Development Of Chemotherapy-induced Peripheral Neuropathy Research Articles

Objective evaluation of chemotherapy-induced peripheral neuropathy using quantitative pain measurement system (Pain Vision\xae), a pilot study

BackgroundIn an evaluation of chemotherapy-induced peripheral neuropathy (CIPN), objectivity may be poor because the evaluation is determined by the patient’s subjective assessment. In such cases, management of neuropathy may be delayed and CIPN symptoms may become severe. In this pilot study, we attempted an objective evaluation of CIPN using a quantitative pain measurement system (Pain Vision®).MethodsThe subjects were patients with gynecologic cancer who underwent chemotherapy using taxane and platinum drugs. The grade of the peripheral sensory nerve disorder was based on the Common Terminology Criteria for Adverse Events (CTC-AE) ver. 4.0 and was evaluated before the initiation of therapy and up to six chemotherapy cycles. A symptom scale assessed by the patients using a peripheral neuropathy questionnaire (PNQ) was also evaluated. Simultaneously during these evaluations, graded electric current was applied from the probe to a fingertip and measured both the lowest perceptible current and lowest current perceived as pain by Pain Vision®. From these values, the pain degree was calculated from the following formula: (pain perception current value - lowest perceptible current value) ÷ lowest perceptible current value × 100. We compared the pain degrees by Pain Vision® during CIPN development with the value obtained before chemotherapy initiation.ResultsForty-one patients were enrolled. In the evaluation by a medical professional, 28 (64.3%) patients developed CIPN during 2.5 ± 1.1 chemotherapy cycles (mean ± standard deviation). The pain degree by Pain Vision® at grade 1 and 2 CIPN development according to the evaluation (CTC-AE) was significantly decreased compared to that before chemotherapy initiation (126.0 ± 114.5 vs. 69.8 ± 46.8, p = 0.001, and 126.0 ± 114.5 vs. 32.8 ± 32.6, p = 0.004). Changes in the pain degree by Pain Vision® were also found during scale B and C, D CIPN development in the patient evaluation (PNQ) (115.9 ± 112.4 vs. 70.6 ± 56.5, p = 0.005, and 115.9 ± 112.4 vs. 46.3 ± 42.9, p = 0.004). In the 13 patients in whom CIPN did not occur, no significant decrease in the pain degree by Pain Vision® was detected (p = 0.764). There was no discontinuation of the measurements because of adverse events such as discomfort from the electric current.ConclusionThe decrease in the pain degree measured by Pain Vision® was associated with the onset of CIPN symptoms. Particularly, detection of CIPN by Pain Vision® was possible, though most of the CIPN that occurred was low grade or mild symptom. Pain Vision® might become a noninvasive and convenient objective CIPN detection tool to supplement subjective CIPN evaluation.Trial registrationThe study approval number in the institution; H25–140. Registered December 17, 2013.

Taxanes and platinum derivatives impair Schwann cells via distinct mechanisms

Impairment of peripheral neurons by anti-cancer agents, including taxanes and platinum derivatives, has been considered to be a major cause of chemotherapy-induced peripheral neuropathy (CIPN), however, the precise underlying mechanisms are not fully understood. Here, we examined the direct effects of anti-cancer agents on Schwann cells. Exposure of primary cultured rat Schwann cells to paclitaxel (0.01 μM), cisplatin (1 μM), or oxaliplatin (3 μM) for 48 h induced cytotoxicity and reduced myelin basic protein expression at concentrations lower than those required to induce neurotoxicity in cultured rat dorsal root ganglion (DRG) neurons. Similarly, these anti-cancer drugs disrupted myelin formation in Schwann cell/DRG neuron co-cultures without affecting nerve axons. Cisplatin and oxaliplatin, but not paclitaxel, caused mitochondrial dysfunction in cultured Schwann cells. By contrast, paclitaxel led to dedifferentiation of Schwann cells into an immature state, characterized by increased expression of p75 and galectin-3. Consistent with in vitro findings, repeated injection of paclitaxel increased expression of p75 and galectin-3 in Schwann cells within the mouse sciatic nerve. These results suggest that taxanes and platinum derivatives impair Schwan cells by inducing dedifferentiation and mitochondrial dysfunction, respectively, which may be important in the development of CIPN in conjunction with their direct impairment in peripheral neurons.

