Thalidomide in patients with malignant pleural mesothelioma
Introduction
Malignant pleural mesothelioma (MPM) is a nearly invariably lethal tumor of the pleura or peritoneum which origin is closely linked to the exposure of asbestos fibres [1]. In general, the survival is dismal with a median of 7–11 months after diagnosis [2].
MPM is notoriously refractory to therapy. Neither surgery nor radiotherapy alone has resulted in increased survival. Long-term survivors are occasionally seen.
So far most studies on chemotherapy have been disappointing [3], [4], [5], but recently a phase III study has reported a survival advantage for the combination of pemetrexed plus cisplatin over cisplatin alone [6]. However, no long-term improvement was obtained. It is, therefore, obvious that new therapies have to be explored.
MPM is a disease characterized by distinct angiogenesis and an increased vessel density has been correlated with a worse outcome [7]. Malignant mesothelioma cells often express vascular endothelial growth factor (VEGF) and to some extent basic fibroblast growth factor (b-FGF) [8], [9]. These factors are closely related with the formation of new vasculature in embryogenesis, wound healing, diabetic neuropathy and tumor progression. Inhibition of tumor-induced angiogenesis should prevent growth and could play an important role in further management of this disease. Although it is not expected that the use of these drugs will completely eradicate tumors, it is hoped they can inhibit progressive growth [10], [11], [12], [13].
Thalidomide has been used in the late fifties as a sedative especially during pregnancy. Unfortunately, teratogenic effects (focomelia) prohibited further use of the drug and its application was abandoned. In recent years, thalidomide has been revisited, using strict contra-conceptive measures. Its major toxicity is peripheral sensory neuropathy and constipation. Recently, its toxicity and efficacy has been described in patients with refractory multiple myeloma and recurrent high-grade gliomas [14], [15].
We have examined the efficacy and toxicity of increasing doses of thalidomide in patients with MPM.
Section snippets
Eligibility
Patients with a histological confirmed diagnosis of MPM were eligible for this study. All tumor stages (IMIG staging) were allowed when one or more target lesions could be measured according to the RECIST criteria. Prior surgery, radiotherapy, chemotherapy (including intra-cavitary therapies) was allowed as long as there was evidence of disease progression. No anti-cancer therapy within the least 4 weeks before registration was allowed, with the exception of palliative radiotherapy to painful
Results
Between July 2001 and November 2002, a total of 42 patients were enrolled in the study. One patient refused medication after registration for psychological reasons and another patient stopped within 5 days because he preferred experimental surgical treatment of his mesothelioma. These two patients are excluded from further analysis. Characteristics of the 40 patients analyzed are presented in Table 1. Half of the patients had received previous (chemo) therapy and the majority was male. The mean
Discussion
Of the available anti-angiogenic drugs, thalidomide is the most extensively tested drug and has predictable toxicity. Although its proper working mechanism is not fully elucidated, the possible anti-tumor mechanisms of action involve: inhibition of angiogenesis, modulation of the cytokine-mediated pathways, alteration of adhesion molecules, the inhibition of cyclooxygenase-2 and stimulation of the immuno response. Expression of VEGF and bFGF in patients with MPM is considered to be high and
Acknowledgement
The authors wish to thank Professor J. Beijnen Pharmacist of the Slotervaart Hospital for the preparation and distribution of the thalidomide tablets.
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2015, Annals of OncologyChemotherapy-induced neuropathy: A comprehensive survey
2014, Cancer Treatment ReviewsCitation Excerpt :Unsurprisingly, the maximum tolerated doses of thalidomide combined with bortezomib are significantly lower than single-agent doses, with peripheral neuropathy as a key dose-limiting toxicity [99]. Nerve conduction studies demonstrate reduced SNAP amplitudes with relatively preserved conduction velocities, in keeping with a sensory axonal neuropathy [95]. Thalidomide neuropathy has been associated with genes governing repair mechanisms and inflammation in the peripheral nervous system like ABCA1, ICAM1, PPARD, SERPINB2 and SLC12A6 [46].
Thalidomide versus active supportive care for maintenance in patients with malignant mesothelioma after first-line chemotherapy (NVALT 5): An open-label, multicentre, randomised phase 3 study
2013, The Lancet OncologyCitation Excerpt :This study does not allow us to comment on the effect of thalidomide in less fit patients, nor a possible response to thalidomide in patients who progressed after first-line chemotherapy. We were reluctant to include these patients in our study, since in the preceding phase 2 study15 no partial responses were seen in this particular group. In our opinion inclusion of patients with progressive disease would not have been ethical, since they had had a 50% chance of treatment with active supportive care only and probably had no chance of response with thalidomide.