Important Research Articles
Mesothelioma patients are often burdened with researching their disease and its treatment. Unfortunately, decades of research into mesothelioma still does not render promising or clear-cut standards of treatment. Below is a sampling of important research articles that relate not only to treatment of mesothelioma but also its causes to give patients a complete understanding of the disease.
Talc Pleurodesis
Mesothelioma patients usually experience discomfort in the chest and shortness of breath caused by accumulation of fluid around the lung, known as pleural effusions. Talc pleurodesis is a palliative surgical procedure designed to alleviate these symptoms. It is lower cost than radical surgery and is associated with a shorter hospital stay. In this procedure, the space between the layer of tissue surrounding the lungs and lining the chest wall (called the pleura) is eliminated by using an irritant such as talc powder to create inflammation. This joins the tissues together, thus not allowing space for fluid build-up.
2-20-07: Talc mediates angiostasis in malignant pleural effusions via endostatin induction. Najmunnisa, N., European Respiratory Journal, 2007; 29: 761–769.
According to a report released from the University of Florida, using talc for pleurodesis procedures is the most effective agent to harden the tissue. However, it is still unclear how effective talc is in completely resolving pleural malignant mesothelioma.
8-18-06: Thoracoscopic Talc Poudrage in Malignant Pleural Effusions: Effective Pleurodesis Despite Low Pleural pH. Y Aelony, RR King and C Boutin. Chest 1998; 113;1007-1012.
This study concludes that thoracoscopic talc poudrage (TTP) is an effective pleurodesis technique in patients with malignant pleural effusions, even when the pleural pH is low. The short hospital stay and high success rate make this approach a good choice in palliating symptomatic malignant pleural effusions.
10-07-06: Prolonged Survival After Talc Poudrage for Malignant Pleural Mesothelioma. Aelony Y, Yao JF. PubMed. Department of Internal Medicine, Kaiser Permanente Medical Center, Harbor City, CA 90710, USA. (Nov. 1995)
Study concludes that TTP remains a safe, low-morbidity, inexpensive primary palliative treatment option for malignant pleural mesothelioma and a valid control arm option for therapeutic trials. TTP is ideal for patients who wish to avoid thoracotomy, long hospital stays and morbidity from multimodality therapy.
Pleurectomy with Decortication (P/D)
Pleurectomy with decortication (P/D) is a lung-sparing surgery which involves the removal of the parietal pleura (the membrane lining the thoracic wall) and decortication of the visceral pleura (the membrane lining of the lung). Part of the diaphragm and/or the pericardium (the membrane lining the heart) may also be removed, depending on the extent of the tumor. There is a risk of local recurrence of disease, however this procedure is comparable in survival rates to the more radical extrapleural pneumonectomy, and is associated with higher post-operative quality of life.
1-30-2006: Improved Survival with Interferon Alpha Maintenance Therapy Following Pleurectomy/Decortication and Radiation for Malignant Pleural Mesothelioma, as presented by Dr. Robert Cameron to the Society of Thoracic Surgeons, January 30, 2006.
Dr. Robert Cameron, Director of the Mesothelioma Program at UCLA, has performed this surgery for qualifying patients for over a decade. His approach of "less is more" guides his work in removing all visible tumor while keeping the healthy, often uninvolved lung intact. His philosophy also translates into his multimodal approach including radiation and maintenance therapy.
Dr. Cameron gave the above presentation to the Society of Thoracic Surgeons in 2006 to demonstrate that "maintenance therapy" such as interferon alpha may have a role in treating mesothelioma patients. The median survival of patients who underwent his pleurectomy with decortication, followed by radiation and maintenance therapy of interferon alpha was 37 months. We recommend you view the presentation for yourself.
5-21-04: Radical Pleurectomy/Decortication and Intraoperative Radiotherapy Followed by Conformal Radiation with or without Chemotherapy for Malignant Pleural Mesothelioma. J Thorac Cardiovasc Surg 2002; 124:1183-9. Terry T. Lee, MD, et al,
In one retrospective study, Drs. Terry T. Lee et al assert that the multi-modal approach of performing a pleurectomy/decortication followed by radiotherapy and, in some cases, chemotherapy appears to be a comparably successful alternative to extrapleural pneumonectomy. In the study, 32 patients with malignant pleural mesothelioma were evaluated between 1995 and 2000. The median overall survival was reported to be 18.1 months. The median interval between operation and the progression of the tumor was 12.2 months. Surgery does not completely eradicate all tumor, and local control was the main problem encountered. For this reason, adjuvant therapies such as post-surgery radiation and/or chemotherapy or intra-operative hyperthermic chemo perfusion are needed.