Abstract 986: Targeting nicotinic acetylcholine receptors for the prevention and reversal of chemotherapy-induced peripheral neuropathy

Abstract While chemotherapy has played a significant role in the survival of cancer patients, exposure to drugs such as the taxanes, platinum-based compounds, and bortezomib often results in chemotherapy-induced peripheral neuropathy (CIPN), a consequence of peripheral nerve fiber dysfunction or degeneration. CIPN is characterized by sensory symptoms such as numbness, burning pain, and allodynia, resulting in an overall decrease in quality of life. Paclitaxel (Taxol), a taxane that is commonly used to treat breast, lung, and ovarian cancers, has been found to cause CIPN in 59-78% of cancer patients. There is currently no effective preventative or therapeutic treatment for this side effect, which can be a dose-limiting factor or delay treatment. Our studies have established that the prototypical nicotinic acetylcholine receptor (nAChR) agonist, nicotine, is capable of preventing and reversing the development of paclitaxel-induced CIPN, and does not stimulate tumor growth or interfere with the cytotoxic properties of paclitaxel. Male C57BL/6J mice were treated with paclitaxel (8 mg/kg, i.p.) every other day for a total of four injections. Nicotine was either infused via a subcutaneous 7-day osmotic minipump (24 mg/kg/day) starting 48 hours prior to paclitaxel treatment, or acutely injected (0.9 mg/kg, i.p.) following paclitaxel treatment. Von Frey filament testing revealed that nicotine can prevent and reverse paclitaxel-induced mechanical allodynia; the latter effect of nicotine can be inhibited by the α7 nAChR antagonist methyllycaconitine (10 mg/kg, s.c.). Also, α7 nAChR knockout mice exhibit a greater sustained decrease in mechanical threshold after paclitaxel administration than wild-type mice, suggesting the involvement of this receptor in CIPN development and maintenance. This hypothesis was supported by the reversal of paclitaxel-induced mechanical allodynia by the α7 nAChR silent agonist R-47. While nicotine activates its receptors in the tumors cells, based on stimulation of the PI3K/Akt pathway, MTT/MTS colorimetric assays showed that concentrations of nicotine ranging from 0.1 to 10 µM fail to significantly increase the viability of A549 or H460 non-small cell lung cancer cells, murine Lewis lung carcinoma cells, or primary human lung cancer cells. Most importantly, the paclitaxel-induced decreases in H460 proliferation and LLC viability are not significantly attenuated by 1 µM nicotine. Moreover, 1 µM nicotine does not interfere with paclitaxel-induced apoptosis of A549 cells. Finally, R-47 also suppresses CIPN without increasing lung tumor cell viability and colony formation, or interfering with the cytotoxicity of paclitaxel. Our in vitro findings are supported by studies demonstrating that nicotine does not enhance tumor volume or cause premature death in tumor-bearing mice. These data suggest that nAChRs may be promising drug targets for the prevention and treatment of CIPN. Citation Format: S Lauren Kyte, Wisam Toma, Ganeshsingh Thakur, M Imad Damaj, David A. Gewirtz. Targeting nicotinic acetylcholine receptors for the prevention and reversal of chemotherapy-induced peripheral neuropathy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 986. doi:10.1158/1538-7445.AM2017-986

Selected Risk Nutritional Factors for Chemotherapy-Induced Polyneuropathy.

The present study seeks to identify the nutritional risk factors involved in the development of neuropathies induced by chemotherapeutic treatments. Unlike the gastrointestinal or hematological adverse effects of chemotherapy there is no protective treatment strategy for polyneuropathy. The aim of this study was to find possible deficiencies in nutritional factors, which can be used for supplementation in the future for prevention of chemotherapy-induced neuropathy development. We analyzed 70 patients undergoing paclitaxel chemotherapy and evaluated the risk factors involved in chemotherapy-induced peripheral neuropathy (CIPN). Several risk factors were considered in the development of CIPN, including deficiency of vitamin B1, B6, and D and fatty acids. The occurrence of CIPN complication in 60% cases was observed. We found significant differences in vitamin D and saturated fatty acid concentration. Vitamin D levels in the group without CIPN were estimated to be 38.2 (24.95, 47.63) nmol/L, whereas in the group with CIPN it was determined to be 25.6 (19.7, 32.55) nmol/L, p = 0.008. The level of total saturated fatty acids in the group without CIPN was of 32.613 Area % (31.322; 36.262), whereas in the group with CIPN it was of 34.209 Area % (32.86; 39.386), p = 0.01. The obtained results suggest a diet lower in saturated fatty acid content during chemotherapy. The most significant finding was that supplementation of vitamin D before chemotherapy could be an efficient neuroprotective in CIPN prophylaxis, as significantly lower levels 25OH derivative of vitamin D were observed in the CIPN group throughout the study period.

Gait, balance, and patient-reported outcomes during taxane-based chemotherapy in early-stage breast cancer patients.

