Acute Oxaliplatin-induced Peripheral Neuropathy Research Articles

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 > 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.

A randomized controlled trial of hand/foot-cooling by hilotherapy to prevent oxaliplatin-related peripheral neuropathy in patients with malignancies of the digestive system

Both acute and chronic symptoms of oxaliplatin-induced peripheral neuropathy (OIPN) affect patients' treatment dose and duration as well as quality-of-life. Hand/foot-cooling has been shown to reduce taxane-induced peripheral neuropathy but there is unclear evidence in the setting of oxaliplatin. In a monocentric, open-label phase II trial, patients with malignancies of the digestive system receiving oxaliplatin-based chemotherapy were randomly assigned to receive either continuous cooling of hands and feet using hilotherapy at 11°C during oxaliplatin infusion compared with usual care (no cooling). The primary endpoint was grade ≥2 neuropathy-free rate in 12 weeks after initiation of chemotherapy. Secondary endpoints included OIPN-related treatment alterations, acute OIPN symptoms and perceived comfort of the intervention. The intention-to-treat population included 39 patients in the hilotherapy group and 38 in the control group. The grade ≥2 neuropathy-free rate at 12 weeks was 100% in the experimental group versus 80.5% in the control group (P= 0.006). This effect was persistent at 24 weeks (66.0% versus 49.2%, respectively) (P= 0.039). Next, treatment alterations-free rate at week 12 was 93.5% in the hilotherapy group compared with 83.3% in the control group (P= 0.131). Patients in the hilotherapy group experienced significantly less acute OIPN symptoms of numbness or tingling [odds ratio (OR) 0.05, 95% confidence interval (CI) 0.02-0.11, P < 0.0001], pain (OR 0.06, 95% CI 0.02-0.15, P < 0.0001) and/or cold sensitivity (OR 0.02, 95% CI 0.01-0.05, P < 0.0001) in fingers or toes as well as less pharyngeal cold sensitivity (OR 0.14, 95% CI 0.05-0.42, P= 0.0005). The majority of patients in the hilotherapy group rated the intervention as neutral, rather comfortable or very comfortable. In this first study on hand/foot-cooling in oxaliplatin alone, hilotherapy significantly reduced the incidence of grade ≥2 OIPN at 12 and 24 weeks. Hilotherapy also reduced acute OIPN symptoms and was generally well tolerated.

The Class I HDAC Inhibitor, MS-275, Prevents Oxaliplatin-Induced Chronic Neuropathy and Potentiates Its Antiproliferative Activity in Mice.

Oxaliplatin, the first-line chemotherapeutic agent against colorectal cancer (CRC), induces peripheral neuropathies, which can lead to dose limitation and treatment discontinuation. Downregulation of potassium channels, which involves histone deacetylase (HDAC) activity, has been identified as an important tuner of acute oxaliplatin-induced hypersensitivity. MS-275, a class I histone deacetylase inhibitor (HDACi), prevents acute oxaliplatin-induced peripheral neuropathy (OIPN). Moreover, MS-275 exerts anti-tumor activity in several types of cancers, including CRC. We thus hypothesized that MS-275 could exert both a preventive effect against OIPN and potentially a synergistic effect combined with oxaliplatin against CRC development. We first used RNAseq to assess transcriptional changes occurring in DRG neurons from mice treated by repeated injection of oxaliplatin. Moreover, we assessed the effects of MS-275 on chronic oxaliplatin-induced peripheral neuropathy development in vivo on APCMin/+ mice and on cancer progression when combined with oxaliplatin, both in vivo on APCMin/+ mice and in a mouse model of an orthotopic allograft of the CT26 cell line as well as in vitro in T84 and HT29 human CRC cell lines. We found 741 differentially expressed genes (DEGs) between oxaliplatin- and vehicle-treated animals. While acute OIPN is known as a channelopathy involving HDAC activity, chronic OIPN exerts weak ion channel transcriptional changes and no HDAC expression changes in peripheral neurons from OIPN mice. However, MS-275 prevents the development of sensory neuropathic symptoms induced by repeated oxaliplatin administration in APCMin/+ mice. Moreover, combined with oxaliplatin, MS-275 also exerts synergistic antiproliferative and increased survival effects in CT26-bearing mice. Consistently, combined drug associations exert synergic apoptotic and cell death effects in both T84 and HT29 human CRC cell lines. Our results strongly suggest combining oxaliplatin and MS-275 administration in CRC patients in order to potentiate the antiproliferative action of chemotherapy, while preventing its neurotoxic effect.