5-21-04: A phase II trial of pleurectomy/decortication followed by intrapleural and systemic chemotherapy for malignant pleural mesothelioma. J Clin Oncol, 12(6), 1156-1163. Rusch, V., Saltz, L., Venkatraman, E., Ginsberg, R., McCormack, P., Burt, M., Markman, M., Kelsen, D. (1994). Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
In another study, Dr. Valerie Rusch et al investigated the effectiveness of a combined modality treatment consisting of surgical resection followed by intrapleural chemotherapy and then systemic chemotherapy. A median survival of 17 months was observed for the 27 patients who underwent pleurectomy/decortication and subsequent chemotherapy treatment. The survival rate at one year was 68% and 40% at two years. As was also stated in this study, local control was the most prominent difficulty in preventing relapse. The researchers found this treatment technique to be comparable to and in some cases better than other multimodality approaches, also concluding that improvement in local control is needed.
5-21-04: Surgical treatment of mesothelioma: pleurectomy. Chest, 116(6), 446S-449S. Roberts, J.R. (1999). Department of Cardiac and Thoracic Surgery, Vanderbilt Hospital, Nashville, TN
This report compares the P/D with the EPP and emphasizes the need for randomized trials to be able to scientifically and statistically compare the two procedures. In addition, the use of postoperative radiation or intrapleural chemotherapy, which is commonly used in conjunction with surgery, has shown no significant improvement on long-term survival or symptom palliation. Due to this lack of data, there is no definitive standard of care for mesothelioma. There was no significant difference found in overall survival rates, however pleurectomy is associated with much less postoperative morbidity and mortality. It has been suggested that extrapleural pneumonectomy improves local control and may increase survival in patients with favorable histology and earlier stage disease, but may also expose the patient to more distant metastases.
Extrapleural Pneumonectomy (EPP)
An extrapleural pneumonectomy (EPP) is a surgery which removes one lung and part of the parietal pleura. It also removes the diaphragm and the pericardium.
11-05-07: Radical surgery for malignant pleural mesothelioma: results and prognosis. Interact Cardiovasc Surg. Hiroshima University, Japan. Mimura, T., Ohbayashi, C., Okada, M., Sakuma, T., Soejima, T., & Tsubota, N. (2007)
This report carried out a retrospective review of 34 patients who underwent P/D surgery and 31 patients who underwent EPP. They found the median survival after P/D to be 17 months, and 13 months after EPP. The survival rate at three years was 24% and 33%, respectively. An analysis of the data revealed that older age, non-epithelial histology, and stage III-IV disease are negatively contributing factors. The surgical procedure performed was not shown to impact the outcome.
9-29-04: Long-Term Survivorship and Quality of Life after Cytoreductive Surgery Plus Intraperitoneal Hyperthermic Chemotherapy for Peritoneal Carcinomatosis. Annals of Surgical Oncology, 10(2):155-162, 2003. R. McQuellon, et al,
6-30-04: Prevention, Early Detection, and Management of Complications After 328 Consecutive Extrapleural Pneumonectomies. J Thorac Cardiovasc Surg 2004; 128:138-1469. David J. Sugarbaker, MD, et al,
5-21-04: Pleuropneumonectomy in the Treatment of Malignant Pleural Mesothelioma. Chest. 1999;116:450S-454S. Sean C. Grondin, MD, et al,
1-31-04: Radical surgery for mesothelioma. BMJ, 328(7434), 237-238. Peto, J., Swift, S., Treasure, T., & Waller, D. (2004)
This report calls attention to the growing need for mesothelioma research and subsequent improvements in treatment. It can take twenty to forty years for mesothelioma symptoms to develop, putting patients at a disadvantage for catching the disease in its earliest stages. Surgery and adjuvant therapies are currently the most successful options for mesothelioma treatment, with reports in the UK of five-year survival rates as high as 48% in selected subsets of patients with favorable histology and no nodal metastases.
4/30/03: Witness a surgery broadcast by Brigham and Women’s Hospital, performed by Dr. David Sugarbaker.
Comparison Articles
Much debate and research exists regarding these two methods of surgical resection in treating mesothelioma. Because no randomized clinical studies have been conducted to compare P/D to EPP, much of the survival data, quality of life issues, as well as the techniques behind the surgeries remain unproven.
3-10-2008: “Radical Decortication/Pleurectomy Best Surgical Approach for N2 Malignant Mesothelioma.” Doctors Guide Dispatch. By Ed Sussman. Based on presentation title: Which is the Best Surgical Approach for N2 Positive Epithelial Malignant Mesothelioma? Long-Term Outcome After Extrapleural Pneumonectomy Versus Radical and VATS Decortication/Pleurectomy. Abstract 42
There is no current well-established treatment for malignant pleural mesothelioma. An even greater variety in the mode of treatment occurs at later stages of cancer. A study conducted in the United Kingdom found that for patients with stage 3 epithelial type mesothelioma, survival was significantly more improved with radical pleurectomy/decortication surgery than with less radical treatment procedures.