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity of several commonly used chemotherapy drugs including taxanes, vinca alkaloids, and platinum compounds. Development of CIPN is highly variable, both in self-reported symptoms and functional consequences, and can be severe enough to alter dose intensity. To describe the natural histories of both patient-reported symptoms of CIPN and functional impairments in breast cancer patients undergoing taxane-based chemotherapy. Thirty-three breast cancer patients (32 female/1 male; 47.8±11.2years; n=17 stage II/n=16 stage III) were enrolled. Patients completed self-reports of symptoms and function (e.g., EORTC QLQ-CIPN20) and objective measures of physical function (i.e., balance and gait testing) in an outpatient oncology clinic at five timepoints: (1) baseline-prior to starting chemotherapy, (2-4) before starting subsequent chemotherapy cycles, and (5) 1-3months after receiving their last taxane infusion. Significant negative changes in both patient-reported outcomes and objective functional measures were observed. Decreased balance was observed after the first chemotherapy cycle (28% increase in medial-lateral excursion of the center of pressure, p=0.016) and progressed with cumulative exposure (43% increase, p<0.001). Patients also demonstrated slower walking speeds (5% decrease, p=0.003) as they progressed through treatment. These functional deficits were mirrored with increased patient-reported symptom severity for all EORTC QLQ-CIPN20 subscales (all p<0.05). This study longitudinally assessed patient-reported outcomes concurrently with balance and gait testing in patients undergoing taxane therapy. Taxane treatment was associated with the development of clinically relevant problems in both CIPN symptoms and patient function.

A randomised, placebo-controlled trial assessing the efficacy of an oral B group vitamin in preventing the development of chemotherapy-induced peripheral neuropathy (CIPN).

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect resulting from neurotoxic chemotherapeutic agents. This study aimed to assess the efficacy and safety of an oral B group vitamin compared to placebo, in preventing the incidence of CIPN in cancer patients undergoing neurotoxic chemotherapy. A pilot, randomised, placebo-controlled trial was conducted. Newly diagnosed cancer patients prescribed with taxanes, oxaliplatin or vincristine were invited to participate. A total of 71 participants (female 68%, male 32%) were enrolled into the study and randomised to the B group vitamin (n=38) arm or placebo (n=33). The data from 47 participants were eligible for analysis (B group vitamins n=27, placebo n=22). The primary outcome measure was the total neuropathy score assessed by an independent neurologist. Secondary outcome measures included serum vitamin B levels, quality of life, pain inventory and the patient neurotoxicity questionnaires. Outcome measures were conducted at baseline, 12, 24 and 36weeks. The total neuropathy score (TNS) demonstrated that a B group vitamin did not significantly reduce the incidence of CIPN compared to placebo (p=0.73). Statistical significance was achieved for patient perceived sensory peripheral neuropathy (12weeks p=0.03; 24weeks p=0.005; 36weeks p=0.021). The risk estimate for the Patient Neurotoxicity Questionnaire (PNQ) was also statistically significant (OR=5.78, 95% CI=1.63-20.5). The European Organisation of Research and Treatment of Cancer (EORTC) quality of life, total pain score and pain interference showed no significance (p=0.46, p=0.9, p=0.37 respectively). A trend was observed indicating that vitamin B12 may reduce the onset and severity of CIPN. An oral B group vitamin as an adjunct to neurotoxic chemotherapy regimens was not superior to placebo (p>0.05) for the prevention of CIPN. Patients taking the B group vitamin perceived a reduction in sensory peripheral neuropathy in the PNQ. Moreover, a robust clinical study is warranted given that vitamin B12 may show potential in reducing the onset and severity of CIPN. Trial number: ACTRN12611000078954 Protocol number: UH2010000749.

Chemotherapy-induced peripheral neuropathy: an update on the current understanding.

Chemotherapy-induced peripheral neuropathy is a common side effect of selected chemotherapeutic agents. Previous work has suggested that patients often under report the symptoms of chemotherapy-induced peripheral neuropathy and physicians fail to recognize the presence of such symptoms in a timely fashion. The precise pathophysiology that underlies chemotherapy-induced peripheral neuropathy, in both the acute and the chronic phase, remains complex and appears to be medication specific. Recent work has begun to demonstrate and further clarify potential pathophysiological processes that predispose and, ultimately, lead to the development of chemotherapy-induced peripheral neuropathy. There is increasing evidence that the pathway to neuropathy varies with each agent. With a clearer understanding of how these agents affect the peripheral nervous system, more targeted treatments can be developed in order to optimize treatment and prevent long-term side effects.

