Oxaliplatin-induced Peripheral Neuropathy Research Articles

Platinum Deposition in the Central Nervous System: A Novel Insight into Oxaliplatin-induced Peripheral Neuropathy in Young and Old Mice.

Numerous factors can contribute to the incidence or exacerbation of peripheral neuropathy induced by oxaliplatin (OXA). Recently, platinum accumulation in the spinal cord of mice after OXA exposure, despite the efficient defenses of the central nervous system, has been demonstrated by our research group, expanding the knowledge about its toxicity. One hypothesis is platinum accumulation in the spinal cord causes oxidative damage to neurons and impairs mitochondrial function. Thus, the main aim of this study was to investigate the relationship between aging and OXA-induced neuropathic pain and its comorbidities, including anxious behavior and cognitive impairment. By using an OXA-induced peripheral neuropathy model, platinum and bioelement concentrations and their influence on oxidative damage, neuroprotection, and neuroplasticity pathways were evaluated in Swiss mice, and our findings showed that treatment with OXA exacerbated pain and anxious behavior, albeit not age-induced cognitive impairment. Platinum deposition in the spinal cord and, for the first time, in the brain of mice exposed to OXA, regardless of age, was identified. We found that alterations in bioelement concentration, oxidative damage, neuroprotection, and neuroplasticity pathways induced by aging contribute to OXA-induced peripheral neuropathy. Our results strive to supply a basis for therapeutic interventions for OXA-induced peripheral neuropathy considering age specificities.

Oxaliplatin-induced peripheral neuropathy with hepatic arterial versus intravenous infusion in metastatic colorectal cancer.

Oxaliplatin, a major drug in metastatic colorectal cancer (mCRC), is responsible for cumulative, dose-limiting peripheral neuropathy (PN). Whether the hepatic arterial infusion (HAI) route can limit oxaliplatin-induced PN in comparison with the intravenous (IV) route has not been specifically explored so far. We compared the frequency and severity of PN in oxaliplatin-naive patients with mCRC included in trials that evaluated treatment with oxaliplatin administered either by HAI (ACCORD 04, CHOICE, OSCAR, and PACHA-01 trials) or by IV route (FFCD 2000-05 trial). We retrieved anonymized, prospectively collected data from trial databases for the ACCORD 04, CHOICE, and FFCD 2000-05 trials and through a review of Gustave Roussy patients' electronic medical records for PACHA-01 and OSCAR trials. The primary endpoint was the incidence of clinically significant PN (grades 2 to 4) according to the cumulative dose of oxaliplatin received. Secondary endpoints were time to onset of neuropathy as a function of the cumulative dose of oxaliplatin, discontinuation of oxaliplatin for neurotoxicity, and safety. A total of 363 patients were included (IV, 300; HAI, 63). In total, 180 patients in the IV group (60%) and 30 patients in the HAI group (48%) developed clinically significant PN, with no significant difference between the two groups (p = 0.23). No difference was shown in the time to onset of PN either (p = 0.23). The administration of oxaliplatin HAI rather than IV in the treatment of mCRC does not reduce the incidence, precocity, and severity of PN.

1878P Efficacy of surgical gloves (SG) as compression therapy to prevent oxaliplatin-induced peripheral neuropathy (PN): The ELEGANT trial

1878P Efficacy of surgical gloves (SG) as compression therapy to prevent oxaliplatin-induced peripheral neuropathy (PN): The ELEGANT trial

ART26.12, a novel fatty acid-binding protein 5 inhibitor, shows efficacy in multiple preclinical neuropathy models.