Qualitative Evaluation of the Influence of Acute Oxaliplatin-Induced Peripheral Neuropathy on Quality of Life and Activities of Daily Life.

Introduction/AimsOxaliplatin often causes acute or chronic peripheral neuropathy in patients with an intestinal or pancreatic tumor, but in‐depth insights in its influence on quality of life (QoL) are lacking. We explored the influence of acute oxaliplatin‐induced peripheral neuropathy (OIPN) on daily QoL in these patients.MethodsWe performed semistructured interviews with a purposive sample of patients receiving oxaliplatin and possibly experiencing acute OIPN. Interviews were audio‐recorded, transcribed verbatim, and coded by two researchers. Data were analyzed by using the constant comparative method for content analysis with ATLAS.ti software.ResultsAfter nine patients, saturation took place. In total, 11 patients were interviewed. Four themes were extracted from the data: (1) adverse effects, (2) physical (un)well‐being, (3) emotional aspects, and (4) treatment aspects. All participants were suffering from acute OIPN to a certain extent, leading to restrictions in daily activities such as household chores, but also to a decrease in mobility and independency. Other adverse effects such as general malaise and gastrointestinal side effects also influenced the participants’ well‐being, as did the diagnosis and prognosis of their disease.ConclusionAcute OIPN, together with other side effects of chemotherapeutic treatment and the difficulties that come with the diagnosis of cancer and its prognosis, largely influences patients’ daily QoL. Managing expectations (by patient education) seems important.

The Incidence of Oxaliplatin-Induced Peripheral Neurotoxicity at Khartoum Oncology Hospital: A Cross-Sectional Survey

Objective:Using oxaliplatin-based chemotherapy in the treatment of cancer patients can cause a unique form of acute and chronic peripheral neurotoxicities. This study mainly aims to assess the incidence of oxaliplatin-induced peripheral neuropathy (OXAIPN).Methods:A cross-sectional study among 121 patients treated with oxaliplatin-based chemotherapy was conducted during the period of January to April 2019 at Khartoum Oncology Hospital. The incidence of acute neurotoxicity was assessed using a descriptive questionnaire for most common hyperexcitability and transient symptoms, while the incidence of chronic neurotoxicity was measured by the 20-item European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for patients with chemotherapy-induced peripheral neuropathy and graded by the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.03.Results:Acute and chronic OXAIPN were found in 49.6% and 41.3% of patients, respectively. Most of the patients who developed acute OXAIPN symptoms manifested cold-induced pharyngolaryngeal dysesthesias (73.3%) or perioral paresthesias (71.7%). No significant association exists between the severity of chronic neurotoxicity and basic demographics. Most (79.1%) of the patients did not inform the doctors about their complaints, and 43.5% of those who informed doctors did not take any medication to manage OXAIPN.Conclusions:This study exhibits that oxaliplatin-based chemotherapy can cause symptoms of peripheral neurotoxicity in most of the patients with colorectal or gastric cancer in the form of acute neurotoxicity or chronic neurotoxicity.

Incidence, severity, longitudinal trends and predictors of acute and chronic oxaliplatin-induced peripheral neuropathy in Taiwanese patients with colorectal cancer.

The purpose of this study was to evaluate the longitudinal incidence, severity, pattern of changes or predictors of oxaliplatin-induced peripheral neuropathy (OXAIPN) in Taiwanese patients with colorectal cancer. A longitudinal repeated measures study design was employed, and 77 participants were recruited from the colorectal and oncology departments of two teaching medical centres in Taiwan. Physical examinations were performed, and self-reports regarding adverse impacts of OXAIPN and quality of life were obtained at five time points throughout 12 cycles of chemotherapy (C/T). The incidence of OXAIPN increased with C/T cycles (31.1%-81.9%), and the upper limb numbness and cold sensitivity were most significant acute OXAIPN symptoms (29.9%-73.6%). Findings also documented significant increases in overall severity, symptom distress, interference and physical results associated with OXAIPN over the course of C/T. Predictors of OXAIPN severity varied by treatment cycle, including younger patient, higher cumulative dose of oxaliplatin, greater body surface area, receipt of chemotherapy in winter and the occurrence of OXAIPN during prior C/T cycles. The results from this study might help healthcare providers to recognise the symptom characteristics, degree of influences, trends and high-risk group of OXAIPN, facilitating early evaluation and potential interventions to mitigate or prevent negative effects of OXAIPN on patients.