Comorbidities and Risk of Chemotherapy-Induced Peripheral Neuropathy Among Participants 65 Years or Older in Southwest Oncology Group Clinical Trials.

Neuropathy is a debilitating toxicity associated with various chemotherapy agents. We evaluated the association between common comorbid conditions and the development of peripheral neuropathy in patients treated with taxane-based chemotherapy. We examined the Southwest Oncology Group database to identify phase II and III trials that included taxane therapy from 1999 to 2011. We linked the Southwest Oncology Group clinical records to Medicare claims data according to Social Security number, sex, and date of birth. The following disease conditions potentially associated with peripheral neuropathy were evaluated: diabetes, hypothyroidism, hypercholesterolemia, hypertension, varicella zoster, peripheral vascular disease, and autoimmune diseases. Multivariate logistic regression was used to model the odds of experiencing grade 2 to 4 neuropathy. A total of 1,401 patients from 23 studies were included in the analysis. Patients receiving paclitaxel were more likely to experience grade 2 to 4 neuropathy compared with docetaxel (25% v 12%, respectively; OR, 2.20; 95% CI, 1.52 to 3.18; P < .001). The inclusion of a platinum agent was also associated with greater neuropathy (OR, 1.68; 95% CI, 1.18 to 2.40; P = .004). For each increase in age of 1 year, the odds of neuropathy increased 4% (P = .006). Patients with complications from diabetes had more than twice the odds of having neuropathy (OR, 2.13; 95% CI, 1.31 to 3.46; P = .002) compared with patients with no diabetes. In contrast, patients with autoimmune disease were half as likely to experience neuropathy (OR, 0.49; 95% CI, 0.24 to 1.02; P = .06). The other conditions were not associated with neuropathy. We found that in addition to drug-related factors, age and history of diabetes were independent predictors of the development of chemotherapy-induced peripheral neuropathy. Interestingly, we also observed that a history of autoimmune disease was associated with reduced odds of neuropathy. Patients with diabetic complications may choose to avoid paclitaxel or taxane plus platinum combination therapies if other efficacious options exist.

Brainstem processing of peripheral punctate stimuli in patients with and without chemotherapy-induced peripheral neuropathy: a prospective cohort functional MRI study

BackgroundChemotherapy-induced peripheral neuropathy affects 30% of cancer survivors. Findings from animal studies suggest that brainstem descending inhibitory pathways are important in chronic neuropathic pain. An aberrant descending pain modulation system has been implicated in human neuropathic pain. Whether aberrant descending pain modulation before chemotherapy is associated with development of chemotherapy-induced peripheral neuropathy is unclear. We aimed to assess descending pain modulation systems using functional MRI (fMRI) in chemotherapy-naive patients with cancer to determine whether differences are associated with subsequent development of the neuropathy. MethodsIn this multicentre prospective cohort study, adult patients with cancer and no chronic pain, neuropathy, or risk factors for neuropathy were recruited from the oncology clinic before onset of chemotherapy. After patients had given written informed consent, descending inhibitory pathways were challenged (jittered punctate stimuli 256 mN Somedic von Frey filament) during a 3T fMRI scan, and images analysed with FSL software. Sample size was based on published fMRI estimates. Chemotherapy-induced peripheral neuropathy was diagnosed with the CIPN20 questionnaire. Findings30 patients were recruited (mean age 60·4 years [SD 7·9]). We report a preliminary analysis of the first 12 patients (60·6 [8·3], six women); six had colorectal cancer, four gynaecological cancer, and two lung cancer. Seven patients (three men, four women) developed chemotherapy-induced peripheral neuropathy. After data brain extraction, registration, B0 unwarping, and motion correction, FEAT was used for first and second level analysis. Mean group level comparisons between patients with and without the neuropathy were conducted with mixed-effects analysis (z threshold 2·3, regions considered significant at p<0·05, cluster uncorrected for preliminary analysis) and adjusted for sex, age, and cancer type. Patients with chemotherapy-induced peripheral neuropathy had increased activation in the nucleus cuneiformis and primary somatosensory cortex compared with patients who did not develop the disorder. InterpretationThese preliminary results suggest that baseline differences exist, before peripheral nerve injury, in the descending pain modulation system of patients who go on to develop chemotherapy-induced peripheral neuropathy. These differences might aid development of biomarkers to guide chemotherapy choices. Limitations of the study include the small sample size for the present analysis, the observational nature of the study, and the possibility of unknown confounders. Strengths include the prospective design in a unique patient cohort and the high sensitivity of fMRI. FundingWellcome Trust via Scottish Translational Medicine and Therapeutics Initiative (STMTI).

