The troublesome toxicity of peripheral neuropathy with thalidomide

The development of peripheral neuropathy in patients with multiple myeloma being treated with thalidomide is a well-recognized toxicity. This troublesome side-effect may limit the ability to continue effective treatment and also has been documented to affect the quality of life of cancer patients [1]. Thalidomide is most frequently reported to cause a length-dependent axonal neuropathy [2]. The clinical features are typically tingling or painful distal paresthesia affecting the feet and sometimes the hands, with or without sensory loss in the lower limbs. Mild motor involvement and severe proprioceptive failure have been reported in severe cases. The cardinal sign on nerve electrophysiologic studies (NES) is a 50% decrease in the sensory nerve action potential amplitude with relative conservation of nerve conduction velocities. The mechanism by which thalidomide causes neuropathy remains unclear. Hypotheses include alteration of the course of Wallerian degeneration through down-regulation of tumor necrosis factor-a production [3,4] and inhibition of activation of nuclear factor-kB which is required for nerve-growth factor mediated sensory neuron survival [5]. Aronson et al. [6] showed that serum from patients with thalidomide-induced neuropathy caused morphologic changes in cultured rat dorsal root ganglion cells. Studies involving sural nerve biopsies have shown evidence of Wallerian degeneration and selective loss of large-diameter fibers without demyelination [3,7]. The reported incidence of any neuropathy with thalidomide varies from 25% to 75%, partly dependent on whether cases are defined using clinical criteria alone or with NES, and does not appear to depend on the underlying disease being treated [8]. Three prior studies have specifically focussed on the development of peripheral neuropathy in patients with relapsed or refractory myeloma treated with thalidomide. Offidani et al. [9] reported results from 59 patients with myeloma treated with thalidomide+ oral melphalan, with peripheral neuropathy developing in 39% as defined by clinical criteria [9]. Tosi et al. [10] described long-term toxicity results in a group of 40 patients who had received more than 1 year of treatment with thalidomide+dexamethasone. NES were performed in patients with clinically significant features of neuropathy with 75% of patients ultimately developing evidence of neuropathy. Our center has described 75 patients treated with dose-escalating thalidomide with or without interferon in a multi-center prospective trial who were monitored clinically as well as with serial NES. Thirty-one out of 75 patients (41%) developed neuropathy during thalidomide with 15% of patients ceasing treatment because of this toxicity. The actuarial incidence of neuropathy increased from 38% at 6 months to 73% at 12 months [8]. Although development of some degree of neuropathy is frequently seen, more severe neuropathy affecting the patient’s ability to function is less common. A recent systematic review of phase II trials of thalidomide monotherapy in patients with relapsed or refractory myeloma reported a rate of grade 3 or 4 neuropathy in 6% of 1674 patients treated across 42 different studies with grade 1 or 2 neuropathy seen in 22% [11]. Of interest in the small number of studies that have used single-agent thalidomide for treatment of newly diagnosed myeloma, the development of grade 3 or more neuropathy appears to be rare [12].