Malignant Mesothelioma of the Pleural Space
Malignant Mesothelioma of the Pleural Space
Grondin and Sugarbaker provide an excellent, thorough review of malignant pleural mesotheliomas. Nearly 3,000 new mesotheliomas will be diagnosed in the United States this year. On the positive side, epidemiologists estimate that workplace regulations enforced in the early 1970s will lead to a decrease in incidence over the next 30 years, and suggest that, by 2030, a plateau of about 1,000 cases per year will be reached.
Unfortunately, a nihilistic approach to this disease predominates. In evaluating reports on the treatment of mesothelioma, one has to realize that most series remain small and that very little phase III data exist to answer questions. Reviewing small series, one must remember that up to 15% of patients with mesothelioma have an indolent course, and in rare cases, survival durations of up to 15 years have been reported among untreated patients.
Diagnosis and Staging
Modern day radiologic evaluation by computed tomography (CT) and magnetic resonance imaging (MRI) allows for a much better clinical assessment of disease extent than was possible previously. Positron emission tomography (PET) is emerging as a powerful tool in differentiating between benign and malignant pleural changes and also in staging established mesotheliomas. Transdiaphragmatic involvement can be evaluated by laparoscopy.
The role of pleuroscopy and thoracoscopy in evaluating unexplained pleural effusions cannot be overemphasized. It is indeed very important to place pleuroscopy and thoracoscopy incisions strategically in a candidate for resection. A single-incision pleuroscopy often will suffice in establishing the diagnosis, and multiple-port thoracoscopy usually is not required. Resection is much easier when the pleural cavity has been breached only at one site.
The ability of pathologists to render a diagnosis of mesothelioma with less material is also an improvement, and both electron microscopic and immunocytochemical studies are key factors responsible for this improvement.
Referral to expert pathologists is another option when the diagnosis is uncertain.
Although a better staging classification than the Butchart system clearly was needed, unfortunately, three different staging systems are currently being used and described in the various reports. Lets hope that we will be able to agree on one system for the sake of uniformity in staging and reporting.
Recent Reports of Chemotherapy
In reviewing the results of chemotherapy in mesothelioma, Grondin and Sugarbaker have omitted two recent reports. In 1996, Hunt et al achieved a response rate of 52% with the combination of cisplatin (Platinol), methotrexate, and vinblastine.
In 1998, Byrne et al reported a 47% response rate with the use of cisplatin and gemcitabine (Gemzar). A recently opened Southwest Oncology Group (SWOG) phase II trial (SWOG 9810) is evaluating the latter combination in patients with unresectable disease.
Brigham and Womens Hospital Multimodality Approach
Dr. Sugarbaker and his group are to be congratulated for pursuing a multimodality approach to this disease. We knew that mesotheliomas are radiosensitive, but that the delivery of radiation therapy with curative intent was difficult. Single-modality chemotherapy had never yielded response rates greater than 15%; however, combination chemotherapy is showing interesting early results.
In addition, we had learned from the surgical series that operative mortality could be reduced and that positive microscopic margins are frequent after resection; hence, the need for adjuvant therapy to maximize local control. We had also learned that systemic failures are significant in long-term survivors of extrapleural pneumonectomy, pointing to the need for systemic therapy if one wanted to improve the overall results.
The Brigham Group has adopted an approach of upfront surgery followed by adjuvant chemotherapy and radiation therapy. At the University of Washington, based on our experience with the multimodality treatment of lung cancer, we felt that the delivery of chemotherapy should be easier prior to surgery. (Our approach is described in more detail below.)
It is unclear to me why cyclophosphamide, Adriamycin, and Platinol (CAP) chemotherapy was changed to the combination of carboplatin (Paraplatin) and paclitaxel (Taxol) in the Brigham protocol. Was it difficult to deliver CAP in the adjuvant setting?
I agree completely with Drs.Grondin and Sugarbaker that one of the major advantages of extrapleural pneumonectomy over pleurectomy is that it permits a safer and possibly more aggressive delivery of radiation therapy once the lung has been removed. The Brighams experience with extrapleural pneumonectomy is by far the largest reported, and their operative mortality of 4% is to be noted and applauded.
The surgical technique of extrapleural pneumonectomy is fairly standard. I recommend the use of polytetrafluoroethylene (PTFE) grafts to repair the diaphragmatic defect, and, on the right side, suggest a tight repair in an attempt to push the liver away from the radiation field.
The use of large surgical clips to mark areas of concern helps target radiation therapy. Also, I believe it is important for the surgeon to have good communication with the pathologist to facilitate meticulous mapping of the tumor and its margins. This, in turn, makes it easier to plan radiation therapy.
University of Washington Multimodality Approach
Our trimodality approach at the University of Washington Medical Center consists of induction chemotherapy with the combination of cisplatin, methotrexate, and vinblastine followed by extrapleural pneumonectomy and adjuvant fast-neutron radiation therapy. To date, nine patients have completed this approach, and the results are early but interesting.
Six patients have demonstrated a clinical response to chemotherapy, including one complete pathologic response in a patient with a sarcomatous mesothelioma. Fast-neutron radiation therapy has been well-tolerated. There have been no 90-day perioperative deaths. International Mesothelioma Interest Group (IMIG) pathologic staging has revealed one complete response,five stage III mesotheliomas, and three stage IV tumors.
Three patients have died, two of recurrent disease at 1 year; the third patient died 8 months after surgery for cirrhosis, without evidence of cancer at autopsy. Follow-up on the other six patients remains short.
Diffuse malignant mesothelioma remains a very deadly disease for which multimodality therapy may be applicable in a minority of patients. The types of modalities to use and their sequence remains to be defined.
The various innovative therapies being evaluated are exciting. To date, intrapleural therapies have shown varying results, but the effects seen are superficial, and achieving deep penetration remains a problem.
1. Hunt KJ, Longton G, Williams MA, et al: Treatment of malignant mesothelioma with methotrexate and vinblastine, with or without platinum chemotherapy. Chest 109:1239-1242, 1996.
2. Byrne MJ, Davidson JA, Musk AW, et al: Cisplatinum and gemcitabine treatment for mesothelioma: A phase II study (abstract). Proc Am Soc Clin Oncol 17:464a, 1998.
3. Rusch VW, Piantadosi S, Holmes CE: The Lung Cancer Study Group: The role of extrapleural pneumonectomy in malignant pleural mesothelioma. J Thorac Cardiovasc Surg 102:1-9, 1991.