The role of pannexin 1 in chemotherapy-induced peripheral neuropathy (CIPN).

6 Background: CIPN is a debilitating side effect and dose limiting toxicity of anticancer drug therapies. CIPN induces pathological changes in dorsal root ganglia (DRG), leading to increased cross-talk between sensory neurons and satellite glial cells (SGCs), specifically ATP mediated SGC-neuron signaling. We therefore investigated CIPN in mice with neuron- or glia-specific deletion of the ATP-releasing channel Pannexin 1 (Panx 1). Methods: To induce CIPN, mice were given two i.p. oxaliplatin (oxa) injections two days apart. Controls received saline (sal). We used C57Bl6 wildtype and transgenic mice with neuron- or glia-specific Panx1 deletion (NFHcre or GFAPcre:Panx1F/F) and littermate controls (Panx1F/F), 7-11 per group. Tactile sensitivity of the hindpaws was assessed prior to and every week after injections for 3 weeks using von Frey filaments. The number of paw withdrawals to 10 stimulations with each filament and pain thresholds (corresponding to filament that elicits 8/10 responses) were recorded. Overall mouse condition was assessed using Open Field Tests. Results: C57Bl6 mice developed transient tactile hypersensitivity after oxa injection, which was most prominent at day 9 and ceased at day 21. Oxa-injected mice had lower tactile thresholds (at 9 days: sal 5.5±0.3g vs. oxa 2.7±0.4g, p &lt; 0.001) and higher response rates to filaments compared to sal-injected controls (p &lt; 0.05), but revealed no changes in any other behavior. Mice with glia-specific Panx1 deletion did not display significant tactile hypersensitivity at any time after oxa (tactile threshold at 9 days: sal 5.5±0.3g vs. oxa 5.8±0.2g), whereas oxa induced tactile hypersensitivity did occur in mice with neuron-specific Panx1 deletion (at 9 days: sal 6±0g vs. oxa 1.3±0g, p &lt; 0.0001) and Panx1F/F littermates (at 9 days: sal 6.0±0g vs. oxa 1.3±0.1g, p &lt; 0.0001). Conclusions: We found that oxaliplatin induces transient CIPN, but no other behavioral changes in wildtype mice. Deletion of the ATP-releasing channel Panx1 in glia, but not in neurons, prevented CIPN development. This points to a new molecule (Panx1) and a new cell type (glia) as potential novel targets for pain therapy.

An exercise regimen prevents development paclitaxel induced peripheral neuropathy in a mouse model.

Peripheral neuropathy is a major, dose-limiting complication of many chemotherapeutic agents. Currently there is no effective method to prevent development of chemotherapy-induced peripheral neuropathy (CIPN). Recent studies have shown that exercise can improve regeneration of peripheral nerves but its effect in preventing peripheral neuropathy is unknown. In this study, we examined the effect of a rigorous treadmill exercise program that was started 1 week before administration of paclitaxel and continued throughout the study in a mouse model of CIPN. We showed that exercise can partially abrogate features of axonal degeneration induced by paclitaxel including reduction in epidermal nerve fiber density in the plantar hind paw and thermal hypoalgesia. Furthermore, detyrosinated tubulin that is elevated in nerves treated with paclitaxel was normal in exercised animals. This study points to a relatively simple and potentially effective therapeutic option to reduce the neurotoxic effects of chemotherapy.

Chemotherapy-induced peripheral neuropathy: review for clinical practice

BACKGROUND AND OBJECTIVES: Chemotherapy-induced peripheral neuropathy is the most common neurological syndrome secondary to antineoplastic therapy primarily affecting patients being treated with taxanes and platinum derivatives. Sensory neuropathy is the most frequent type. This study aimed at carrying out a narrative review of the literature on the pathophysiology, clinical manifestations, impact, evaluation, diagnosis treatment and prevention of chemotherapy-induced peripheral neuropathy. CONTENTS: Recent studies have shown association among inflammatory molecules, oxidative stress and development of chemotherapy-induced peripheral neuropathy. Most frequent symptoms are limbs numbness and tingling, with neuropathic pain having significant impact on the functionality of patients submitted to antineoplastic therapy. Several evaluation tools have been tested, being electroneuromyography considered the golden standard for chemotherapy-induced peripheral neuropathy diagnosis. There are different pharmacological strategies for its therapy and prevention. CONCLUSION: It is known that chemotherapy-induced peripheral neuropathy is a frequent syndrome negatively interfering with cancer patients’ treatment and quality of life. Different drugs are associated to different risk levels, which show its neurobiological complexity. Prevention, diagnostic and treatment strategies have to greatly evolve to minimize its frequency and severity.

