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Review Article Vincristine-Induced Peripheral Neuropathy in Pediatric Cancer Patients

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Review Article Vincristine-Induced Peripheral Neuropathy in Pediatric Cancer Patients Am J Cancer Res 2016;6(11):2416-2430 www.ajcr.us /ISSN:2156-6976/ajcr0042915 Review Article Vincristine-induced peripheral neuropathy in pediatric cancer patients Erika Mora1, Ellen M Lavoie Smith2, Clare Donohoe2, Daniel L Hertz3 1Department of Pediatrics, Division of Pediatric Heme/Onc, University of Michigan Medical School, Ann Arbor, MI, USA; 2Department of Health Behavior and Biological Sciences, University of Michigan School of Nursing, Ann Arbor, MI, USA; 3Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI 48109-1065, United States Received October 26, 2016; Accepted October 28, 2016; Epub November 1, 2016; Published November 15, 2016 Abstract: Vincristine is a chemotherapeutic agent that is a component of many combination regimens for a vari- ety of malignancies, including several common pediatric tumors. Vincristine treatment is limited by a progressive sensorimotor peripheral neuropathy. Vincristine-induced peripheral neuropathy (VIPN) is particularly challenging to detect and monitor in pediatric patients, in whom the side effect can diminish long term quality of life. This review summarizes the current state of knowledge regarding VIPN, focusing on its description, assessment, prediction, prevention, and treatment. Significant progress has been made in our knowledge about VIPN incidence and progres- sion, and tools have been developed that enable clinicians to reliably measure VIPN in pediatric patients. Despite these successes, little progress has been made in identifying clinically useful predictors of VIPN or in developing ef- fective approaches for VIPN prevention or treatment in either pediatric or adult patients. Further research is needed to predict, prevent, and treat VIPN to maximize therapeutic benefit and avoid unnecessary toxicity from vincristine treatment. Keywords: Vincristine, peripheral neuropathy, prevention, assessment, pharmacogenetics, pediatric oncology Introduction leading to severe motor and sensory perip- heral neuropathies affecting quality of life, but The vinca alkaloids are a class of agents origi- also contributing to treatment delays and dose nally derived from the Madagascar periwinkle reductions. This review will focus on describing plant and historically utilized in diabetic pati- vincristine-induced peripheral neuropathy (VI- ents for their presumed hypoglycemic effects. PN), and summarizing the available literature In the late 1950’s, it was realized that certain around assessing, predicting and treating this vinca alkaloids caused bone marrow suppres- adverse effect in pediatric patients. sion in mice as well as prolongation of life in rats with acute lymphoblastic leukemia (ALL) Clinical use [1]. Subsequently, this class of anti-mitotic agents has become extensively incorporated Vinblastine (VBL) and vincristine (VCR) were the into multi-agent chemotherapy regimens for a first two vinca alkaloid compounds to be suc- vast number of malignancies including ALL, cessfully incorporated into chemotherapy regi- lymphomas, sarcomas, neuroblastoma, and mens. These agents work by arresting dividing kidney, liver, lung, brain and breast tumors cells in metaphase by binding to the β-subunit amongst others. Additionally, immunosupp- of tubulin heterodimers to prevent polymeriza- ressant effects have led to their use in idio- tion and incorporation into microtubules [2]. In pathic thrombocytopenic purpura and throm- more recent decades, vindesine and vinorel- botic thrombocytopenic purpura. Vincristine, bine have come to market as semi-synthetic the most commonly used vinca alkaloid in pedi- vinca alkaloids. Vindesine has similar antitumor atric patients, frequently has dose-limiting neu- activity as vincristine, but increased myelosup- rotoxicity which can be devastating; not only pression and lack of clear improvement in neu- Vincristine-induced peripheral neuropathy ropathic adverse events has limited its clinical (and taxanes) target the β-tubulin subunit of usefulness [3]. Vinorelbine, on the other hand, microtubules, which are critical components is composed of an eight-member catharnine of nerve fiber axons. Due to the affinity of ring, as opposed to the nine-member rings of the vincas for both mitotic spindles and axo- the other vinca alkaloids, which allows for nal microtubules, particularly with vincristine, increased capacity to bind to mitotic spindles these agents cause axonopathy that manif- over axonal microtubules, leading to decreased ests as a slowly progressive axonal sensori- neurotoxicity with this agent [4]. Vinorelbine is motor neuropathy [9, 10]. Several additional most commonly used to treat breast and non- mechanisms