Oxaliplatin-induced peripheral neuropathy in south indian cancer patients: A prospective study in digestive tract cancer patients

Purpose:The aim of the current study is to report our prospective experience on the prevalence of oxaliplatin-induced peripheral neuropathy (OXAIPN) in patients with digestive tract cancers treated with oxaliplatin-based combination therapy.Materials and Methods:A total of 219 patients scheduled to be treated with oxaliplatin-based combination therapy were prospectively examined at baseline and follow-up during the therapy between November 2014 and December 2016. The incidence of acute OXAIPN was measured using a descriptive questionnaire (yes/no question) based on sum of number of symptoms present and NCI-CTCAE version 4.03 was applied to clinically grade the severity of chronic OXAIPN.Results:Acute and chronic OXAIPN was found in 108 of 219 (49.3%) and 127 of 219 (58%) patients, respectively. Out of 11 acute OXAIPN symptoms, the vast majority of patients manifested cold-induced pharyngolaryngeal (63.8%) dysesthesias or perioral (61.1%) paresthesias. Development of acute OXAIPN was predictive of subsequent development of chronic OXAIPN (P = 0.0001). All the patients received a median cumulative dose of 780 mg/m2 (range: 130–1040 mg/m2). There was a significant correlation between the patients who received the median cumulative dose and the development of chronic OXAIPN. The incidences of OXAIPN in patients with median cumulative dose of ≤780 mg/m2 was 51/120 (42.5%) and >780 mg/m2 was OXAIPN 76/99 (76.7%) (P = 0.0001).Conclusion:The current study results demonstrate that the vast majority of patients who receive oxaliplatin-based combination chemotherapy will manifest acute OXAIPN that may contribute to the development of chronic peripheral neuropathy on repeated courses of drug administration.

Clinical and electrophysiological studies of oxaliplatin-induced peripheral neuropathy

To identify the sensitive scales and the early change of nerve conduction for chronic oxaliplatin-induced peripheral neuropathy (OXLIPN), and to investigate correlation between the symptoms of acute OXLIPN and chronic OXLIPN. Between December 2014 and August 2015, 16 colorectal cancer patients confirmed by pathology, from department of Oncology, Chinese PLA General Hospital, scheduled to receive XELOX, completed the acute neurotoxic symptoms questionnaire at the end of 1 cycles and the scales of TNSc and NCI-CTC at the baseline and the end of 4 cycles. Nerve conduction studies (bilateral peroneal nerves and sural nerves) were performed in 11 patients at the baseline and the end of 4 cycles. After chemotherapy, TNSc increased 1-9 points for all cases, while NCI-CTC increased 1 point for only 9 cases, the remaining 7 cases had the same NCI-CTC score before and after chemotherapy, where TNSc increased 1-6 points. Left sural nerve a-SNAP (amplitude of sensory nerve action potential) was (15.3±5.8)μV before chemotherapy and(12.3±5.0)μV after chemotherapy. Right sural nerve a-SNAP was (17.4±8.6)μV before chemotherapy and (13.3±6.7)μV after chemotherapy. After chemotherapy, these datum were significantly reduced for left peroneal nerve distal and proximal a-CMAP (amplitude of compound muscle action potential), bilateral sural nerve a-SNAP and left sural nerve SCV (sensory conduction velocity) (P<0.05). After chemotherapy, TNSc was correlated significantly with the acute neurotoxic symptoms questionnaire (Spearman r=0.698, P=0.003). TNSc is more sensitive to the severity and changes in chronic OXLIPN than NCI-CTC. Sural nerve a-SNAP has a higher sensitivity for the early changes of nerve conduction studies in chronic OXLIPN. Patients who have more symptoms of acute OXLIPN are those who eventually develop more severe chronic OXLIPN.

Voltage‐gated sodium channel polymorphisms play a pivotal role in the development of oxaliplatin‐induced peripheral neurotoxicity: Results from a prospective multicenter study