Probing for chemotherapy-induced peripheral neuropathy in live dorsal root ganglion neurons with atomic force microscopy

Chemotherapy-induced peripheral neuropathy (CIPN) remains a major reason for cancer patients to withdraw from their lifesaving therapy. CIPN results in irreversible sensory and motor impairments; however, the epidemiology is largely unknown. Here, we report for the first time that chemotherapy drug vincristine not only reduced axonal regeneration in primary dorsal root ganglion neuron but also induced substantial changes in cell mechanical properties detected by atomic force microscopy (AFM). Confocal imaging analysis revealed vincristine-induced microtubule depolymerization. By using AFM for high-resolution live cell imaging and quantitative analysis, we observed significant changes in cell surface roughness and stiffness of vincristine-treated neurons. Elastic modulus was decreased (21-45%) with increasing dosage of vincristine. Further study with paclitaxel, another well-known CIPN drug, confirmed the link between cell mechanics and cytoskeleton organization. These data support that our system can be used for probing potential CIPN drugs that are of enormous benefit to new chemotherapy drug development. From the Clinical EditorThis study concludes that reduced cell elasticity in dorsal root ganglion neurons accompanies the development of chemotherapy-induced peripheral neuropathy, providing a model system that enables testing of upcoming chemotherapy agents for this particularly inconvenient and often treatment-limiting complication.

Use of sodium bicarbonate to promote weight gain, maintain body temperature, normalize renal functions and minimize mortality in rodents receiving the chemotherapeutic agent cisplatin

A simple method to reduce adverse effects of the chemotherapeutic agent cisplatin on animal health is described. Animals receiving normal saline (0.9% NaCl) s.c. prior to once weekly injections of cisplatin (3mg/kg i.p.×3 or 4 weeks) exhibited failure of weight gain, lowered body temperature, elevations in creatinine and ketone levels and increased kidney weight ratios. By contrast, rats treated with sodium bicarbonate (4% NaHCO3 in saline s.c.) prior to cisplatin (3mg/kg i.p.×3 or 4 weeks) exhibited normal weight gain, body temperature, creatinine and ketone levels, as well as normal kidney weight ratios (over 16 or 28 days, respectively). Cisplatin-induced neuropathy (i.e. mechanical and cold allodynia) developed equivalently in both groups. Our studies suggest that NaHCO3 pretreatment promotes animal health and minimizes weight loss, body temperature dysregulation and signs of renal toxicity (i.e. increases in creatinine and kidney weight ratio) following repeated cisplatin treatment without altering the development of chemotherapy-induced peripheral neuropathy.

Prevention of paclitaxel‐induced peripheral neuropathy by lithium pretreatment

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect that occurs in many patients undergoing chemotherapy. It is often irreversible and frequently leads to early termination of treatment. In this study, we have identified two compounds, lithium and ibudilast, that when administered as a single prophylactic injection prior to paclitaxel treatment, prevent the development of CIPN in mice at the sensory-motor and cellular level. The prevention of neuropathy was not observed in paclitaxel-treated mice that were only prophylactically treated with a vehicle injection. The coadministration of lithium with paclitaxel also allows for administration of higher doses of paclitaxel (survival increases by 60%), protects against paclitaxel-induced cardiac abnormalities, and, notably, does not interfere with the antitumor effects of paclitaxel. Moreover, we have determined a mechanism by which CIPN develops and have discovered that lithium and ibudilast inhibit development of peripheral neuropathy by disrupting the interaction between paclitaxel, neuronal calcium sensor 1 (NCS-1), and the inositol 1,4,5-trisphosphate receptor (InsP3R) to prevent treatment-induced decreases in intracellular calcium signaling. This study shows that lithium and ibudilast are candidate therapeutics for the prevention of paclitaxel-induced neuropathy and could enable patients to tolerate more aggressive treatment regimens.

