Prevalence, Intensity and Consequences of Bortezomib-induced Neuropathic Disorders.

Overview

Cancer-induced peripheral neuropathies (CIPN) remain a real problem in oncology (Balayssac et al., 2011). These CIPN are induced by certain classes of anticancer drugs such as taxanes (paclitaxel and docetaxel), platinum salts (cisplatin and oxaliplatin), alkaloids of Madagascar periwinkle (vincristine), bortezomib, thalidomide and eribulin (Balayssac et al., 2011; Vahdat et al., 2013). These CIPN essentially translate into sensory disorders such as paresthesia, dysesthetics or numbness. More rarely, these CIPN may be associated with motor or vegetative disorders (Balayssac et al., 2011). According to the recent meta-analysis by Hershman et al., no treatment can be proposed as a "gold standard" for preventing or treating CIPN (Hershman et al., 2014). As a result, oncologists reduce or stop doses of neurotoxic anticancer drugs because patients with CIPN have a marked deterioration in quality of life and co-morbidities such as anxiety, depression and sleep disorders (Hong et al., 2014; Mols et al., 2014). Therefore, understanding the pathophysiology of CIPN is essential to propose new therapeutic strategies. Among neurotoxic anticancer drugs, bortezomib remains relatively little studied in terms of pathophysiology compared to platinum salts or taxanes, while the neurotoxicity of bortezomib remains a limiting factor in treatment. Since 2012, the FDA and EMA have validated the administration of bortezomib subcutaneously instead of intravenously in order to limit the neurotoxicity of bortezomib (Minarik et al., 2015). Indeed, a large study (N=222) reported that subcutaneous administration of bortezomib allowed the same therapeutic efficacy to be maintained while improving the safety profile and in particular limiting peripheral neuropathies (CIPN all grades: 38% vs. 53%, p=0.044, grade\> 2: 24% vs. 41%, p=0.012 and grade\> 3: 6% vs. 16%, p=0.026) However, a recent retrospective study (N=446) reports that the prevalence of bortezomib-induced peripheral neuropathies after subcutaneous administration remains relatively high: all grade: 41%, grade\> 2: 18%, grade\> 3: 4%, and above all that this prevalence is not different between subcutaneous and intravenous routes (Minarik et al., 2015).

Only 2 studies evaluated quantitatively and qualitatively the sensitivity disorders in patients with bortezomib-induced peripheral neuropathy by intravenous (Boyette-Davis et al., 2011; Cata et al., 2007). In these 2 studies, the patients presented a distribution of the sensitive disorders characteristic of the so-called stocking-glove distribution of the CIPN affecting the distal extremities of the limbs. A quantification of the sensory thresholds (QST) was carried out and revealed a number of sensitive anomalies. Neuropathic patients suffer from deficits in tactile sensitivity and disorders of thermal sensitivity. In Cata et al. study, patients showed hypersensitivity to painful cold (CIPN patients vs. healthy controls: 10.4±2°C vs. 3±1°C, p\<0.05), hot perception deficit (CIPN patients vs. healthy controls: 40.2±1.4°C vs. 37±0.74°C, p\<0.05) and a painful hot sensitivity deficit. However, the cold sensory disorders would be more inconstant, because in neuropathic patients suffering from bortezomib-induced peripheral neuropathy, another study by the same team found only warm tactile and thermal sensory anomalies, but did not reveal a cold perception anomaly (Boyette-Davis et al., 2011). Finally, a few rare cases of bortezomib-induced hearing impairment have been described in the literature (Chim and Wong, 2008; Engelhardt et al., 2005). This ototoxicity is thought to be linked to an alteration in the functioning of peroxisomes (Lee et al., 2015). No studies have actually evaluated the long-term prevalence of bortezomib-induced neuropathy. The only studies with long-term follow-up have carried out a cumulative assessment over 22 months (Pantani et al., 2014), 32 months (Dimopoulos et al., 2013) and 60 months (Wang et al., 2016) of the therapeutic response and adverse reactions induced by bortezomib. No studies dedicated to neurological adverse events have been conducted in the long term. Thus, the prevalence, duration, intensity and reversibility of bortezomib-induced neuropathy are poorly known in the long term (more than 5 years). On the other hand, a measurement tool such as the QLQ-CIPN20 questionnaire (EORTC) evaluating the intensity of sensory, motor and vegetative disorders associated with CIPN, a questionnaire presented as the most specific tool in the evaluation of CIPN (Lavoie Smith et al., 2013; Postma et al., 2005), has never been tested in this patient population. This study project aims to provide precise knowledge on the prevalence, intensity and consequences of bortezomib-induced neuropathy in the short (2016-2014) and medium (2014-2012) term after subcutaneous injection and in the long term (2012-2008) after intravenous injection, knowing that at the Clermont-Ferrand University Hospital, the route of administration of bortezomib was intravenous. Retreat to at least 9 years of age could provide information on the kinetics of onset and disappearance of neuropathy after chemotherapy treatments (data unknown in the literature to date). Finally, these data acquired in a French context relating to bortezomib-induced neuropathy may be used in future studies evaluating new intervention strategies to prevent and/or treat bortezomib-induced neuropathy. This observational study will combine retrospective treatment data from the CHIMIO® chemotherapy prescribing software with data obtained from patients by answering questionnaires. Patients will be identified from the CHIMIO® chemotherapy prescription software database. The algorithm (computer query) will identify all patients who received bortezomib-based chemotherapy for the multiple myeloma indication between 2008 and 2016. All the questionnaires used are validated in the scientific literature.