Painful neuropathy is a pathological condition caused by numerous factors including diabetes, chemotherapy or cancer. ART26.12 is a novel fatty acid-binding protein 5 inhibitor, which our group showed could prevent and treat persistent pain in a preclinical model of oxaliplatin-induced peripheral neuropathy. In the current study, the efficacy of orally dosed ART26.12 was tested in multiple neuropathy models of different aetiology. Paw withdrawal threshold to von Frey monofilaments and latency to escape a cold plate were used as measurements of mechanical and cold sensitivity. ART26.12 (25 and 50 mg/kg BID), dosed prior to the induction of paclitaxel-induced peripheral neuropathy (PIPN), reversed mechanical allodynia induced by paclitaxel in both male and female rats, and ART26.12 (50 mg/kg BID) prevented the induction of PIPN in female rats. ART26.12 (50 mg/kg BID) also had a protective effect on body weight in the PIPN model. ART26.12 (25 and 100 mg/kg BID) reversed mechanical allodynia when treating established streptozotocin-induced diabetic neuropathy in male rats. In a model of breast cancer-induced bone pain in female rats, ART26.12 (100 mg/kg BID) reversed mechanical allodynia within 1 h of dosing. In the same model, ART26.12 (25 mg/kg BID) reversed mechanical allodynia from day 4 of treatment. Overall, these preclinical data suggest that ART26.12 is a safe and efficacious therapeutic drug for continued development towards the prevention and treatment of peripheral neuropathy. This work now shows that ART26.12, a novel and selective inhibitor of FABP5, can prevent and treat multiple preclinical models of peripheral neuropathy. Given its excellent safety profile, further work is warranted to develop ART26.12 as a potential therapeutic tool for pain management.

Problems of oxaliplatin-induced neuropathy in patients with colorectal cancer

Aim. To investigate the methods of early diagnosis of oxaliplatin-induced peripheral neuropathy (PN).Materials and methods. The study included 52 patients with diagnosis of metastatic colorectal cancer receiving 1st line polychemotherapy per the mFOLFOX6 scheme ± targeted therapy who prior to each cycle filled out the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy (EORTC QLQ CIPN 20) and were subject to neurological examination using the Neuropathy Disability Scale (NDS).Results. The analysis included 28 patients who completed polychemotherapy: 16 (57,2 %) men and 12 (42,8 %) women, mean age 60.0 ± 10.0 years. Fridman’s two-way analysis of variance by ranks showed significant changes in the scores (sensory, motor, autonomic) of the EORTC QLQ CIPN 20 questionnaire with the increase in the number of chemotherapy cycles (р = 0.001). Significant increase in the sensory and motor scores was observed after the 3rd cycle, in the autonomic – after the 6th cycle. Significant increase in NDS score was observed starting at the 3rd cycle, and vibration sensitivity on the medial ankle or at the base of the 1st toe significantly decreased after the 1stcycle. Median number of cycles at which oxaliplatin dose was reduced or the drug was discontinued due to clinically significant symptoms of PN irrespective of questionnaire results and neurological examination was 6.Conclusion. According to the results of the study, the following conclusions were made: 1) sensory scale of the 3-part EORTC QLQ CIPN 20 questionnaire (9 questions of 20) or motor scale (7 questions of 20), vibration sensitivity can be considered as stand-alone informative tests; 2) in a large patient cohort, NDS score increase to 5, EORTC QLQ CIPN 20 sensory scale score increase to 12 and higher or decreased vibration sensitivity on the medial ankle or at the base of the 1st toe to 4.5 arbitrary units should be considered early manifestations of PN; 3) for a routine algorithm, it is acceptable to consider a combination of 9 questions of the sensory or 7 questions of the motor scales of the EORTC QLQ CIPN 20 questionnaire and evaluation of vibration sensitivity on the medial ankle or at the base of the 1st toe to decide on oxaliplatin dose reduction or measures for prevention of peripheral neuropathy symptom worsening.

Motor disorders related to oxaliplatin-induced peripheral neuropathy: long-term severity and impact on quality of life.

Sensory chemotherapy-induced peripheral neuropathy (CIPN) is well-recognized, but motor CIPN remains understudied. This secondary analysis focused on the long-term severity and impact of motor disorders, their relation to sensory CIPN, neuropathic pain, psychological distress, and health-related quality of life (HRQoL) after oxaliplatin-based chemotherapy in colorectal cancer (CRC) survivors. Data from a multicenter, cross-sectional study were re-analyzed to explore motor CIPN among CRC survivors up to 5years post-chemotherapy, with no longitudinal follow-up. Questionnaires assessed sensory and motor CIPN (QLQ-CIPN20), neuropathic pain (DN4), anxiety and depression (HADS), and HRQoL (QLQ-C30). Among 405 CRC survivors, 31.1% had sensory CIPN as previously described. When categorizing the 405 CRC survivors based on the years since their last oxaliplatin-based chemotherapy, the motor scores derived from the QLQ-CIPN20 showed no significant difference between years (p = 0.08). Motor CIPN scores correlated with female gender, higher oxaliplatin dose intensity, sensory CIPN, and neuropathic pain. Motor CIPN also linked to decreased HRQoL and increased psychological distress. The study underscores the detrimental impact of motor disorders on CRC survivors post-oxaliplatin-based chemotherapy. Oncologists should prioritize assessing and managing motor manifestations alongside sensory symptoms to enhance post-cancer quality of life. NCT02970526 (2016-11-22). https://classic. gov/ct2/show/NCT02970526?term=NCT02970526&draw=2&rank=1 .

