately determine the stage of a patient who has not been resected. Patients with very early stage disease may be lumped together with far more advanced patients in the same study. The disease itself is heterogenous, with many different prognostic factors, most notably three pathologic subtypes--epithelial, sarcomatoid, and biphasic--that have different natural histories, and varying responses to treatment. Finally, response assessment is problematic, since pleural-based lesions are difficult to measure accurately and reproducibly. Assessment criteria often vary between trials, making some cross-trial comparisons difficult to interpret. Despite these limitations, in recent years, there has been a surge of optimism regarding systemic treatment of this disease. Several cytotoxic agents have been shown to generate reproducible responses, improve quality of life, or prolong survival in mesothelioma. Drugs with single-agent activity include pemetrexed, raltitrexed, vinorelbine, and vinflunine. The addition of pemetrexed or raltitrexed to cisplatin prolongs survival. The addition of cisplatin to pemetrexed, raltitrexed, gemcitabine, irinotecan, or vinorelbine improves response rate. The combination of pemetrexed plus cisplatin is considered the benchmark front-line regimen for this disease, based on a phase III trial in 456 patients that yielded a response rate of 41% and a median survival of 12.1 months. Vitamin supplementation with folic acid is essential to decrease toxicity, though recent data suggests that there may be an optimum dose of folic acid that should be administered; higher doses may diminish the effectiveness of pemetrexed. There are also several unresolved questions about the duration and timing of treatment with pemetrexed that are the subject of planned clinical trials. It is essential to recognize that the improvements observed with the pemetrexed/cisplatin combination, though real, are still modest. Other active drugs or drug combinations may be more appropriate for specific individuals, and further research is still needed to improve upon these results. Since the majority of mesotheliomas in the United States occur in the elderly, non-cisplatin-containing pemetrexed combinations may be more appropriate for some patients. Now that effective agents have been developed for initial treatment, several classical cytotoxic drugs and many novel agents are being evaluated in the second-line setting. These include drugs targeted against the epidermal growth factor, platelet-derived growth factor, vascular endothelial growth factor, src kinase, histone deacetylase, the proteasome, and mesothelin. Given the progress made in recent years, there is reason to believe that more effective treatments will continue to be developed.

In plain English

This article is a review by a single author of drug treatments for mesothelioma. It reports no new study of its own and does not examine asbestos exposure. The author summarized earlier and ongoing clinical trials of chemotherapy and newer targeted drugs. Among the trials reviewed was a 456-patient phase III trial. In that trial, pemetrexed plus cisplatin gave a response rate of 41% versus 17% for cisplatin alone, and a median survival of 12.1 versus 9.3 months. A 250-patient trial of raltitrexed plus cisplatin reported a 24% response rate and 11.2 months median survival, compared with 14% and 8.8 months for cisplatin alone. The author described early trials of several targeted drugs as showing little activity. The author also noted that trials in this uncommon disease are small, that patients are hard to stage without surgery, and that tumors are hard to measure. The author concluded that chemotherapy improves survival, response and quality of life, though the gains with pemetrexed and cisplatin are still modest.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Review and opinion article (single author) of systemic drug treatments for mesothelioma
• Who was studied: No study population of its own; the author reviewed published and ongoing clinical trials of drug treatments in mesothelioma patients, with a focus on recent studies and novel agents
• Exposure: Not an asbestos exposure study; the article reviews chemotherapy drugs (such as pemetrexed, raltitrexed, cisplatin, gemcitabine, vinorelbine) and novel targeted agents as treatments
• Main results:
  • In the 456-patient phase III trial the author reviewed, the response rate was 41% for pemetrexed plus cisplatin vs 17% for cisplatin alone (P < 0.001)
  • In that same reviewed trial, median survival was 12.1 months for pemetrexed plus cisplatin vs 9.3 months for cisplatin alone (P = 0.020)
  • In a reviewed 250-patient phase III trial, raltitrexed plus cisplatin gave a 24% response rate and 11.2 months median survival, vs 14% and 8.8 months for cisplatin alone
  • The author reported that imatinib produced no responses in 4 phase II trials
  • In a reviewed 108-patient randomized phase II trial, progression-free survival was 6.9 months with bevacizumab added to gemcitabine plus cisplatin vs 6.0 months with placebo (HR 0.93, P = 0.88)
  • The author judged the improvements with pemetrexed plus cisplatin to be real but still modest
• The authors' conclusion: The author concluded that mesothelioma no longer inspires nihilism and that chemotherapy improves survival, response and quality of life, with many novel agents under investigation
• Limitations the authors state:
  • The author noted that the trials reviewed are mostly small because the disease is uncommon
  • The author noted that staging systems are surgically based, so patients who have not had surgery are hard to stage accurately
  • The author noted that response assessment is problematic because pleural-based lesions are hard to measure

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Systemic Therapy, Histology, Chemotherapy, Median Overall Survival, Clinical Trial, Staging, Sarcomatoid.

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• Systemic treatment of malignant pleural mesothelioma — F. Grosso, G.V. Scagliotti (2012)
• Malignant pleural mesothelioma: current concepts in treatment — A. Tsiouris, R.K. Walesby (2007)
• Pemetrexed for malignant pleural mesothelioma: Is it a standard second-line therapy? — K. Tamura, Y. Fujiwara (2010)
• Pemetrexed in the treatment of malignant mesothelioma: results from an expanded access program in Germany — M. Reck, R.A. Stahel, et al. (2010)

Browse more research in Current Treatment Options in Oncology, or return to medical research.