Severity Of Oxaliplatin-induced Peripheral Neuropathy Research Articles

Predictors for development of oxaliplatin-induced peripheral neuropathy in cancer patients as determined by ordered logistic regression analysis.

BackgroundOxaliplatin causes acute cold-induced neurotoxicity and chronic cumulative neuropathy, which can require dose modification and impacts quality of life. However, effective strategies for managing oxaliplatin-induced peripheral neuropathy (OIPN) among affected patients remain elusive.ObjectiveThis retrospective study aimed to identify predictors for the development of OIPN.MethodsParticipants comprised 322 cancer patients at our hospital who were receiving oxaliplatin between January 2017 and March 2021. For the regression analysis of factors associated with OIPN, variables were manually extracted from medical charts. The severity of OIPN was evaluated using the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 5. Multivariate ordered logistic regression analysis was performed to identify predictors for the development of OIPN. Optimal cut-off thresholds were determined using receiver operating characteristic analysis. Values of P <0.05 (2-tailed) were considered significant.ResultsSignificant risk factors identified included higher body mass index (BMI) (odds ratio [OR] = 1.06, 95% confidence interval [CI] = 1.00–1.12; P = 0.043), female sex (OR = 1.67, 95%CI = 1.06–2.61; P = 0.026) and higher total dosage (OR = 2.39, 95%CI = 1.67–3.42; P = < 0.0001).ConclusionHigh BMI, female sex and high total dosage were identified as significant predictors for the development of OIPN.

Development of hepatic impairment aggravates chemotherapy-induced peripheral neuropathy following oxaliplatin treatment: Evidence from clinical and preclinical studies

Oxaliplatin often induces peripheral neuropathy, a dose-limiting adverse reaction, and in rare cases leads to sinusoidal obstruction syndrome. We thus conducted a retrospective cohort study to examine the relationship between oxaliplatin-induced peripheral neuropathy (OIPN) and hepatic impairment, and then perform a fundamental study to analyze the underlying mechanisms. Analysis of medical records in cancer patients treated with oxaliplatin indicated that laboratory test parameters of hepatic impairment including AST, ALT and APRI (AST to platelet ratio index) moderately increased during oxaliplatin treatment, which was positively correlated with the severity of OIPN (grades 1–4), and associated with later incidence of survivors with OIPN grades ≥2. In mice, hepatic injury induced by CCl4 or ethanol accelerated OIPN in mice, an effect prevented by inactivation of high mobility group box 1 (HMGB1), known to participate in OIPN, by the neutralizing antibody or thrombomodulin alfa capable of promoting its thrombin-dependent degradation. Oxaliplatin also aggravated the hepatic injury in mice. CCl4 released HMGB1 from cultured hepatic parenchymal cells, and oxaliplatin at clinically achievable concentrations released HMGB1 from hepatic parenchymal and non-parenchymal cells. Our clinical and preclinical data suggest that the development of mild hepatic impairment during oxaliplatin treatment is associated with later aggravation of OIPN.

Serum neurofilament light chain levels as a biomarker of neuroaxonal injury and severity of oxaliplatin-induced peripheral neuropathy

We set out to determine the usability of serum neurofilament light chain (sNfL), serum glial fibrillary acidic protein (sGFAP), and retinal parameters by using optical coherence tomography (OCT) as reliable biomarkers of the progression of oxaliplatin-induced peripheral neuropathy (OIPN). Forty-three patients scheduled to undergo oxaliplatin-based chemotherapy at the National Cancer Center of Korea between June 2018 and October 2019 were prospectively assessed at baseline, 3 months, and 6 months of chemotherapy. Patients were assessed on clinical scales and underwent OCT, sNfL, and sGFAP level measurement at each follow-up visit. By applying the National Cancer Institute-Common Toxicity Criteria (NCI-CTC), OIPN was classified as grade 1 in 12 (28%) patients, grade 2 in 25 (58%), and grade 3 in 5 (12%) at 6 months of chemotherapy. sNfL levels increased during oxaliplatin administration, while serial sGFAP levels or retinal parameters did not change. Patients with grade-3 OIPN showed significantly higher mean sNfL levels than patients with grade 0–2 OIPN at 6 months of treatment. At 4–6 months after completion of chemotherapy, sNfL levels were significantly reduced compared to the levels at 6 months of chemotherapy. Monitoring of sNfL during chemotherapy can indicate ongoing neuroaxonal injury and the severity of OIPN.