Molecular insights into oxaliplatin-induced peripheral neuropathy in colorectal cancer: Unraveling a potential signature.

Molecular insights into oxaliplatin-induced peripheral neuropathy in colorectal cancer: Unraveling a potential signature.

Prazosin as an Adjuvant to Increase Effectiveness of Duloxetine in a Rat Model of Oxaliplatin-Induced Peripheral Neuropathy

ObjectivesDuloxetine, the only American Society of Clinical Oncology (ASCO) treatment recommended for chemotherapy-induced peripheral neuropathy (CIPN) in cancer survivors, is not effective for 40% of survivors. This study examined the ability of a duloxetine-prazosin combination to prevent the development of allodynia and hyperalgesia in a rat model of oxaliplatin-induced peripheral neuropathy (OPIN). MethodsFemale (n = 24) and male (n = 41) rats were started on duloxetine (15 mg), prazosin (2 mg), or a duloxetine-prazosin combination one week prior to administration of the chemotherapy drug, oxaliplatin, and continued the duloxetine-prazosin combination for 32 days. Behavioral testing for mechanical allodynia and mechanical hyperalgesia was done with selected von Frey filaments over the course of the study. ResultsOverall percent paw withdrawal for rats that received the duloxetine-prazosin combination was significantly lower in female (p < .001 for both conditions) and male (p = .029 for allodynia; p < .001 for hyperalgesia) than those that received water. No significant posttreatment differences were found for allodynia or hyperalgesia between rats treated with duloxetine and rats that received the duloxetine-prazosin combination in either sex. ConclusionsThese finding provide preliminary evidence that a duloxetine-prazosin combination can prevent the posttreatment development of allodynia and hyperalgesia in both male and female rats; however, the results suggest that the duloxetine-prazosin combination is no more efficacious than duloxetine alone in preventing chronic OIPN. Implications for Nursing PracticeThe profession of nursing is built on clinical practice supported by scientific research. The current study addressed the clinical practice problem of prevention and management of painful OIPN, which is a priority area in oncology nursing.

New drugs to prevent oxaliplatin-induced peripheral neuropathy: A double-blind, randomized study.

3568 Background: Postoperative adjuvant chemotherapy for colorectal cancer reduces postoperative recurrence; however, it often causes undesirable adverse events. Oxaliplatin, the mainstay of postoperative adjuvant chemotherapy is particularly likely to cause chemotherapy-induced peripheral neuropathy (CIPN) and hypersensitivity reactions (HSR) that may make it difficult to continue treatment. Various agents have been tested for prevention or treatment of CIPN caused by oxaliplatin, but none have proven effective. Reactive oxygen species contribute oxaliplatin-induced PN; therefore, super oxide dismutase (SOD) could potentially suppress them, but its very short serum half-life has made clinical application difficult. We developed a lecithinized human copper/zinc SOD (Cu/Zn-SOD) (PC-SOD) in which four phosphatidylcholine derivative molecules are bound covalently to each SOD dimer. Compared with SOD, PC-SOD enhanced stability in plasma and stronger tissue affinity, and exerts therapeutic effects in animal models of several diseases, including CIPN. Methods: This double-blind, randomized study included 90 patients with stage II/III colorectal cancer. All patients were slated to receive 12 cycles of mFOLFOX6. In each cycle, patients received PC-SOD or a placebo immediately before oxaliplatin. The primary endpoint of this study was the number of cycles before NCI-CTCAE Grade 2 (G2) CIPN occurred. One of the secondary endpoints was the number of cycles before DEB-NTC G2 PN occurred. Results: Forty-three patients received PC-SOD. No serious adverse events were observed that could be related to PC-SOD. The incidence of neutropenia, diarrhea, stomatitis, and malaise were lower in the study group, but the differences were not significant. Additionally, 3 patients (7.0%) in the study group and 11 (23.4%) in the placebo group had HSR. Although there was no difference in the number of cycles between the two groups until NCI-CTCAE G2 PN occurred, the study group had a significantly greater number of cycles before DEB-NTC G2 PN compared to the placebo group (P=0.08). The study group had a significantly greater number of cycles before NCI-CTC G1 PN (P=0.01) and HSR (P=0.03) compared to the placebo group. The number of cycles before HSR or NCI-CTCAE G2 PN occurred was greater in the study group , but the difference was not significant. The average total oxaliplatin dose was higher in the study group but the difference was not statistically significant. Conclusions: The primary endpoint did not occur; however, the study group had a significantly greater number of cycles before DEB-NTC G2 PN. Notably, the study group also had a significantly greater number of cycles before HSR. These results show that PC-SOD may suppress HSR as well as PN, both of which limit administration of oxaliplatin. Thus, this drug is expected to improve not only patient quality of life, but also the prognosis of patients. Clinical trial information: 2031210466.