Abstract 933: Peripheral neuropathy induced by chronic administration of Cisplatin, taxol and bortezomib in several murine models

Abstract Cisplatin (CDDP), Taxol (TAX) and Bortezomib (BZ) are chemotherapeutic drugs commonly employed in clinical practice for the treatment of solid and haematological tumors. Their clinical use is limited by the development of a peripheral neuropathy characterized by sensory alterations, pain and, in part, by motor and autonomic dysfunctions. Several rat models had been performed to study and describe the mechanisms of the peripheral neurotoxicity induced by these drugs. However, since only few cancer cell lines are able to induce the development of cancer in the rat, we focused our attention on mice models to allow the combined study of the antineoplastic activity and of the neurotoxic effects of the anticancer compounds. Moreover, different mice strains should be useful for different kind of studies. Here we investigated the interactions between the mice genotype and their drug response to determine the susceptibility to the development of chemotherapy-induced peripheral neuropathy. To this aim, we investigated the neurophysiological and neuropathological alterations induced by the chronic treatment with different chemotherapy drugs in female Balb/c, CD1 and c57 mice and in male c57 and FVB mice. Mice were injected with Cisplatin (2, 4 mg/Kg, ip, 2qw), or Taxol (50, 70, 80 mg/Kg, iv, 1qw) or Bortezomib (0.4, 0.8 mg/Kg, iv, 2qw) for a period of 4-6 weeks. At the end of the treatment the nerve conduction velocities (NCVs) were determined in the caudal and in the digital nerves and the dorsal root ganglia (DRG) and sciatic nerves collected for the neuropathological analysis; behavioural tests were performed to study if these drugs are able to induce allodynia or hyperalgesia. In all mice models we observed that TAX and CDDP induced a significant alteration in body weight at the end of the treatment. All the drugs induced a significant reduction in the caudal and digital NCV in Balb/c and CD1 mice. TAX and BZ caused the axonal degeneration of the sciatic nerves while CDDP and BZ morphological alterations in the DRG. In c57 female mice, only BZ induced a significant reduction in caudal NCV while in c57 male mice only CDDP caused neurophysiological impairments. By contrast, male FVB mice showed any neurophysiological alterations. All these models, except FVB mice, have shown the onset of allodynia and hyperalgesia at the end of the treatment. In conclusion we can affirm that, even if at different extent, Balb/c, CD1 and c57 mice were able to develop the different chemotherapy-induced peripheral neuropathies. Moreover, also the gender seemed to be involved in the severity of the neuropathy. By contrast, FVB mice were less susceptible to the neurotoxic damage. This study would give a useful guideline for the choice of mouse strains in the combined studies of the antineoplastic activity and of the neurotoxic effects of chemotherapy drugs. Partially supported by a grant from “Fondazione Banca del Monte di Lombardia”. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 933. doi:1538-7445.AM2012-933

A prospective surveillance model for physical rehabilitation of women with breast cancer

Chemotherapy-induced peripheral neuropathy (CIPN) results from damage to or dysfunction of the peripheral nerves. The development of CIPN is anticipated for the majority of breast cancer patients who receive neurotoxic chemotherapy, depending on the agent used, dose, and schedule. Sensory symptoms often predominate and include numbness, tingling, and distal extremity pain. Weakness, gait impairment, loss of functional abilities, and other deficits may develop with more severe CIPN. This article outlines a prospective surveillance model for physical rehabilitation of women with breast cancer who develop CIPN. Rehabilitative efforts for CIPN start at the time of breast cancer diagnosis and treatment planning. The prechemotherapy evaluation identifies patients with preexisting peripheral nervous system disorders that may place them at higher risk for the development of CIPN. This clinical evaluation should include a history focusing on symptoms and functional activities as well as a physical examination that objectively assesses the patient's strength, sensation, reflexes, and gait. Ongoing surveillance following the initiation of a neurotoxic agent is important to monitor for the development and progression of symptoms associated with CIPN, and to ensure its resolution over the long term. CIPN is managed best by a multidisciplinary team approach. Early identification of symptoms will ensure appropriate referral and timely symptom management. The prospective surveillance model promotes a patient-centered approach to care, from pretreatment through survivorship and palliative care. In this way, the model offers promise in addressing and minimizing both the acute and long-term morbidity associated with CIPN.

Abstract 4184: Development of ixabepilone-induced CIPN is related to pre-treatment with paclitaxel in a mouse model