A Prospective Study of Chronic Oxaliplatin-Induced Neuropathy in Patients with Colon Cancer: Long-Term Outcomes and Predictors of Severe Oxaliplatin-Induced Neuropathy.

Background and PurposeThe objective of this study was to determine the incidence and long-term outcomes of oxaliplatin-induced peripheral neuropathy (OIPN), as well as predictors of its severe form.MethodsSixty-nine patients who were taking oxaliplatin for colon cancer were prospectively followed prior to starting chemotherapy and after 4, 8, and 12 cycles of chemotherapy. Thirty-six patients completed the follow-up at 1 year after the end of chemotherapy. The patients were assessed using clinical assessment scales and nerve conduction studies (NCS) at each follow-up visit.ResultsBy applying the National Cancer Institute Common Toxicity criteria, OIPN was classified as grade 1 in 30 (44%) patients, grade 2 in 25 (36%), and grade 3 in 10 (14%) at the completion of therapy. At 1 year after the treatment, OIPN of grades 1, 2, and 3 was found in 50, 3, and 11% of the patients, respectively. Multivariate analysis showed that reductions of the amplitude of the sensory action potential of >11.5% in the median nerve between baseline and four cycles of chemotherapy (odds ratio=5.603, p=0.031) and of >22.5% in the sural nerve between four and eight cycles of chemotherapy (odds ratio=5.603, p=0.031) were independently associated with the risk of developing grade-3 OIPN.ConclusionsWhile the severity of OIPN can improve after oxaliplatin discontinuation, more than half of the patients in this study still had OIPN at 1 year after discontinuation. Early changes in the NCS results for sensory nerves can predict the development of severe OIPN during treatment.

In this issue

REVIEW Factors associated with the development and severity of oxaliplatin-induced peripheral neuropathy: a systematic review ORIGINAL ARTICLE Efficacy of icotinib in lung squamous-cell cancer: A real-world experience from single institution ORIGINAL ARTICLE Clinical and palliative care outcomes for patients of poor performance status treated with antiprogrammed death-1 monoclonal antibodies for advancedmelanoma ORIGINAL ARTICLE Addition of oxaliplatin to neoadjuvant radiochemotherapy in MRI-defined T3, T4 or N+ rectal cancer: a randomized clinical trial

Factors associated with the development and severity of oxaliplatin-induced peripheral neuropathy: a systematic review.

Oxaliplatin is a platinum-derivative chemotherapeutic agent used for colorectal cancer in the adjuvant and metastatic setting in combination with folinic acid and 5-fluorouracil. Oxaliplatin causes an acute cold-induced neurotoxicity and a chronic cumulative neuropathy, which can require dose modification and impact quality of life. To date, no prevention and treatment strategies have proved effective thus reinforcing the importance of identifying at-risk patients in order to maximize therapeutic benefit while minimizing neurotoxicity. Here we reviewed studies on risk and prognostic factors associated with the development and severity of oxaliplatin-induced peripheral neuropathy. A systematic search was conducted in MEDLINE and Embase, and studies investigating clinical and patient-related factors associated with oxaliplatin-induced peripheral neuropathy as their primary focus were identified, and quantitative data were extracted when available. We identified 15 studies, of which only three were prospective. Notable factors were acute neurotoxicity symptoms predicting chronic neuropathy, baseline laboratory findings, patient demographics such as age and gender, comorbidities, and environmental factors. No factor was consistently identified across multiple studies other than the association with oxaliplatin dose. Further investigation into these factors may yield insight into potential neuropathy prevention and treatment strategies.

A prospective study to evaluate the usefulness of the clanging tuning fork test and the nerve conduction velocity test for oxaliplatin-induced peripheral neuropathy.