The associations of oxaliplatin-induced peripheral neuropathy, sociodemographic characteristics, and clinical characteristics with time to fall in older adults with colorectal cancer.

Our purpose was to investigate the associations between falls and oxaliplatin-induced peripheral neuropathy (OIPN), sociodemographic characteristics, and clinical characteristics of older patients with colorectal cancer. The study population consisted of older adults diagnosed with colorectal cancer whose data were obtained from the Surveillance, Epidemiology, and End Results database combined with Medicare claims. We defined OIPN using specific (OIPN 1) and broader (OIPN 2) definitions of OIPN, based on diagnosis codes. Extensions of the Cox regression model to accommodate repeated events were used to obtain overall hazard ratios (HRs) with 95% CIs and the cumulative hazard of fall. The unadjusted risk of fall for colorectal cancer survivors with versus without OIPN 1 at 36months of follow-up was 19.6% versus 14.3%, respectively. The association of OIPN with time to fall was moderate (for OIPN 1, HR=1.37; 95% CI, 1.04-1.79) to small (for OIPN 2, HR=1.24; 95% CI, 1.01-1.53). Memantine, opioids, cannabinoids, prior history of fall, female sex, advanced age and disease stage, chronic liver disease, diabetes, and chronic obstructive pulmonary disease all increased the hazard rate of falling. Incorporating fall prevention in cancer care is essential to minimize morbidity and mortality of this serious event in older survivors of colorectal cancer.

Danggui Sini decoction alleviates oxaliplatin-induced peripheral neuropathy by regulating gut microbiota and potentially relieving neuroinflammation related metabolic disorder.

Danggui Sini decoction (DSD), a traditional Chinese medicine formula, has the function of nourishing blood, warming meridians, and unblocking collaterals. Our clinical and animal studies had shown that DSD can effectively protect against oxaliplatin (OXA)-induced peripheral neuropathy (OIPN), but the detailed mechanisms remain uncertain. Multiple studies have confirmed that gut microbiota plays a crucial role in the development of OIPN. In this study, the potential mechanism of protective effect of DSD against OIPN by regulating gut microbiota was investigated. The neuroprotective effects of DSD against OIPN were examined on a rat model of OIPN by determining mechanical allodynia, biological features of dorsal root ganglia (DRG) as well as proinflammatory indicators. Gut microbiota dysbiosis was characterized using 16S rDNA gene sequencing and metabolism disorders were evaluated using untargeted and targeted metabolomics. Moreover the gut microbiota mediated mechanisms were validated by antibiotic intervention and fecal microbiota transplantation. DSD treatment significantly alleviated OIPN symptoms by relieving mechanical allodynia, preserving DRG integrity and reducing proinflammatory indicators lipopolysaccharide (LPS), IL-6 and TNF-α. Besides, DSD restored OXA induced intestinal barrier disruption, gut microbiota dysbiosis as well as systemic metabolic disorders. Correlation analysis revealed that DSD increased bacterial genera such as Faecalibaculum, Allobaculum, Dubosiella and Rhodospirillales_unclassified were closely associated with neuroinflammation related metabolites, including positively with short-chain fatty acids (SCFAs) and sphingomyelin (d18:1/16:0), and negatively with pi-methylimidazoleacetic acid, L-glutamine and homovanillic acid. Meanwhile, antibiotic intervention apparently relieved OIPN symptoms. Furthermore, fecal microbiota transplantation further confirmed the mediated effects of gut microbiota. DSD alleviates OIPN by regulating gut microbiota and potentially relieving neuroinflammation related metabolic disorder.

