Mesothelioma: Treatment & Medication

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Mesothelioma: Treatment & Medication
http://emedicine.medscape.com/article/280367-treatment
Author: Winston W Tan, MD, Assistant Professor of Medicine, Mayo Medical School; Consulting Staff, Mayo Group Practices, Contributor Information and Disclosures

Treatment

Medical Care

Treatment options for the management of malignant mesothelioma include surgery, chemotherapy,13, 14 radiation, and multimodality treatment. Surgery in patients with disease confined to the pleural space is reasonable.


Chemotherapy
Currently, cisplatin as a single drug has been used as the standard drug for phase III clinical trials. None of the standard treatment options has improved survival. (See related CME at Advances in the Systemic Therapy of Malignant Pleural Mesothelioma and Chemotherapy Does Not Improve Survival in Patients With Mesothelioma.) The most active agents are anthracycline, platinum, and alkylating agents; each produces a response rate of 10-20%.
Vogelzang et al presented the results of a phase III study of pemetrexed in combination with cisplatin versus cisplatin alone. Pemetrexed (500 mg/m2/d) and cisplatin (75 mg/m2/d) or cisplatin (75 mg/m2/d) was given on day 1. Both arms were given every 21 days. The median survival time in the cisplatin/pemetrexed arm was 12.1 months versus 9.3 months for cisplatin alone. The response rate was 41.3% for the cisplatin/pemetrexed arm and 16.7% for the cisplatin arm. Folic acid and vitamin B-12 were given routinely to prevent the adverse effects of pemetrexed. This trial established the regimen as the standard choice for this disease.15 See related CME at Management of Metastatic Non-Small Cell Lung Cancer (Slides With Transcript).
Santoro et al reported the results of an expanded access program that the activity of pemetrexed/cisplatin and pemetrexed/carboplatin in chemonaive patients had similar time to progressive disease and 1-year survival rates. The pemetrexed/cisplatin group demonstrated a response rate of 26.3% compared with 21.7% for the pemetrexed/carboplatin group, similar 1-year survival rates (63.1% vs 64%) and median time to progressive disease (7 vs 6.9 months).16
The combination of pemetrexed plus gemcitabine as first-line chemotherapy for patients with peritoneal mesothelioma is active and can be an option for patients who cannot take cisplatin. A phase II study of gemcitabine 1000 mg/m2 on day 1 and day 8 and pemetrexed 500 mg/m2 day 8 every 21 days for 6 cycles or until progression showed a response rate of 15% (95% CI, 3.2-37.9%) with 3 patients with partial response. Disease control rate was 50%. The most common nonhematologic toxicities include fatigue (20%), constipation (10%), vomiting (10%), and dehydration 10%. Hematologic toxicities include neutropenia (60%) and febrile neutropenia (10%).17
Single-agent pemetrexed showed a response rate of 10.5%, median time to progressive disease was 6 months, and median survival was 14 months in chemo-naive patients. Of the pretreated patients, the response rate was 12.1% and median time to progressive disease was 4.9 months.18
A 1999 phase II study by Byrne et al using cisplatin (100 mg/m2) on day 1 and gemcitabine (1000 mg/m2) administered intravenously on days 1, 8, and 15 of a 28-day cycle for 6 cycles showed response rates of 47.6% (complete and partial response), 42.8% (stable disease), and 9.5% (progressive disease). The median response duration was 25 weeks, progression-free survival was 25 weeks, and the overall survival was 41 weeks. Toxicity was mainly gastroenterologic and hematologic in nature.19
Several other combinations have been found to be active, including cisplatin/doxorubicin (Adriamycin)/mitomycin C, bleomycin/intrapleural hyaluronidase, cisplatin/doxorubicin (Adriamycin), carboplatin/gemcitabine, and cisplatin/vinblastine/mitomycin C.20 The cisplatin/gemcitabine combination has yielded the best results.
Ranpirnase (Onconase) is a novel cytotoxic ribonuclease. It is a nonmyelosuppressive agent with minimal apparent toxicity to vital organs. It binds to the cell surface and penetrates the cell's interior through the energy-dependent endocytotic process. In the cytosol, it degrades tRNA, and this damage constitutes a signal for apoptosis and contributes to inhibition of cell growth and proliferation.21
The dose-limiting toxicity was renal manifested by proteinuria, azotemia, peripheral edema, flushing, myalgia, dizziness, and decreased appetite.
In a Phase II study by Miluski et al, 105 patients with 0-2 performance status were treated with ranpirnase. Median survival time was 6 months for the intent to treat and 8.3 months for the treatment target group. Among the 81 patients assessable for tumor response, 4 had partial response, 2 had minor regressions, and 35 experienced stabilization of previously progressive disease.22
With the isolation of mesothelial cell lines, several chemotherapeutic agents are being tested to assess their efficacy. One explanation for the poor response to chemotherapy is the low apoptotic rate, as evidenced by low BCL2 and BAX expression.23 These data suggest that apoptosis is not a key phenomenon in mesothelioma development and histologic differentiation.
Numerous trials of chemotherapeutic agents have been performed; however, until recently, the studies were small, the staging systems used were different, and the measurements of disease were inaccurate.
Radiation
Results with radiation therapy are also disappointing.24
Radiation has no effect on survival, but it has caused significant palliation in 50% of patients treated for chest pain and chest wall metastasis.
Trimodality therapy
This involves a combination of all 3 standard strategies (ie, surgery, chemotherapy, radiation).
One trimodality approach involved extrapleural pneumonectomy followed by combination chemotherapy and radiotherapy. Overall survival rates were 45% at 2 years and 22% at 5 years.
Lymph node involvement was a significant negative prognostic factor. The epithelial type had a better survival rate compared with the sarcomatous or mixed type (65% vs 20% at 2 y and 27% vs 0% at 5 y).
Survival based on the Brigham staging system was 22 months for stage I, 17 months for stage II, and 11 months for stage III.
Overall median survival was 17 months, yielding a 2-year survival rate of 36% and a 5-year survival rate of 14%. Epithelial cell type survival was better, with a 2-year survival rate of 68% and 5-year survival rate of 46%.
Different chemotherapeutic regimens found to be useful in the trimodality treatment include cyclophosphamide/doxorubicin (Adriamycin)/cisplatin, carboplatin/paclitaxel, and cisplatin/methotrexate/vinblastine. External beam radiotherapy is delivered in a standard fractionation over 5.5-6 weeks.
Surgical Care

