Mesothelioma - Combination Chemotherapy
Combination chemotherapy
Doxorubicin-based regimens: Doxorubicin is the anthracycline most frequently included in chemotherapeutic regimens. Initially encouraging response rates experienced with the doxorubicin-cisplatin combination in two phase II studies carried out in Germany (RR: 46%) and Italy (RR: 25%) (Henss et al, 1988; Ardizzoni et al, 1991) failed to be confirmed by a subsequent, randomised CALGB study of doxorubicin-cisplatin vs mitomycin-cisplatin treatment (Chahinian et al, 1993). The doxorubicin-cisplatin doublet was only able to produce a 14% response rate and proved inferior to the mitomycin-cisplatin combination (RR: 26%). Median survival duration from study entry was 7.7 and 8.8 months, respectively, with no significant differences between treatments. An Italian group administered the triplet doxorubicin-cisplatin-mitomycin to 24 Malignant Pleural Mesothelioma (MPM) patients and reported a response rate of 20.9%. Thus, the observed level of activity was similar to that obtained with the respective doublets (Pennucci et al, 1997).
The combination of doxorubicin, cisplatin and cyclophosphamide was tested by another prospective trial and produced a similar rate of response (Shin et al, 1995). A multi-institutional randomised study was designed to compare the activity of doxorubicin-cyclophosphamide with a triplet consisting of these agents in addition to dacarbazine. With a response rate of 13%, the triplet did not prove superior to the doublet (RR: 11%) (Samson et al, 1987).
The combination of doxorubicin and ifosfamide has also been investigated within two studies. One study giving doxorubicin and ifosfamide every 3 weeks achieved a response rate of 12.5% (Carmichael et al, 1989). Based on the same trial design, another group applied dose-escalated doxorubicin at 75 mg m-2, with a 32% response rate (Dirix et al, 1994). However, the 7-month median survival was poor and toxicity high, limiting the value of this schedule in the treatment of Malignant Pleural Mesothelioma (MPM).
Disappointing response rates have also been shown by the anthracyclines epirubicin and rubidazone as combined with ifosfamide and dacarbazine (Zidar et al, 1983; Magri et al, 1992).
Cisplatin-based regimens: Apart from combinations with anthracyclines, cisplatin has also been tested in numerous other chemotherapy regimens. Three trials evaluated cisplatin combined with etoposide, showing response rates from 12 to 24% (Eisenhauer et al, 1988; Planting et al, 1995; White et al, 2000). The doublet combination of cisplatin and DHAC attained an insufficient response rate of 17.3% (Samuels et al, 1998). Moderate antitumour activity (RR: 25%) was achieved by the doublet cisplatin-mitomycin in one arm of CALGB 8435, but median survival was poor (7.7 months) (Chahinian et al, 1993). A 25% response rate and a 13-month mean duration of response have been indicated for the cisplatin-vinblastine combination (Tsavaris et al, 1994). The cisplatin-mitomycin-C-vinblastine triplet did not prove to be superior to the doublets (RR: 23%), yet produced a symptomatic benefit for 63% of the patients with particularly good response for pain (Middleton et al, 1998).
Likewise, other treatments combining such conventional cytotoxics as methotrexate with vincristine and mitomycin with vindesine have failed to prove effective (Dimitrov et al, 1982; Gridelli et al, 1992).