Paeoniflorin ameliorates oxaliplatin-induced peripheral neuropathy via inhibiting neuroinflammation through influence on gut microbiota

Oxaliplatin (OXA)-induced peripheral neuropathy (OIPN) is a severe side effect that greatly limits OXA clinical use and threatens patients' life and health. Paeoniflorin exhibits extensive anti-inflammatory and neuroprotective effects, but whether it can protect against OIPN and the underlying mechanisms remain unclear. This study aimed to investigate the effects of paeoniflorin on OIPN and probe into the underlying mechanisms. The OIPN model was established through oxaliplatin injection in rats. The ameliorative effects of paeoniflorin on OIPN was assessed by nociceptive hypersensitivities through pain behavioral methods. Neuroinflammation were examined by measuring the levels of inflammatory cytokines and immune cells infiltration. The signaling pathway of TLR4/MyD88/NF-κB was evaluated by Western blotting. Gut microbial changes were detected by 16S rDNA sequencing technology. In addition, antibiotics-induced microbiota eradication and fecal microbial transplantation (FMT) were applied for exploring the function of gut microbiota in the protective effects of paeoniflorin. The results revealed that paeoniflorin significantly alleviated mechanical and cold hypersensitivity, mitigated neuroinflammation and influenced gut microbial composition in OIPN rats. Fecal microbiota transplantation further verified that gut microbiota was required for paeoniflorin ameliorating OIPN and that the underlying mechanism involved downregulation of TLR4/MyD88/NF-κB signaling. Specifically, Akkermansia, Dubosiella and Corynebacterium might serve as crucial genera regulated by paeoniflorin in the treatment of OIPN. In summary, our investigations delineate paeoniflorin's ameliorative effects on OIPN by alleviating neuroinflammation through regulations of gut microbiota. This suggests that paeoniflorin may serve as a new potential strategy for treatment of OIPN in clinical practice.

Exploration for Blood Biomarkers of Human Long Non-coding RNAs Predicting Oxaliplatin-Induced Chronic Neuropathy Through iPS Cell-Derived Sensory Neuron Analysis.

Oxaliplatin, a platinum-based chemotherapeutic agent, frequently causes acute and chronic peripheral sensory neuropathy, for which no effective treatment has been established. In particular, chronic neuropathy can persist for years even after treatment completion, thus worsening patients' quality of life. To avoid the development of intractable adverse effects, a predictive biomarker early in treatment is awaited. In this study, we explored extracellular long non-coding RNAs (lncRNAs) released from primary sensory neurons as biomarker candidates for oxaliplatin-induced peripheral neuropathy. Because many human-specific lncRNA genes exist, we induced peripheral sensory neurons from human induced pluripotent stem cells. Oxaliplatin treatment changed the levels of many lncRNAs in extracellular vesicles (EVs) released from cultured primary sensory neurons. Among them, the levels of release of lncRNAs that were considered to be selectively expressed in dorsal root ganglia were correlated with those of lncRNAs in plasma EV obtained from healthy individuals. Several lncRNAs in plasma EVs early after the initiation of treatment showed greater changes in patients who did not develop chronic neuropathy that persisted for more than 1year than in those who did. Therefore, these extracellular lncRNAs in plasma EVs may represent predictive biomarkers for the development of chronic peripheral neuropathy induced by oxaliplatin.

Tetrandrine alleviates oxaliplatin-induced mechanical allodynia via modulation of inflammation-related genes.

