Docetaxel for Malignant Mesothelioma

Docetaxel has activity in a wide variety of solid tumors. To evaluate its efficacy in malignant mesothelioma, previously untreated patients (pts.) were treated with docetaxel 100 mg/m[Superscript 2], 1-hour infusion administered every 21 days.
Dexamethasone 8 mg twice daily was also administered for five days starting 24 hours prior to docetaxel infusion. A total of 20 pts. Were accrued to the first stage of the study between December 1996 and April 1997. Nineteen of the 20 pts. Had histological confirmation of mesothelioma and the tumors were carcinoembryonic antigen and mucin negative. In one patient (pt.) the histology could not be confirmed and he was considered ineligible. Characteristics of the remaining 19 pts. Include: 5% ECOG Performance Status (PS) 0; 68% PS 1; 26% PS 2; median age 69 years (range 57--81); 89% male. Only one pt. Had a partial response, with an overall response rate of 5% (95% CI 0.16--26.4). Three pts. (16%) had stable disease, 11 (58%) progressed on treatment and 4 (21%) were not evaluable for response. One pt. With stable disease has not relapsed so far after 16 months of follow-up.
There were three deaths during the treatment phase: One died of gastrointestinal hemorrhage, one from rapidly progressive disease with brain metastasis and one definite treatment related septic death with multi-organ failure.

The major toxicity seen was myelosuppression with grade 4 leucopenia in 17 pts. (90%) and grade 4 granulocytopenia in 8 (42%) pts. Other rare grade 4 non-hematologic toxicities included: Vomiting (1 pt.), diarrhea (1 pt.), hypersensitivity reaction (1 pt.) and cardiac toxicity (1 pt.). The study was terminated after the first accrual stage due to insufficient responses. In conclusion: Docetaxel is not an effective agent in malignant mesothelioma and does not warrant further investigation. (Conducted by ECOG and supported in part by PHS grants CA18653, CA23318, CA52743, CA13650, CA49957, CA66636, CA21115 from the NCI, NIH and the DHHS.)

Chemotherapy in malignant pleural mesothelioma

We reviewed the published literature of clinical studies in malignant pleural mesothelioma, including phase II trials of the newer antifolates and plant derivatives, as well as older single- agent and combination chemotherapy trials. We excluded trials with less than 15 patients, although we have mentioned smaller trials in the text to make a specific point, as well as ones that show promise. We have also included confidence intervals when cited in the original reports, or calculated them when absent.

No drugs have consistently induced a response greater than 20%. Higher response rates have been reported with detorubicin, high-dose methotrexate, and edatrexate at 26%, 37%, and 25%, respectively, but these have yet to be confirmed. Agents that produce response rates in 10% to 20% of patients include doxorubicin, epirubicin, mitomycin, cyclophosphamide, ifosfamide, cisplatin, and carboplatin. Combination chemotherapy trials do not demonstrate a consistently greater response rate than single-agent trials. However, the combination of doxorubicin, cisplatin, bleomycin, and mitomycin demonstrated a response rate of 44% (95% confidence interval, 27% to 63%), but this remains unconfirmed. Intrapleural therapy using interferon gamma, particularly for small-volume disease, shows promise.

The successful treatment of unresectable pleural mesothelioma awaits the discovery of active drugs. Recent trials of high-dose methotrexate and other antifolates are encouraging. Newer agents, including suramin, should be evaluated in phase II trials. Off-protocol combination therapy cannot be recommended over single-agent therapy, but studies that use combinations of the newer agents should be conducted.