544 Background: Neurotoxicity is the most frequent dose-limiting toxicity of oxaliplatin. Cumulative sensory peripheral neurotoxicity results in discontinuation of chemotherapy for cancer and impairs neurological function irreversibly. To develop new strategies to continue chemotherapy according to the treatment plan without more severe neurotoxicity, objective assessment tools for oxaliplatin-induced peripheral neuropathy (OIPN) are needed. The clanging tuning fork test (CTFT) and the nerve conduction velocity test (NCVT) are widely used forbenign neuropathies. However, little is known about their clinical usefulness for OIPN. Methods: Colorectal cancer patients were prospectively monitored at baseline and during chemotherapy with modified FOLFOX6. The incidence and severity of OIPN were recorded using NCI-CTC grading (ver. 4.0). CTFT was conducted every 2 weeks and NCVT every 8 weeks. A generalized estimating equation model was used to examine the correlations between NCI-CTC grade and CTFT/NCVT. The accuracy of the assessment was evaluated using receiver operating characteristic (ROC) curve analysis. Results: Twenty-one patients without peripheral sensory neuropathy (PSN) were enrolled. Mean CTFT values were 13.4 ± 0.7 sec at baseline, 14.1 ± 0.4 sec with grade 0 PSN, 14.0 ± 0.4 sec with grade 1 PSN, 12.5 ± 0.7 sec with grade 2 PSN, and 7.5 ± 0.9 sec with grade 3 PSN. The mean CTFT value with grade 3 PSN was significantly shorter than with the other grades (p&lt;.001, all). ROC curve analysis showed that variation in CTFT provides a high-accuracy assessment of grade 3 PSN (AUC=0.898, 95% CI: 0.764-1.000, p=.004), and its optimal cut-off value was -3.5 sec (sensitivity and specificity for grade 3 PSN were 86% and 79%, respectively). Unlike CTFT, NCVT showed little association with OIPN. Conclusions: CTFT was found to be very effective for assessing grade 3 OIPN. The present results suggest that CTFT, a simple, quick, and non-invasive examination, is a promising assessment tool for OIPN. Clinical trial information: 000004305.

Long-term course of oxaliplatin-induced polyneuropathy: a prospective 2-year follow-up study.

This prospective study sought to identify the potential reversibility of oxaliplatin-induced peripheral neuropathy (OXAIPN) by following-up its long-term course 2 years after discontinuation of oxaliplatin (OXA)-based chemotherapy. Participants were 91 colorectal cancer patients treated with OXA-based chemotherapy. Neurological assessment, clinical Total Neuropathy Score© (TNSc©) and nerve conduction studies were performed at baseline (T0), the end of chemotherapy (T1) and 2 years (T2) after discontinuation of chemotherapy. A total of 73 of 91 (80%) patients experienced OXAIPN at T1. At a median follow-up of 25 months, persistence of chronic OXAIPN was present in 61 of 73 patients (84%) and complete resolution was present in 12 patients (17%). Longitudinal comparison of TNSc© values between T1 and T2 revealed that the overall severity of OXAIPN in those 61 patients significantly decreased over time. Median TNSc© values were nine (range: 2-15) at T1 vs. four (range: 2-12) at T2 (P < 0.001). Likewise, sensory nerve conduction measures at T2 significantly improved in all sensory nerves tested, compared with T1. Severity of OXAIPN at T2 was significantly associated (P < 0.001) with high severity of OXAIPN at T1. In conclusion, persistence of OXAIPN beyond 2 years after finishing chemotherapy is common. Clinical and neurophysiological improvement is observed, although recovery is often incomplete.

Efficacy and tolerability of oxycodone for oxaliplatin-induced peripheral neuropathy and the extension of folfox therapy in colorectal cancer patients.