Oxaliplatin, a platinum-based chemotherapy drug, causes neuropathic pain, yet effective pharmacological treatments are lacking. Previously, we showed that tetrandrine (TET), with anti-inflammatory properties, reduces mechanical allodynia in nerve-injured mice. This study explores the effect of TET on oxaliplatin-induced mechanical allodynia and gene changes in mice. Male C57BL/6J mice received oxaliplatin intraperitoneally to induce mechanical allodynia. Post-treatment with TET or vehicle, the mechanical withdrawal threshold (WMT) was assessed using von Frey filaments. TET alleviated oxaliplatin-induced mechanical allodynia. RNA sequencing identified 365 differentially expressed genes (DEGs) in the Control vs. Oxaliplatin group and 229 DEGs in the Oxaliplatin vs. TET group. Pearson correlation analysis of co-regulated DEGs and inflammation-related genes (IRGs) revealed 104 co-regulated inflammation-related genes (Co-IRGs) (|cor| > 0.8, P < 0.01). The top 30 genes in the PPI network were identified. Arg2, Cxcl12, H2-Q6, Kdr, and Nfkbia were highlighted based on ROC analysis. Subsequently, Arg2, Cxcl12, Kdr, and Nfkbia were further verified by qRCR. Immune infiltration analysis indicated increased follicular CD4 T cell infiltration in oxaliplatin-treated mice, reduced by TET. Molecular docking showed strong binding affinity between TET and proteins encoded by Arg2, Cxcl12, Kdr, and Nfkbia. In summary, TET may alleviate oxaliplatin-induced peripheral neuropathy in clinical conditions.

Incidence, Severity and Clinical Correlation of Oxaliplatin Induced Neuropathy in Patients with Colorectal Cancer: A Single Institutional Experience

Background: Colorectal cancer is the third most commonly diagnosed cancer worldwide, and its incidence is increasing in developing countries. Chemotherapy plays a significant role in the treatment of locally advanced and metastatic colorectal cancer. Oxaliplatin has remained the backbone of the treatment of colorectal carcinoma. The primary dose-limiting toxicity of oxaliplatin is neuropathy, which can reduce compliance during therapy and impair daily living activities. With limited data regarding the occurrence of oxaliplatin-induced peripheral neuropathy (OIPN) in the Indian population, we aimed to determine the incidence and severity of oxaliplatin-induced neurotoxicity and its clinical correlation with various clinical parameters in patients with colorectal carcinoma in a cancer care centre from North-East India. Material and Methods: A prospective observational analysis was performed on all histologically confirmed cases of colorectal adenocarcinoma who received oxaliplatin-based chemotherapy either in an adjuvant setting or first-line palliative setting at Dr. B. Borooah Cancer Institute between April 2019 to March 2020. Results: Our study evaluated 76 patients with colorectal carcinoma with a mean age of 54.07 ± 10 years. The majority (65.8%) of the patients had adenocarcinoma of the colon, and 34.2% had rectal adenocarcinoma. Twenty-three (30.3%) patients presented with metastatic disease. Oxaliplatin-based chemotherapy regimens were either CAPOX (72.4%) or FOLFOX (27.6%). Acute OIPN was observed in 59 patients (77.6%), and the most common symptom was cold-induced perioral paraesthesia. The most frequent grade for acute OIPN was grade II (30.3%). Chronic OIPN was seen in 47 (61.8%) patients, with the majority developing grade II neuropathy and was manifested mainly after 4th cycle of chemotherapy. The incidence of OIPN was higher in the patients aged ≥60 years, with a cumulative oxaliplatin dose of &gt; 1000 mg/m2 and baseline low serum magnesium or calcium level. Conclusion: Oxaliplatin is one of the essential chemotherapy drugs used in colorectal cancer with significant dose-limiting toxicity of peripheral neuropathy. Well-timed identification of neuropathic symptoms can increase treatment adherence and improve the patient’s quality of life.&#x0D;

Study protocol: fish oil supplement in prevention of oxaliplatin-induced peripheral neuropathy in adjuvant colorectal cancer patients – a randomized controlled trial. (OxaNeuro)

