Review
Peripheral neuropathy: A persisting challenge in paclitaxel-based regimes

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Abstract

Cumulative peripheral neuropathy (PNP) still remains a limitation to optimal treatment with paclitaxel (PAC), especially in more dose–dense schedules. This primary sensory PNP may affect the majority of patients after administration of certain cumulative dosages of PAC, while the exact mechanisms of PAC-induced PNP are not known. While a number of preclinical models revealed its vehicle Cremophor EL (CrEL) to be mainly responsible for ganglionopathy, axonopathy and demyelination, clinical data also supports a strong and independent effect of PAC itself, which is most likely based on disturbances in the microtubules in perikaryons, axons and glia cells. Indeed, clinical trials of CrEL-free formulations of PAC still report grade III neurotoxicity as dose-limiting. As treatment options of PAC-induced PNP are rare the use of specific scoring systems for screening purposes is strongly encouraged. In this report we review and discuss the pathogenesis, incidence, risk factors, diagnosis, pharmacodynamics and treatment options for PAC-induced PNP.

Introduction

After the initial discovery of paclitaxel (PAC) as a novel and promising antineoplastic agent deriving from the bark of the Pacific yew Taxus brevifolia in 1971 [1], its initial clinical application in phase I studies almost 20 years ago was severely complicated by the appearance of life-threatening type I anaphylactic reactions [2]. These severe hypersensitivity reactions (sHSR) could have been induced by PAC itself or its polyoxyethylated castor oil vehicle, Cremophor EL (CrEL) required to keep lipophilic PAC in solution when administering it intravenously 3, 4. A combination of corticosteroids, and H1 and H2 antihistaminics as premedication diminished these reactions significantly but could never avoid them completely [3]. In vitro studies clearly show that CrEL is able to induce complement activation and thus might be an important factor in triggering these sHSR [5]. Meanwhile, new CrEL-free drug formulations of PAC are under investigation, which so far appear not to induce sHSR 6, 7. The second challenge that needed to be overcome has been hematological toxicity primarily appearing in the form of severe neutropenia [2]. The clinical usage of growth factors (G-CSF) [8] and the important discovery that a reduction of infusion time from 24 to 3 h reduced the incidence of grade III/IV neutropenia [9] contributed greatly to patient safety in today’s schedules. Neurotoxicity, mainly seen as cumulative sensory peripheral neuropathy (PNP) 10, 11, 12, 13, 14 represents the most important non-hematological toxicity 8, 15 associated with PAC administration, especially in the currently applied regimes with the drug given once a week 16, 17, 18, 19, 20, 21. Due to its cumulative effects, PNP is usually seen in a majority of patients in the course of their therapy [19]. As treatment options are rare and recent data supports that PAC itself and not its vehicle CrEL is associated with PNP development [22], PNP is representing the remaining challenge for further improvement of PAC administration, which also includes the novel CrEL-free drug formulations of PAC 6, 7. Here, we review pathogenesis, incidence, risk factors, diagnosis and prognosis of PAC-induced PNP as well as pharmacodynamic aspects and treatment options. Furthermore, we discuss different scoring systems currently available for the close monitoring of PNP development in order to maintain patient safety and quality-of-life (QoL).

Section snippets

Pathogenesis

PAC promotes the polymerization of tubulin leading primarily to mitotic cell arrest 23, 24. However, normal function of microtubules is required for a number of vital cellular interphase processes, including motility, maintenance of shape, intracellular transport and signal transduction 25, 26, 27. Ultrastructural studies have highlighted the critical role of microtubules for the neuronal growth cone which is essential for dendrite growth and cell movement [28]. PAC has been shown in animal

Incidence and risk factors

The incidence of reported significant neuropathy may vary between different regimes [15]. Factors affecting the development of neuropathy could include application of PAC as a single agent or in combination with other chemotherapeutics, single and cumulative dose levels, schedules and individual features of the subjects studied (e.g., age, pretreatment, comorbidities). Due to the diversity of existing PAC-based regimes we will focus in this paragraph on the weekly schedule, that is widely

Clinical manifestations and diagnosis

PAC given as a single agent or in combination with cisplatin predominantly induces a cumulative sensory neuropathy 10, 11, 12, 13, 14, 15, 19. Primary symptoms may include numbness/paraesthesia, tingling and burning in a symmetric stocking-and-glove distribution [15]. Usually, the lower extremities are affected first, but a simultaneous onset in the upper and lower extremities has also been reported 15, 45. Motor neuropathy is much less frequent then sensory symptoms and includes a mild distal

Pharmacodynamics

In the more dose–dense PAC schedules (e.g., weekly) clinically significant PNP appeared after administration of cumulative doses of around 1500 mg/m2 [56]. Dependent on the applied screening tool, cumulative neuropathy can be detected much earlier in treatment [19]. Furthermore, infusion duration and the level of applied doses have important effects on PAC pharmacokinetic parameters as well 9, 56, 57, 58, 59, 60. Eisenhauer et al. [9] showed that a reduction of infusion time from 24 to 3 h

Prognosis, treatment options and prophylaxis

Mild sensory neuropathies appear often to be reversible within few months whilst more severe forms may persist significantly longer [15]. Tricyclic antidepressants and anticonvulsants are nowadays widely used in the treatment of neuropathic pain [69]. However, clinical studies focusing on the symptomatic treatment of chemotherapy-induced PNP are rare. In a placebo-controlled trial the tricyclic antidepressant nortryptiline showed only a very modest effect on the relief of paraesthesia in the

Conclusions and future perspectives

Despite all improvements that have been achieved for the treatment with paclitaxel (PAC) during the last two decades PNP persists as a challenge especially in the currently applied more dose–dense regimes. The exact pathogenesis of PAC-induced PNP remains still unclear [15]. Pharmacodynamic investigations including Cremophor EL (CrEL), unbound PAC (uPAC) and total PAC (tPAC) support a strong effect of PAC itself [22]. Like therapeutic efficacy [67] side-effects such as neutropenia 60, 65, 66

Conflict of interest statement

None declared.

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