1-31-07: Extrapleural Pneumonectomy Is the Preferred Surgical Management in the Multimodality Therapy of Pleural Mesothelioma: Con Argument. Robert B. Cameron, MD. David Geffen School of Medicine at UCLA.
Dr. Cameron's argument against the EPP fleshes out many of the most significant pros and cons behind each surgery. This is a must read for patients deciding between surgeries. Dr. Cameron's rationale is:
- There is no evidence the EPP is superior to the lung-sparing P/D
- Both surgeries carry potentially serious risk
- Only experienced surgeons should attempt either surgery
- "The EPP should not become the (Sir Edmund Hillary) operation onf Thoracic Surgery: being done simply because it is there and because it can be done."
1-16-06: Consensus Report: Pretreatment Minimal Staging and Treatment of Potentially Resectable Malignant Pleural Mesothelioma. J. Meerbeeck, M. Boyer.
This report shows
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There is no evidence the EPP is superior to the lung-sparing P/D.
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There is no evidence that multi-modal therapy is superior since clinical trials are not appropriately designed and risk selective patient recruitment.
- A new, uniform clinical staging system is needed, along with a large clinical database/registry.
1-16-06: Surgical Management of Malignant Pleural Mesothelioma: a Systematic Review and Evidence Summary. D. Maziak, A. Gagliardi, A. Haynes, J. Mackay, W. Evans. The Cancer Care Ontario Program in Evidence-based Care Lung Cancer Disease Site Group.
5-21-04: Surgical Treatment of Malignant Pleural Mesothelioma - A Review. Ruth, et al, Chest; 2003; 23:551-561.
This report shows
- Median Survival after Pleurectomy is 9 to 20 months.
- Median Survival with Extra-Pleural Pneumonectomy is 9 to 19 months.
- When comparing EPP with pleurectomy/decortication, a lower recurrence rate has been reported (10% after EPP vs 52% after pleurectomy), but EPP patients have higher rates of tumor relapses in distant sites of body.
- Mortality rate for EPP is around 5% and morbidity is between 25-50%.
- For Pleurectomy/Decortication, mortality rate is 1-2%.
- Intrapleural chemo approach has probably not shown full potential.
- The combination of complete surgery, whether EPP or P/D, along with radiation therapy seems promising but only in selected patients.
- To evaluate merits of treatment options, need to conduct a radmonized phase II clinical trial, comparing defined treatment arm with a no treatment arm.
There does not seem to be a survival benefit for patients undergoing EPP in comparison to patients undergoing pleurectomy.
2-07-02: Surgical Roles and Novel Therapies, preface by Roger Worthington
The Division of Thoracic Surgery at the Brigham and Women's Hospital in Boston Massachusetts provides diagnostic and treatment services to patients with benign and malignant neoplasms and other disorders of the lung, esophagus, mediastinum and chest wall. Their website provides complete review of services available, how to set up an appointment, whom to call, and how to prepare for surgery and rehabilitate afterwards. http://www.chestsurg.org
Multimodal Approach
1-28-08: Induction chemotherapy, extrapleural pneumonectomy (EPP) and adjuvant hemi-thoracic
radiation in malignant pleural mesothelioma (MPM): Feasibility and results. Rea, F, Marulli, G.,
Lung Cancer (2007) 57, 89—95
This article describes the use of a trimodal approach in malignant pleural mesothelioma (MPM). Specifically patients were initially treated with chemotherapy (Carboplatin and Gemcitabine) followed by extrapleural pneumonectomy (EPP) and radiation therapy. A total of 21 patients took part in this study. Overall the results were not particularly remarkable. No complete response was seen in any of the patients treated. Furthermore about half of the patients experienced some form of morbidity. Median survival was 25 months, with only a 19% five year survival. The highest survival was seen in patients who originally had a low-grade confined tumor. The authors point out that much more work (larger studies) are needed to accurately and confidently evaluate the benefits of various experimental treatments. (Submitted by Nikos Hontzeas)
5-21-04: A phase II trial of surgical resection and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma. J Thorac Cardiovasc Surg, 122(4), 788-795. Rusch, V.W., Rosenzweig, K., Venkatraman, E., Leon, L., Raben, A., Harrison, L., Bains, M.S., Downey, R.J., & Ginsberg, R.J. (2001)
Biomarkers
6-05-07: MESOMARK available. The world’s first in vitro test to measure and monitor biomarkers in mesothelioma is available in the United States for humanitarian use only. Find laboratory locations near you and talk to your doctor about the assay test.