Abstract The mechanisms and underlying factors that predispose individuals to development of chemotherapy-induced peripheral neuropathy (CIPN) are not clearly understood. CIPN results in the dose attenuation, delay, or discontinuation of drug in patients otherwise responding to chemotherapy. Moderate to severe CIPN can interfere with function and activities of daily living. Microtubule-stabilizing agents, including taxanes and epothilones are strongly associated with development of CIPN. Ixabepilone, the first FDA-approved epothilone, is specifically used in taxane-resistant metastatic breast cancer. Any ixabepilone-induced CIPN may be as high as 71% depending on administration regimen. Specific risk factors for development of this side effect are unknown. Here we present data using a murine model of sensory hyperalgesia that suggests pretreatment with paclitaxel, currently a labeling indication for use of ixabepilone in metastatic breast cancer, is itself a predisposing factor for development of ixabepilone-induced peripheral neuropathy. Wild type DB/A2 adult mice were treated with intraperitoneal 25 mg/kg paclitaxel, 2.5 mg/kg ixabepilone, or diluent (cremophor: ethanol) every other day for 4 doses. Mice were analyzed by rota-rod to test sensory-motor function and by hot and cold plate to test for temperature hyperalgesia. There was no difference in performance of either of the three treatment groups following the initial treatment cycle. Mice were then treated with a further cycle of chemotherapy, either the same as they received initially, except that half of the paclitaxel-treated group was crossed-over to ixabepilone. Rota-rod and hot plate testing again failed to show a difference between groups. However, cold-plate testing showed a statistically significant increase in cold hyperalgesia in mice treated first with paclitaxel followed by ixabepilone in comparison to all other treatment groups. EM and immunofluorescence analyses of dorsal root ganglia and sciatic nerve sections from mice in all four treatment groups are ongoing. Although preliminary, these results suggest that prior chemotherapy regimens have a significant effect on development of CIPN in this model. The exact mechanisms of injury are under evaluation. A complementary clinical study is underway in women with breast cancer to understand the effect of ixabepilone on an ultrastructural level and its potential role in the development of peripheral neuropathy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4184.

Paclitaxel and cisplatin versus paclitaxel and cisplatin plus all-trans retinoic acid for the prevention of chemotherapy-induced neuropathy: A randomized phase II trial

e14506 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse event, similar to that of diabetes where there is reduction of the expression and transport of Neural Growth Factor (NGF). Retinoic acid regulates genes related to cellular proliferation and NGF expression. We conducted this clinical trial to determine the effect of all-trans retinoic acid (ATRA) on the development of CIPN with paclitaxel and cisplatin in patients with advanced non-small cell lung cancer (NSCLC). Methods: Ninety five patients with advanced NSCLC were included to receive chemotherapy based on paclitaxel 175 mg/m2 and cisplatin 80 mg/m2 every 3 weeks for a maximum of 6 cycles. The patients were randomized to receive ATRA 20 mg/day or placebo 1 week before treatment until after completing 2 cycles. Prior to chemotherapy and after 2 cycles of treatment neurophysiology tests, clinical exam and serum NGF levels (34 patients) were performed. Results: There were no differences in general characteristics of the patients between groups. NGF serum levels were lower in the placebo group 4.89 pg/ml baseline and 4.6 pg/ml 2C (p = 0.007) versus ATRA 4.8 pg/ml and 4.7 pg/ml (p=0.107). The electrophysiological studies showed a greater degree of motor axonal damage in the right (p=0.003) and left (p=0.013) tibial nerves in the placebo group after 2C. In the ATRA group there were no significant differences baseline and after chemotherapy. Conclusions: ATRA might have a neuroprotective effect in patients with NSCLC treated with paclitaxel and cisplatin. A phase III trial is needed to confirm these findings. No significant financial relationships to disclose.

Feasibility and validity of the Patient Neurotoxicity Questionnaire during taxane chemotherapy in a phase III randomized trial in patients with breast cancer: N-SAS BC 02

The aim of the study was to determine the feasibility and validity of a newly developed patient-based instrument--the Patient Neurotoxicity Questionnaire (PNQ)--for grading chemotherapy-induced peripheral neuropathy (CIPN). We prospectively collected data from 300 female patients who were treated with taxane chemotherapy for primary breast cancer as part of a national multicenter phase III randomized trial (N-SAS BC 02). We evaluated patient compliance with the PNQ and several validation parameters, including concordance between CIPN grades noted by physicians (National Cancer Institute Common Toxicity Criteria) and patients (PNQ), and the concurrent validity and responsiveness of the PNQ versus the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) utilizing data at pre-treatment and before three, five, and seven treatment cycles. The questionnaire completion rate was >90% at all assessments. Evaluation by physicians always resulted in lower neuropathy assessment scores compared with those reported directly by patients (weighted kappa coefficients, 0.02-0.06). Both PNQ sensory and motor scores were significantly correlated with the FACT/GOG-Ntx (r = 0.66 and 0.51, respectively). In the repeated measures analysis of variance model, PNQ grades increased considerably as treatment continued, indicating progressively worsening CIPN over time. The PNQ has an applicable degree of feasibility and validity, useful for the diagnosis of CIPN as well as for clinical treatment decision-making, where the development of CIPN is a potential treatment-limiting consideration. Physicians underreport and underestimate the severity of CIPN symptoms compared with patients, thereby supporting the importance of assessing patient-reported outcomes using the PNQ.