Mesothelioma - Peritoneal Mesothelioma
Chemotherapy Single Agents
Mesothelioma is notorious for its resistance to many chemotherapeutic agents. Possible mechanisms of resistance have implicated overexpression of the multi-drug resistance-associated protein (MRP) and of gamma-glutamylcysteine synthetase rather than P-glycoprotein .190a Trials of single agents are summarized in Table 89.7. In large series, response rates to single agents rarely exceed 20%, with few, if any, complete responses. These results are in general agreement with those obtained in a nude mouse model of human mesothelioma.56,60,61
The most widely tested agents include anthracyclines (doxorubicin, epirubicin) and platinum analogues (cisplatin, carboplatin); response rates are 12 to 15%. Response rates to were no differences in median survival (14.4 versus 14.1 months) or median progression-free time (8.5 versus 7.7 months), and sites of first recurrence were similar. These data revealed that aggressive multimodal therapy incorporating PDT can be delivered for patients with higher-stage DMM, but first-generation PDT does not prolong survival or increase local control for DMM.
Novel multi-modal approaches involving surgery are being developed, using such techniques as pleural perfusion of various chemotherapeutic and biologic agents,205a as well as gene therapy, as described below, and further reinforce the importance of surgery in the management of patients with DMM.
Radiotherapy
Results of radiotherapy for pleural mesothelioma have been generally disappointing (Table 89.6). Conventional doses below 3,000 cGy have produced only temporary relief of symptoms in some cases, and doses in excess of 4,000 cGy are needed to achieve adequate palliation.112 These doses are difficult to administer in view of the large tumor volume, including the entire hemithorax, diaphragm, and adjacent mediastinum. In one such trial using anterior and posterior portals, 14 patients with pleural mesothelioma were treated with a total of 3,500 to 7,500 cGy (mean 4,500) by three sessions of 330 cGy each per week. Tolerance was reported to be good and pain was controlled.
Survival ranged from 1 to 41 months (median 15 months).96 In another trial, 14 patients were similarly treated with 4,000 to 6,000 cGy. Chest pain disappeared in 10 patients, but survival remained short (mean 10 months).288 The results of 'radical' radiotherapy, however, were almost identical to those of palliative radiotherapy at the Dana Farber Cancer Institute in Boston.112
Elaborate techniques, such as combined photon and electron beams, use of various blocks, and tissue compensators to shield the lung, have not convincingly yielded superior results.2 Complex treatment plans using CT scans to include the entire pleura down to the base of the diaphragm have been proposed to deliver up to 4,250 cGy by parallel opposed fields with lung and liver blocks, supplemented with electrons up to 3,600 cGy.147 The fissures which are commonly involved may not be adequately treated, however. One case treated with fast neutron therapy has remained free of recurrence for over 78 months.27
30%, again with few complete responses. There is no evidence that doxorubicin combinations are superior to doxorubicin alone or to regimens without doxorubicin. Sarcoma-type regimens with doxorubicin combined with dacarbazine (DTIC) or with cyclophosphamide, vincristine, and dacarbazine (Cyvadic) have been disappointing. The combination of mitomycin (M) and cisplatin (C) discovered to be effective in a nude mouse model61 has been active in a randomized phase II trial by the Cancer and Leukemia Group B (CALGB),55 where it showed a somewhat higher response rate (26%) than doxorubicin with cisplatin (14%) but no survival advantage. Addition of a third drug to the CM combination included agents such as doxorubicin or vinblastine or interferon-alpha (IFN-‡), with no clear-cut benefit.
Recently, a four-drug combination, including cisplatin, mitomycin, 5-FU, and (VP16) resulted in 38% partial responses among 45 patients in France, with a median survival of 16 months.138a Other doublets using cisplatin combined with a newer agent have yielded results which are remarkable, although still preliminary. In Australia, the combination of gemcitabine and cisplatin yielded a partial response rate of 47.6% in 21 patients, a median survival of 41 weeks, and an estimated 1-year survival of 41%.40a Nine of the 10 responses were seen in 13 patients with the epithelial subtype. In Japan, the combination of irinotecan (CPT-11) with cisplatin produced a 40% partial response rate in 15 patients (see Table 89.8).188a
Pharmacokinetic studies of CPT-11 and of its active metabolite SN-38 in the pleural fluid showed steady state with plasma levels after 6 hours, except in epithelial mesothelioma, where pleural fluid levels of SN-38 were much higher than in plasma. Interestingly, all responses, except one, were seen in the 10 patients with the epithelial type. Some prolonged responses have also been reported with doxorubicin plus 5-azacytidine, 63 methyl CCNU, and actinomycin D311; CAP (cyclophosphamide, doxorubicin, cisplatin); and mitomycin plus fluorouracil.272
A response rate of 53% (9 of 17) was reported with methotrexate and vinblastine.128a Eight of the 9 responders also received cisplatin. Preliminary results with a combination of paclitaxel and carboplatin have shown responses.25a Thus, despite low overall response rates, therapeutic abstention is not justified. Better still is to include patients in formal clinical trials.
Intracavitary Chemotherapy. Intracavitary cisplatin at doses of 90 to 100 mg/m2 with intravenous thiosulfate resulted in 1 response among 8 patients with pleural mesothelioma; among 13 patients with peritoneal mesothelioma, there were 1 CR, 2 PRs, and reduction of ascites in 6 cases.165,198
In 5 patients with early peritoneal mesothelioma, a combined modality approach, with cytoreductive surgery, intraperitoneal doxorubicin plus cisplatin, and external whole abdomen radiotherapy up to 30 Gy, resulted in survival of more than 18 months.9 The intraperitoneal combination of mitomycin and cisplatin was effective in controlling ascites in 6 of 11 patients with peritoneal mesothelioma; 2 patients were without evidence of recurrent disease in the peritoneal cavity for more than 32 and 41 months, respectively.166
A similar regimen in patients with pleural mesothelioma treated with surgery followed by mitomycin and cisplatin, first intrapleurally, then systemically, resulted in a median survival time of 17 months in 27 patients in one trial228 and 13 months in 19 patients in another trial.210 Recently, activity was reported with the use of the liposomal cisplatin L-NDDP.195f The exact role of intracavitary chemotherapy and of intracavitary irradiation remains to be defined by prospective trials.