6-04-07: Diagnostic biomarker of asbestos-related mesothelioma: example of translational research
7-18-06: Mesothelioma test 'a breakthrough'
7-18-06: Osteopontin: marker for mesothelioma
Immunotherapy
2-27-07: Immunotherapy and malignant mesothelioma: clinical perspectives
Asbestos Exposure
2-27-07: Age and sex differences in malignant mesothelioma after residential exposure to blue asbestos (crocidolite)
Gene Therapy
3-10-08: A Conditional Mouse Model for Mesothelioma. Cell Press (2008, March 10). Mouse Model For Mesothelioma Reproduces Human Disease. ScienceDaily. Johan Jongsma.
An important aspect of cancer research is the ability to study cancer and treatment in vivo, rather than in a test tube. Researchers at the Netherlands cancer institute have established a mouse model for mesothelioma. That is, they have been able to create a cancer in mice that behaves nearly the same as mesothelioma in humans. This advancement will enable further research to be conducted on new and better treatment methods.
6-04-07: Mechanisms of action of inhaled fibers, particles and nanoparticles in lung and cardiovascular diseases
3-15-07: DNA may predict benefit of lung cancer treatment
Peritoneal Mesothelioma
1-28-07: Malignant peritoneal mesothelioma: treatment with maximal cytoreductive surgery plus intraperitoneal chemotherapy. Elias D, Bedard V., Gastroenterol Clin Biol. 2007 Oct; 31(10):784-8.
This article deals with treatment of diffuse malignant peritoneal mesothelioma (MPM) which accounts for only 25% of mesothelioma cases, but has some of the lowest overall median survival rates between 12-24 months. Traditionally, treatment of this disease involves surgery followed by systemic chemotherapy. The authors have opted to perform maximal cytoreductive surgery followed by localized intraperitoneal chemotherapy with (or without) hyperthermia. Results for only 22 patients are reported here. Patients were randomly assigned to treatment groups receiving combination chemotherapy with no hyperthermia, and then subsequently one type of chemotherapeutic agent with hyperthermia. However, the extent to which treatment could be delivered was limited by the grade of the tumor and the severity of the disease per patient. Following the treatments the authors reported an overall increase in survival to an excess of 100 months. However, the authors do point out that patients with severe diffuse peritoneal disease were not “eligible” for this study and furthermore, the good results could absolutely be explained by hyperthermic chemotherapy but could be a result of the complete cytoreductive surgery. Thus the authors conclude that these results cannot be compared with those obtained with conventional therapy. (Submitted by Nikos Hontzeas)
Chemoprevention
10-25-06: Recent articles addressing the efficacy trial of ß-Carotene and Retinol as a preventative therapy for persons exposed to asbestos
Chemotherapy
2-27-08: Imnatinib Mesylate Enhances Therapeutic Effects of Gemcitabine in Human Malignant Mesothelioma Xenografts. Bertino et al., Clin Cancer Res 14:2, 2008 p.541-548
This article describes the use of Gemcitabine and Pemetrexed in combination with Imatinib mesylate in the treatment of malignant mesothelioma cancer. The authors follow-up their previously published in vitro work with a mouse in vivo model, in which human malignant mesothelioma tissue is xenografted onto SCID mice. Imatinib mesylate is an inhibitor of platelet-derived growth factor receptor b which has been shown to be activated in mesothelioma. The inhibitor was tested in combination with either Gemcitabine or Pemetrexed and cytotoxicity to cancer cells was observed by previously labeling the cancer cells with a luciferase gene. It was observed that Gemcitabine was cytotoxic to cancer cells whereas Pemetrexed had no effect. Furthermore, the combination of Gemcitabine and Imatinib mesylate further increased cancer cell death. (Submitted by Nikos Hontzeas)
2-27-08: Alpha-Tocopheryl succinate: Toxicity and Lack of Anti-tumor Activity in Immuno-competent Mice. Ireland et al., Food and Chemical Toxicology, 46, 2008 p. 508-512.
Contrary to the Bertino article (above), in this article the authors claim that they could not reproduce in vivo experiments done previously by another group. This is quite interesting as there was a published paper (Tomasetti et al., Int. J. Cancer, 109, 2004 p. 641-642) that claimed to be able to induce apoptosis in malignant mesothelioma cancer cells by exposing these cells to alpha-Tocopheryl succinate, an analogue of vitamin E. This was shown in vivo in mice. Unfortunately, Ireland et al. could not reproduce this experiment. Moreover, according to their results, systemic administration of alpha-Tocopheryl succinate to mice was not only incapable of inducing apoptosis in mesothelioma cancer cells but also was extremely toxic to the mice. Ireland et al. obviously contradict Tomasetti et al., and it will take more work by a third party to validate anyone of these two groups. (Submitted by Nikos Hontzeas)