The current prospective, multicenter study sought to identify single nucleotide polymorphisms of voltage-gated sodium channels (SCNAs) genes that might confer susceptibility to an increased incidence and severity of oxaliplatin-induced peripheral neuropathy (OXAIPN) in patients treated with either leucovorin, 5-fluorouracil, and oxaliplatin (FOLFOX) or oxaliplatin plus capecitabine (XELOX) for colorectal cancer (CRC). A total of 200 patients with CRC were genotyped with real-time polymerase chain reaction using locked nucleic acid hydrolysis probes or allele-specific primers. All patients had received oxaliplatin-based chemotherapy, either in the adjuvant or metastatic setting. The incidence and severity of cumulative OXAIPN was graded using the clinical version of the Total Neuropathy Score and the neurosensory National Cancer Institute Common Toxicity Criteria (version 3.0). The incidence of acute OXAIPN was assessed using a descriptive questionnaire (yes/no response format) at each clinical evaluation. Acute OXAIPN was present in 169 of 200 patients (84.5%), whereas after treatment discontinuation, the cumulative/chronic form of neurotoxicity occurred in 145 of 200 patients (72.5%). In the logistic regression analysis adjusted for confounding factors, the overdominant model (CT vs CC + TT) of 2 single nucleotide polymorphisms (ie, SCN4A-rs2302237 and SCN10A-rs1263292) emerged as being significantly associated with an increased incidence of acute OXAIPN (rs2302237: odds ratio of 2.62 [95% confidence interval (95% CI), 1.15-6.00]; P = .019; and rs12632942: OR of 0.39 [95% CI, 0.17-0.88]; P = .023). However, only SCN4A-rs2302237 emerged as also being predictive of the clinical severity of acute OXAIPN (OR, 2.50 [95% CI, 1.35-4.63]; P = .0029) and the occurrence of cumulative/chronic OXAIPN (OR, 2.47 [95% CI, 1.04-5.85]; P = .037). The results of the current study provide evidence to support a causal relationship between SCNA polymorphisms and OXAIPN. However, further studies from independent groups are warranted to confirm these results.

Vitamin E for prevention of oxaliplatin-induced peripheral neuropathy: a pilot randomized clinical trial

CONTEXT AND OBJECTIVE Oxaliplatin is one of the chemotherapy regimens most used for treating colorectal cancer. One of the main limitations to its use is induction of peripheral neuropathy. Previous studies have shown that vitamin E can reduce the incidence of peripheral neuropathy by 50%. This study aimed to assess the effectiveness of vitamin E for prevention of oxaliplatin-induced peripheral neuropathy. DESIGN AND SETTING Prospective, phase II, randomized pilot study developed at a university hospital in the Greater ABC region. METHODS Patients were randomized five days before starting oxaliplatin treatment, to receive either vitamin E or placebo until the end of the chemotherapy regimen. The outcome was evaluated using the Common Terminology Criteria for Adverse Events (CTCAE), version 3, and specific gradation scales for oxaliplatin-induced peripheral neuropathy. Patients with colorectal and gastric cancer who had been scheduled to receive oxaliplatin-based chemotherapy were included. Both groups received calcium and magnesium supplementation before and after oxaliplatin infusions. RESULTS Eighteen patients were randomized to the vitamin E group and 16 to the placebo group. Cumulative incidence of 83% with peripheral neuropathy grades 1/2 was observed in the vitamin E group, versus 68% in the placebo group (P = 0.45). A trend towards more diarrhea was observed among patients who received vitamin E (55.6% vs. 18.8%; P = 0.06). There were no other significant differences in toxicity between the groups. CONCLUSIONS No significant decrease in the incidence of acute oxaliplatin-induced peripheral neuropathy was demonstrated through vitamin E use.

Peripheral neurotoxicity of oxaliplatin in combination with 5-fluorouracil (FOLFOX) or capecitabine (XELOX): a prospective evaluation of 150 colorectal cancer patients

To report our prospective experience on the incidence and pattern of oxaliplatin (OXA)-induced peripheral neuropathy (OXA-IPN) in patients with colorectal cancer (CRC) treated with either FOLFOX-4 or XELoda + OXaliplatin (XELOX). One hundred and fifty patients scheduled to be treated with either FOLFOX or XELOX for CRC were prospectively monitored at baseline and followed-up during chemotherapy. The incidence and severity of symptoms secondary to OXA-IPN were recorded using three different types of assessment, i.e. the motor and neurosensory National Cancer Institute common toxicity criteria, version 3.0 (NCI-CTCv3), the clinical version of the total neuropathy score (TNSc) and electrophysiological scores. Patients treated with either FOLFOX-4 or XELOX manifested similar incidence rates and severities of acute OXA-IPN. However, FOLFOX-4 was associated with increased incidence of chronic neurotoxicity, compared with XELOX-treated patients (n = 64/77 versus 44/73; P = 0.002), at a very similar OXA median cumulative dose during both regimens. Both the NCI-CTCv3 and TNSc demonstrated that the severity of cumulative OXA-IPN in FOLFOX-4-treated patients is higher than in those treated with XELOX. The incidence of acute neurotoxicity during FOLFOX-4 therapy is similar to XELOX. However, it seems that FOLFOX-4 is more neurotoxic than XELOX in terms of cumulative OXA-IPN, despite comparable OXA cumulative dose.