BackgroundOxaliplatin-induced peripheral neuropathy (OIPN) in general and painful OIPN in particular is a debilitating late effect that severely affects cancer survivors’ quality of life and causes premature cessation of potentially lifesaving treatment. No preventive treatments and no effective treatment for chronic OIPN exist despite many attempts. One of several suggested mechanisms includes neuroinflammation as a contributing factor to OIPN. Fish oil containing long-chain n-3 polyunsaturated fatty acids (n-3 LCPUFAs) are precursors to specialized proresolving mediators that mediate the resolution of inflammation. Our primary hypothesis is that a high supplementation of n-3 LCPUFAs will lower the prevalence and severity of OIPN.MethodsThe OxaNeuro project is an investigator-initiated, multicenter, double-blinded, randomized, placebo-controlled clinical study. We will include 120 patients eligible to receive adjuvant oxaliplatin after colorectal cancer surgery. Patients will receive fish oil capsules containing n-3 LCPUFAs or corn oil daily for 8 months.The primary endpoint is the prevalence of OIPN at 8 months defined as relevant symptoms, including one of the following: abnormal nerve conduction screening, abnormal vibration threshold test, abnormal skin biopsy, or abnormal pinprick test. Additional endpoints include the intensity and severity of OIPN-related neuropathic pain, patient-reported OIPN symptoms, quality of life, mental health symptoms, body composition, and cognitive evaluation. Furthermore, we will evaluate inflammatory biomarkers in blood samples and skin biopsies, including the potential OIPN biomarker neurofilament light protein (NfL) which will be measured before each cycle of chemotherapy.DiscussionIf readily available fish oil supplementation alleviates OIPN prevalence and severity, it will significantly improve the lives of both cancer survivors and palliative cancer patients receiving oxaliplatin; it will improve their quality of life, optimize chemotherapeutic treatment plans by lowering the need for dose reduction or premature cessation, and potentially increase survival.Trial registrationClinicalTrial.gov identifier: NCT05404230Protocol version: 1.2, April 25th. 2023

Pharmacokinetic-toxicodynamic Modeling to Elucidate the Involvement of Dorsal Root Ganglion Neuron in Oxaliplatin-induced Peripheral Neuropathy.

Oxaliplatin (L-OHP)-induced peripheral neuropathy (OIPN) limits L-OHP dosage due to nerve cell damage in the dorsal root ganglion (DRG) caused by platinum (Pt). Despite various recommended approaches for OIPN management, no effective approach has been established. The aim of this study was to evaluate Pt distribution into DRG after repeat administrations of L-OHP in rats and to develop a pharmacokinetic-toxicodynamic (PK-TD) model using Pt concentrations in DRG to predict neuropathy severity. Male Wistar rats were administered L-OHP (3, 5, or 8 mg/kg i.v.) once weekly. Blood and DRG samples were collected following L-OHP administration. For toxicodynamic (TD) study, OIPN was evaluated using the von Frey test. Plasma and DRG Pt concentrations and thresholds values in von Frey test were used for PK-TD modeling using Phoenix WinNonlin® version 8.3 software. Pt concentration in the DRG increased with repeated administration of L-OHP in a dose-dependent manner, indicating Pt accumulation in DRG following multiple administrations. The PK-TD model, consisting of an indirect response model and a transit compartment model with the DRG compartment, adequately described the temporal changes in OIPN with reliable TD parameters (≤36.4% with coefficient of variation). The maximum drug inhibition model could be employed to establish a quantitative correlation between the Pt content present in the DRG and the toxic potency resulting in OIPN. The utility of the PK-TD model for predicting neuropathy outcomes was established, suggesting that models composed of the DRG compartment contribute to determining an optimal dosing strategy for reducing OIPN.

Protective effect of alpha-lipoic acid and epalrestat on oxaliplatin-induced peripheral neuropathy in zebrafish.

Oxaliplatin is a platinum-based anti-cancer drug widely used in colorectal cancer patients, but it may cause peripheral neuropathy. As one of the main causes of oxaliplatin-induced peripheral neuropathy (OPN) is oxidative stress, which is also a key factor causing diabetic peripheral neuropathy (DPN), the aim of this study was to evaluate the preventive effects of alpha-lipoic acid (ALA) and epalrestat (EP), which are used for the treatment of DPN, in an OPN zebrafish model. Tg(nbt:dsred) transgenic zebrafish, with sensory nerves in the peripheral lateral line, were treated with oxaliplatin, oxaliplatin/EP, and oxaliplatin/ALA for 4 days. A confocal microscope was used to visualize and quantify the number of axon bifurcations in the distal nerve ending. To analyze the formation of synapses on sensory nerve terminals, quantification of membrane-associated guanylate kinase (MAGUK) puncta was performed using immunohistochemistry. The number of axon bifurcations and intensity of MAGUK puncta were significantly reduced in the oxaliplatin-treated group compared with those in the embryo medium-treated group. In both the oxaliplatin/EP and oxaliplatin/ALA-treated groups, the number of axon bifurcations and intensity of MAGUK puncta were greater than those in the oxaliplatin-treated group (p < .0001), and no significant difference was observed between larvae treated with oxaliplatin/ALA 1 μM and oxaliplatin/EP 1 μM (p = .4292). ALA and EP have protective effects against OPN in zebrafish. Our findings show that ALA and EP can facilitate more beneficial treatment for OPN.