for vinca-induced peripheral neu- small cell lung cancers and myelosuppression ropathy (VIPN) have been proposed from mech- is its dose-limiting side effect. Finally, vincris- anistic work in cellular and animal models [11, tine has most recently been encapsulated in 12] and the exact mechanism is still not com- sphingomyelin and cholesterol nanoparticles pletely understood. as a vincristine sulfate liposome injection (VSLI) and marketed under the trade name Marqibo. VIPN is experienced by nearly all children who This new formulation of vincristine was desi- receive vincristine treatment [13-15]. The inci- gned to allow for optimized pharmacokinetics, dence and severity varies based on a variety of enhanced drug delivery to tumor tissues, and risk factors, as described in section 5. Signs to allow for dose intensification [5]. It was FDA- and symptoms of VIPN generally fall into three approved in 2012 for the treatment of adult main categories: sensory, motor, and autonom- patients with relapsed/refractory Philadelphia- ic neuropathy [14, 16-18]. Common character- chromosome negative acute lymphoid leuke- istics of sensory neuropathy include numb- mia. ness, tingling, and neuropathic pain experi- enced bilaterally in the upper and lower extrem- Vincristine has poor oral bioavailability and is ities. In most cases, VIPN progresses distally formulated for intravenous administration as to proximally; signs and symptoms often first vincristine sulfate. Vincristine sulfate is a vesi- appear in the toes and feet, and as neuropathy cant and is fatal if given intrathecally. After worsens, clinical abnormalities become evident intravenous administration, vincristine rapidly more proximally within the foot, ankle, and leg, distributes extensively into most body tissues; followed by the fingers and hands. Children who however, there is poor penetration across the receive vincristine become less able to detect blood brain barrier (BBB) and into the central light touch, pinprick sensations, vibration, and nervous system (CNS). The liver is primarily differences in temperature when hot or cold responsible for the metabolism of vincris- objects are applied to the skin. Although less tine, which is a substrate for the cytochrome common, some patients report hoarseness P450 3A (CYP3A) enzyme system, particularly and jaw pain due to vincristine’s damaging CYP3A4 and CYP3A5, making it susceptible to effects on cranial nerves. Hyporeflexia, loss or drug-drug interactions and interpatient varia- reduction in deep tendon reflexes, provides bility in metabolism [6, 7]. Dosing adjustments evidence of both sensory and motor VIPN. should be made in the presence of hyperbiliru- Common motor neuropathy signs and symp- binemia, particularly elevated direct bilirubin. toms include foot-drop and upper and lower Vincristine has a long terminal half-life of 85 extremity weakness. Indicators of autonomic hours and is primarily eliminated in the feces. neuropathy include constipation, urinary reten- Vincristine is rarely myelosuppressive and can tion, and orthostatic hypotension [19, 20]. often be administered even in the presence of leukopenia and thrombocytopenia [8]. When evaluating VIPN patterns over time, sev- eral interesting findings become evident. In the Description of vincristine-induced peripheral first year of vincristine therapy for ALL, hypore- neuropathy (VIPN) flexia is the most common and severe VIPN manifestation, followed by decreased vibra- Peripheral neuropathy is a well-known side tion sensibility and strength [14]. Signs and/or effect of several classes of chemotherapy symptoms can emerge within a week of initiat- including the vincas, taxanes (paclitaxel and ing vincristine therapy and continue to worsen docetaxel), and platins (cisplatin, carboplatin, even after vincristine dosing and frequency is oxaliplatin). As described previously, the vincas decreased, known as the coasting effect [14]. 2417 Am J Cancer Res 2016;6(11):2416-2430 Vincristine-induced peripheral neuropathy VIPN severity can remain unchanged for up to [15, 18, 36]. Objective measures should be 12 months following dose reduction [14], and used to uncover pre-clinical signs of early- can persist for years beyond treatment comple- onset neuropathy that cannot be detected by tion [15]. the patient. When evaluating large nerve fiber function, oncology clinicians typically focus on Assessment assessing deep tendon reflexes and strength. Reflex assessment is the most feasible app- Although peripheral neuropathy is a well-recog- roach because it is quick to complete and can nized side effect of vincristine therapy, VIPN usually be conducted even with very young chil- characteristics, severity and incidence pat- dren. Testing the patient’s ability to feel vibra- terns, and the long-term consequences of VIPN tion, pressure, and light touch, proprioception on
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