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There are a lot of chemotherapy drugs in mesothelioma treatment.
It has been a major challenge for doctors to find chemotherapy drugs that work well in treating malignant mesothelioma. Many trials have been done using epirubicin, doxorubicin, cisplatin and methotrexate, but no standard treatment has been set. This has led researchers to look at newer chemotherapy drugs in combination with some already tried. Drugs and combinations in trial include
Most of the various chemotherapies have been evaluated in mesothelioma, but few have shown response rates better than 20%. This has led to therapeutic nihilism. However, recent results provide the basis for a new, cautious optimism.
Among the “cytotoxic” chemotherapies, doxorubicin showed response rates of 14% and was the gold standard. Its analog, epirubicin was similar. The platinums were also in the low teens.
The antifolates appear active in mesothelioma. Edatrexate showed a 25% response rate, but had high toxicity. The toxicity was treatable, but treating it also lowered the drug effectiveness. Methotrexate has shown a good response rates, but is difficult to give where there is a pleural effusion. Pemetrexed has been evaluated with cisplatin in a phase III clinical trial, the results of which were announced by Dr. Vogelzang at ASCO. In a phase II, the results of pemetrexed alone were squarely in the mid-range of chemotherapies generally, but did include some dramatic responses.
Most studies of gemcitabine alone show no activity in mesothelioma. However, gemcitabine in combination with cisplatin is the current gold standard. This is based primarily on one study which showed a 48% response rate. However, later studies showed response rates of 26%, 16% and 9% for this combination.
Vinorelbine showed a response rate of 24% in one study.) were observed and 16 (55%) had stable disease. The median survival from start of treatment was 10.6 months.
The taxanes, which are natural products, have shown only minimal activity in mesothelioma. Paclitaxel and docetaxel have been evaluated.
Similarly, the camptothecins (e.g. topotecan and irinotecan) have not shown significant responses as single agents. However, in combination with other drugs good results have been reported.
Most studies giving gemcitabine alone have not been successful. A small number of trials using gemcitabine in combination with cisplatin, have produced some promising results. Many doctors now use this combination of drugs to treat malignant mesothelioma. But more trials are needed before it may be considered as standard treatment. There is information on the side effects of gemcitabine in the Side Effects of Cancer Drugs page of CancerHelp UK.
In one study 29 patients were given vinorelbine alone, 6 (24%) patients disease improved and 16 (55%) patients disease remained stable. This has led to further trials using this drug. It is comparing active symptom control (ASC) with ASC and vinorelbine and with ASC, mitomycin, vinblastine and cisplatin.
Topotecan and irinotecan have not shown significant responses when given by themselves. But in combination with other drugs, there have been some good results. A trial has been done looking at irinotecan, cisplatin and mitomycin C (IPM). This trial closed in Feb 2004 and the results will be available soon.
Pemetrexed is a type of chemotherapy drug. It is also called Alimta. It is a little similar to another drug in regular use called methotrexate. It has been used in the largest phase 3 clinical trial ever conducted for malignant pleural mesothelioma. This international trial began in 1998 and results were reported on in May 2002. The study was aimed at finding out whether pemetrexed plus cisplatin was more effective in treating malignant mesothelioma than cisplatin alone.
All patients were given supplements of vitamin B12 and folic acid to help reduce side effects (such as diarrhoea). The outcome of this trial was promising. A number of recent trials are now looking at the use of pemetrexed in combination with other chemotherapy agents.
Pemetrexed has now been licensed in the UK for use in combination with cisplatin to treat mesothelioma. This was announced by the company who developed it on 1st November 2004. But it's not likely to be widely available on the NHS yet. In August 2005 pemetrexed was approved for use in Scotland by the Scottish Medicines Consortium. But it has not yet been approved by the National Institute for Health and Clinical Excellence (NICE) for use in England and Wales. They are currently looking at the evidence and hope to make a decision in 2006.
Ranpirnase, a ribonuclease derived from leopard frog eggs, has been extensively studied in mesothelioma. In a phase II trial of 105 patients with MPM, it demonstrated a response rate of only 5% but was noted to produce stable disease in 43% of patients. Overall survival was 6 months for the intent-to-treat group and 8.3 months in a subset of patients with a good prognosis based on CALGB criteria.
A phase III trial suggested that ranpirnase may have higher efficacy than doxorubicin in certain small subgroups of patients with unresectable malignant mesothelioma, but these retrospective observations had insufficient power to draw any reliable conclusions on efficacy. Larger studies of such subgroups are needed.
Various cytokines, alone or in combination, also have been studied in MPM. A phase II trial investigating -2b interferon in combination with cisplatin and doxorubicin showed a response rate of 29% and a median survival of 9.3 months in patients with advanced MPM. Severe myelosuppression and fatigue were significant limiting toxicities. Intrapleural interleukin-2 was also examined for the treatment of malignant pleural effusions with promising results.
A variety of new approaches are under investigation for the treatment of mesothelioma, based on the targeting of specific markers. SV-40 has been identified as a possible cause of MPM,15 and a candidate vaccine of the SV-40 T-antigen has shown early evidence of efficacy.
Vascular endothelial growth factor (VEGF) is an autocrine growth factor important in the pathogenesis of MPM.100 Three potential inhibitors of VEGF are being investigated for activity against the disease: bevacizumab (rhuMAbVEGF), SU5416, and thalidomide. Bevacizumab, a recombinant anti-VEGF antibody, is in phase II trials in combination with chemotherapy (gemcitabine/cisplatin).
ZD1839 (gefinitib), an inhibitor of the epidermal growth factor receptor, and STI-571 (imatinib), an inhibitor of the platelet derived growth factor receptor, were unsuccessful as monotherapies in epidermal growth factor receptor-positive malignant mesothelioma and MPM, respectively.102103 Since COX-2 is overexpressed in MPM and may constitute a poor prognostic factor, COX-2 inhibitors may have therapeutic potential. Photodynamic therapy has also been investigated, but a randomized trial failed to show any benefit in either survival or local control.
Abbreviations: CALGB = Cancer and Leukemia Group B; COX-2 = cyclooxygenase-2; DHFR = dihydrofolate reductase; EORTC = European Organization for Research and Treatment of Cancer; EPP = extrapleural pneumonectomy; GARFT = glycinamide ribonucleotide formyltransferase; IMIG = International Mesothelioma Interest Group; MPM = malignant pleural mesothelioma; P/D = pleurectomy/decortication; SV = simian virus; TS =thymidylate synthetase; VEGF = vascular endothelial growth factor.
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