The Effects of an App-Based Physical Activity Program on Colorectal Cancer Patients Undergoing Chemotherapy: A Randomized Controlled Trial.

Colorectal cancer is one of the most common malignancies worldwide. Oxaliplatin, which is used as adjuvant chemotherapy, affects quality of life by causing oxaliplatin-induced peripheral neuropathy in colorectal cancer patients. This study examined the effects of an application (app)-based physical activity program for alleviating peripheral neuropathy symptoms in colorectal cancer patients undergoing chemotherapy. This was a randomized controlled study that included 34 patients undergoing chemotherapy after being diagnosed with colorectal cancer. Outcomes were compared between patients who participated in a 6-week app-based physical activity program (experimental group; n = 17) and who received standard booklet education (control group; n = 17). Data were collected using questionnaires, and exercise time was recorded to evaluate intervention adherence. Significant differences were observed between the groups in peripheral neuropathy symptoms (F = 8.93, P = .002), interference with activities (Z = -2.55, P = .011), and quality of life (F = 7.65, P = .003). The experimental group showed significantly higher average exercise times at 1 to 4 weeks (Z = -2.10, P = .026), 5 to 6 weeks (Z = -4.02, P < .001), and 1 to 6 weeks (Z = -3.40, P = .001) than the control group. The app-based physical activity program had a positive effect on participants' exercise adherence and reduced peripheral neuropathy symptoms. Thus, we propose the adoption of a mobile health app that can be used at any time or place as an intervention for preventing or alleviating adverse effects during the treatment of cancer patients. An app-based physical activity program using the mobile health app can be used as a nursing intervention to manage symptoms and increase the health behavior adherence in cancer patients.

Discovery and Preclinical Evaluation of a Novel Inhibitor of FABP5, ART26.12, Effective in Oxaliplatin-Induced Peripheral Neuropathy

Oxaliplatin-induced peripheral neuropathy (OIPN) is a dose-limiting toxicity characterised by mechanical allodynia and thermal hyperalgesia, without any licensed medications. ART26.12 is a fatty acid-binding protein (FABP) 5 inhibitor with antinociceptive properties, characterised here for the prevention and treatment of OIPN. ART26.12 binds selectively to FABP5 compared to FABP3, FABP4, and FABP7, with minimal off-target liabilities, high oral bioavailability, and a NOAEL of 1,000 mg/kg/day in rats and dogs. In an established preclinical OIPN model, acute oral dosing (25–100 mg/kg) showed a cannabinoid receptor type 1 (CB1)-dependent anti-allodynic effect lasting up to 8 hours (persisting longer than plasma exposure to ART26.12). Antagonists of cannabinoid receptor type 2 (CB2), peroxisome proliferator-activated receptor alpha, and transient receptor potential cation channel subfamily V member 1 (TRPV1) may have also been implicated. Twice daily oral dosing (25 mg/kg bis in die (BID) for 7 days) showed anti-allodynic effects in an established OIPN model without the development of tolerance. In a prevention paradigm, coadministration of ART26.12 (10 and 25 mg/kg BID for 15 days) with oxaliplatin prevented thermal hyperalgesia, mitigated mechanical allodynia, and attenuated OXA-induced weight loss. Multi-scale analyses revealed widespread lipid modulation, particularly among N-acyl amino acids in the spinal cord, including potential analgesic mediators. Additionally, ART26.12 administration led to upregulation of ion channels in the periaqueductal grey, and broad translational upregulation within the plasma proteome. These results show promise that ART26.12 is a safe and well-tolerated candidate for the treatment and prevention of OIPN through lipid modulation. PerspectiveInhibition of fatty acid-binding protein 5 (FABP5) is a novel target for reducing pain associated with chemotherapy. ART26.12 is a safe and well-tolerated small molecule FABP5 inhibitor effective at preventing and reducing pain induced with oxaliplatin through lipid modulation and activation of cannabinoid receptors.