Surgical resection has been relied upon because radiation and chemotherapy have been ineffective primary treatments.25 The 2 surgical procedures used are pleurectomy with decortication and extrapleural pneumonectomy.


Pleurectomy with decortication is a more limited procedure and requires less cardiorespiratory reserve. It involves dissection of the parietal pleura, incision of the parietal pleura, and decortication of the visceral pleura followed by reconstruction. It has a morbidity rate of 25% and a mortality rate of 2%.26 It is a difficult procedure because the tumor encases the whole pleura; the local recurrence rate is high.
Extrapleural pneumonectomy is a more extensive procedure and has a higher mortality rate. Recently, the mortality rate has been lowered to 3.8%. It involves dissection of the parietal pleura; division of the pulmonary vessels; and en bloc resection of the lung, pleura, pericardium, and diaphragm followed by reconstruction. It provides the best local control because it removes the entire pleural sac along with the lung parenchyma.
With surgery alone, the recurrence rate is very high and most patients die after a few months. At least half the patients who have local control with surgery have distant metastasis upon autopsy.
In patients with epithelioid type, if fit to tolerate a thoracotomy, the best option is still a thoracotomy and macroscopic clearance of the tumor as part of multimodality therapy.
Consultations

If an infection is suggested initially, consultation with a pulmonary specialist is essential if the infection does not resolve within 2 weeks with adequate antibiotic treatment.
Chest radiographs are mandatory for follow-up if the infection has resolved. If the patient has diffuse calcification of the pleura and a history of weight loss with chronic cough, a full evaluation by a pulmonary specialist and oncologist is necessary.
A referral for thoracoscopy is warranted if the diagnosis is considered and the initial workup is not diagnostic.
Occupational history is important, and family members with exposure to asbestos should also be evaluated.
Diet

Patients are usually cachetic after surgery, chemotherapy, and radiation. Good supportive care and a regular nutritional status assessment are warranted. Patients should be referred to a nutritionist.
Activity

Beginning physical activity as soon as possible is important to prevent postoperative complications.
Pulmonary physiotherapy is very helpful because of the extensive lung resection in such patients.
Medication

Treatment options for the management of malignant mesothelioma include surgery, chemotherapy, radiation, and multimodality treatment. Currently, no therapy is considered standard. The standard methods of surgery, radiation, or chemotherapy alone have not improved survival (see Treatment).

Pemetrexed disodium was recently approved by the US Food and Drug Administration to treat patients with malignant pleural mesothelioma in unresectable disease and those who are not candidates for curative surgery. Several trials from a combination drug to therapy with pemetrexed have been performed. Hughes et al showed a 32% response rate using pemetrexed 500 mg/m2 and carboplatin (AUC-5) on an every 21-day schedule.27 An interesting combination of drugs, including raltitrexed and oxaliplatin, has shown a response rate of 20% in previously treated patients.

Antineoplastic Agent, Miscellaneous

These agents interfere with cell reproduction. Some agents are cell-cycle specific, while others (eg, alkylating agents, anthracyclines, cisplatin) are not phase-specific. Cellular apoptosis (ie, programmed cell death) is also a potential mechanism of many antineoplastic agents.

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