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Mesothelioma Medical Information
John R. Eckardt,
MD Board Certified Oncologist Member of: American Society of Clinical Oncology American Association of Cancer Research
Single-Agent Chemotherapy
Because most patients with mesothelioma are not candidates for surgery or RT, chemotherapy or palliative care are often the only options. To date, single-agent regimens utilizing commercially available cytotoxic agents such as cisplatin, doxorubicin, trimetrexate, or the taxanes docetaxel or paclitaxel have yielded modest results with average response rates no higher than 10% to 20%. Although doxorubicin has been the most frequently investigated, results of a recent meta-analysis suggest that cisplatin is the most active.
Single-agent chemotherapy with newer compounds, such as liposomal anthracyclines (ie, liposomal doxorubicin, daunorubicin), gemcitabine, and pemetrexed, have, likewise, yielded modest results. While the former have proven mostly inactive, phase 2 data with the nucleoside analogue gemcitabine demonstrated response rates ranging from 0% to 31%, while the overall response rate is 14% for the antifolate pemetrexed.
| Agent | N | Response Rate |
|---|---|---|
| Cisplatin | 14-24 | 12.5% to 35.7% |
| Doxorubicn | 15 | 0.0% |
| Liposomal Doxorubicin | 24-32 | 0.0% to 6.0% |
| Liposomal Daunorubicin | 11 | 0.0% |
| Methotrexate | 62 | 36.7% |
| Edatrexate | 20 | 25.0% |
| Docetaxel | 30 | 10% |
| Paclitaxel | 25 | 0.0% |
| Gemcitabine | 16-27 | 0.0% to 31.0% |
| Pemetrexed | 64 | 14% |
Combination Chemotherapy
To date, combination regimens using traditional agents (eg, doxorubicin/cisplatin, doxorubicin/cisplatin/cylophosphamide, cisplatin/etoposide, cisplatin/DHAC) have not yielded substantially higher response rates than single-agent regimens.[19] By contrast, doublets utilizing novel cytotoxic agents such as pemetrexed, gemcitabine, and raltitrexed in combination with a platinum have shown more encouraging results.
Pemetrexed/Cisplatin
Pemetrexed's primary mechanism of action is the inhibition of 3 enzymes involved in purine and pyrimidine synthesis: thymidylate synthase (TS), dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyl transferase (GARFT). Although other drugs, such as raltitrexed and 5-fluorouracil, also target TS, no other agent currently available targets all 3 enzymes.
Encouraging results from phase 1 and 2 trials, in which up to 45% of evaluable patients receiving pemetrexed/cisplatin experienced a partial response (PR), led to the largest phase 3 trial ever undertaken among mesothelioma patients. Vogelzang and colleagues[35,36] randomized 456 eligible patients to pemetrexed 500 mg/m2 intravenous bolus over 10 minutes plus cisplatin 75 mg/m2 administered every 3 weeks (n = 226) or to single-agent cisplatin 75 mg/m2 plus saline (to preserve blinding) administered every 3 weeks (n = 222). The majority of trial patients had stage III or IV disease. Previous reports had documented severe toxicities (eg, grade 4 neutropenia and diarrhea) due to elevated baseline serum homocysteine and methylmalonic acid resulting from folic acid and vitamin B12 deficiencies. Therefore, the 2 treatment arms were modified early during trial recruitment to include supplementation with 350 to 1000 mcg folic acid daily and 1000 mcg intramuscular vitamin B12 every 9 weeks.
A statistically significant longer median survival time was observed in all patients receiving the combination therapy vs all patients receiving cisplatin alone (12.1 months vs 9.3 months, respectively; hazard ratio [HR] = 0.77; P = .020).
Median time to progressive disease was also significantly longer for patients in the pemetrexed/cisplatin arm compared with those in the cisplatin-only arm (5.7 months vs 3.9 months; HR = 0.68, P = .001). Tumor response (PR only), as measured by CT scan, was observed in 41.3% of patients in the pemetrexed/cisplatin arm vs 16.7% of patients in the cisplatin-only arm (P <.001).
Although treatment with pemetrexed/cisplatin resulted in a greater incidence of drug-related serious adverse events (22.5% vs 7.2%, respectively) as well as more grade 3/4 neutropenia, nausea, and vomiting, supplementation with folic acid and vitamin B12 resulted in consistent declines in toxicity. Indeed, significant differences in some toxicities were observed between those who were fully or partially supplemented and those who were never.
Finally, Gralla and colleagues analyzed quality-of-life (QOL) parameters as measured by the LCSS-meso instrument for roughly 96% of patients (n = 448) enrolled in this trial. In addition to the survival advantage noted by Vogelzang, the pemetrexed/cisplatin combination was associated with statistically significant improvements in global QOL and symptom relief in most parameters by week 18, compared with cisplatin only; significant improvements were noted in pain, dyspnea, and cough by week 15 (P < .001). Notable improvements in QOL and symptoms occurred within 6 to 9 weeks of starting treatment.