Clinical pattern and associations of oxaliplatin acute neurotoxicity

The objective of the current prospective, multicenter, international study was to trace the incidence and severity of acute oxaliplatin-induced peripheral neuropathy (OXLIPN) and to determine its clinical pattern. The authors also specifically tested whether patients who had more symptoms of acute OXLIPN eventually would develop a more severe chronic, cumulative form of OXLIPN. One hundred seventy patients (mean ± standard deviation age, 63.7 ± 8.7 years) who were scheduled to receive either combined leucovorin, 5-fluoruracil, and oxaliplatin (FOLFOX) or combined capecitabine and oxaliplatin (XELOX) for metastatic colorectal cancer were monitored prospectively at baseline and were followed in 4 European sites. The incidence of hyperexcitability symptoms secondary to acute OXLIPN was assessed by using a descriptive questionnaire (yes/no question) at each clinical evaluation. Motor and neurosensory criteria according to version 3 of the National Cancer Institute's Common Toxicity Criteria were applied to clinically grade the severity of OXLIPN. Acute OXLIPN was present in 146 of 170 patients (85.9%). The vast majority of these patients manifested cold-induced perioral (95.2%) or pharyngolaryngeal (91.8%) dysesthesias. Severe acute OXLIPN that required prolongation of oxaliplatin infusion from 2 hours to 4 to 6 hours occurred in 32 of 146 patients (21.9%). The increased number of acute OXLIPN symptoms was correlated significantly (Spearman rho correlation coefficient [r]) with both the development (r = 0.602; P < .001) and the degree of the chronic, cumulative form (r = 0.702; P < .001). The current results indicated that the vast majority of patients with colorectal cancer who receive oxaliplatin-based chemotherapy will manifest symptoms of a transient acute syndrome soon after oxaliplatin administration. Patients who have a more complex combination of acute phenomena related to axonal hyperexcitability are those who eventually develop more severe OXLIPN. Therefore, it may be advisable to test agents against acute OXLIPN to verify their effects on the chronic form.

Incidence, characteristics, and associations of oxaliplatin-induced peripheral neuropathy in colorectal cancer patients: Results of a prospective, multicenter, international study.

9090 Background: We sought to trace the incidence and severity of oxaliplatin-induced peripheral neuropathy (OXLIPN) and to determine its clinical pattern. Among other associations, we also specifically aimed at testing whether the degree of acute neuropathy is clinically related to the development and severity of chronic OXLIPN. Methods: 170 patients (mean age 64y), scheduled to be treated with either FOLFOX or XELOX for metastatic colorectal cancer were studied. Patients were prospectively monitored at baseline and followed-up during chemotherapy in four European sites. The motor/neurosensory NCI-CTCv3 criteria and the clinical version of the Total Neuropathy Score were applied to clinically grade the severity of OXLIPN. Nerve conduction studies were also longitudinally performed. Results: Evidence of acute OXLIPN was disclosed in 146/170 patients (85.9%). The vast majority of patients manifested cold-induced perioral (95.2%) or pharyngolaryngeal dysesthesias (91.8%). Other uncommon symptoms, such as jaw spasm were also present. Severe acute OXLIPN, requiring prolongation of OXL infusion from 2 to 4-6 hours was evident in 32/146 patients (21.9%). Overall, 123/170 patients (72.4%) experienced chronic OXLIPN. Severities were grade I: 39 (22.9%); grade II: 52 (30.6%); grade III: 33 patients (19.4%). Worst severities were related to cumulative oxaliplatin dose (r:0.269;p&lt;0.001). Follow-up assessments revealed significant decrease in all sensory action potentials examined. The severity of the acute OXLIPN was significantly correlated with both the development (r:0.450;p&lt;0.001) and degree of the chronic form (r:0.703;p&lt;0.001). Conclusions: Most patients treated with oxaliplatin-based chemotherapy would manifest OXLIPN, mainly of moderate degree. The severity of the acute syndrome appears to clinically correlate with the degree of the chronic form of OXLIPN. Our data suggest that acute phenomena, related to axonal hyperexcitability, could contribute to the development of peripheral neuropathy; thus it could be advisable to test agents against acute OXLIPN in order to verify their effects on the chronic form.