196 Background: The oxaliplatin-based regimen FOLFOX is widely used to treat patients with advanced colorectal cancer (CRC). However, dose-limiting toxicity after continuous oxaliplatin administration can lead to peripheral neuropathy. Several agents, including opioids, that have been employed to treat oxaliplatin-induced peripheral neuropathy (OIPN) have been examined in clinical settings regarding their protective and therapeutic effects. However, the pharmacotherapy of these agents has not yet been established. Therefore, we investigated the efficacy and tolerability of oxycodone for OIPN and subsequently with FOLFOX therapy in CRC patients. Methods: This was a single-center retrospective study of 64 CRC patients who underwent FOLFOX therapy at the Toho University Sakura Medical Center (Sakura, Japan). Controlled-release (CR) oxycodone was concomitantly administered to 29 patients (OXY group), whereas the additional 35 patients (non-OXY group) were not given oxycodone during the FOLFOX treatment course. The incidence and severity of OIPN and the number of FOLFOX cycles were measured and compared between the two groups. Neurological toxicities were assessed according to the Common Terminology Criteria for Advanced Events, version 3.0. Results: All study patients had OIPN. Most patients experienced grade 1 or 2 sensory neuropathy. Grade 3 sensory neuropathy was observed in two patients in the non-OXY group. All patients in the OXY group completed the scheduled FOLFOX therapy, whereas FOLFOX therapy was discontinued in ten patients in the non-OXY group due to severe peripheral neuropathy. The median numbers of FOLFOX cycles in the OXY and non-OXY groups were 13 (range, 6–46) and 7 (range, 2–18), respectively (P &lt; 0.05). The median cumulative oxaliplatin doses were 1072.3 mg/m2 (range, 408.7–3385.3 mg/m2) in the OXY group and 483.0 mg/m2 (range 76.2–1414.1 mg/m2) in the non-OXY group (P &lt; 0.05). Conclusions: Our findings indicate that CR oxycodone might attenuate the severity of OIPN and extend the use of FOLFOX therapy.

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.

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.

Treatment of oxaliplatin-induced peripheral neuropathy with oxycodone and extension of FOLFOX in patients with advanced colorectal cancer.

e19534 Background: FOLFOX is a combination chemotherapeutic regimen that incorporates folinic acid (FOL), 5-fluorouracil (F), and oxaliplatin (OX). FOLFOX is the standard adjuvant and metastatic therapy for advanced colorectal cancer. Peripheral neuropathy (PN) is the most frequent dose-limiting toxicity of oxaliplatin. It is crucial to prevent chemotherapy-induced PN or reduce its severity for optimal treatment delivery and prolongation of survival. We retrospectively evaluated the efficacy of oxycodone in patients with oxaliplatin-induced PN. Methods: The medical records of 56 eligible patients (range 48-74 y.o.) treated at Toho University Medical Center Sakura Hospital were reviewed; of these 56 patients, 27 received oxycodone (range 10-60 mg/day, average 17.8 mg) for oxaliplatin-induced PN (OXC (+) group). Treatment was continued until disease progression, unacceptable toxicity occurred, or until patient withdrawal. Results: One patient in the OXC (-) group showed Grade 3 PN (CTCAE v4.0), other patients showed Grade 1 or Grade 2 symptoms. Chemotherapy was suspended due to PN in 2 patients of the OXC (-) group, while it was not discontinued due to PN in any patient of the OXC (+) group. The number of mFOLFOX6 or mFOLFOX6+B-mab cycles was 15.6±1.5 (AVG±SE) (range 6-36 courses) in the OXC (+) group, and 7.4±0.5 (range 2-15 courses) in the OXC (-) group (P<0.05). The total dose of oxaliplatin was 1172.4±110.5 mg/m2 (range 408.7-2579.9 mg) in the OXC (+) group, and 537.9±43.5 mg/m2 (range 76.2-1235.9 mg) in the OXC (-) group (P<0.05). Conclusions: Treatment with oxycodone reduced the severity of oxaliplatin-induced peripheral neuropathy and contributed to the good performance status of patients receiving FOLFOX chemotherapy. Preventing oxaliplatin-induced PN with oxycodone made it possible to continue the FOLFOX regimen during its effective term and might improve the treatment outcome in patients with advanced colorectal cancer. Distribution of patients Total OXC(+) OXC(-) No. of patients 56 27 29 Stage III 16 3 13 Stage IV 40 24 16 mFOLFOX6 32 10 22 mFOLFOX6-B-mab 24 17 7

Liability of the Voltage-Gated Sodium Channel Gene SCN2A R19K Polymorphism to Oxaliplatin-Induced Peripheral Neuropathy

Aim: It was the aim of this study to test the hypothesis that the voltage-gated sodium channel gene SCN2A R19K polymorphism confers liability to oxaliplatin-induced peripheral neuropathy (OXLIPN). Methods: Sixty-two patients with advanced colorectal cancer were genotyped, using allele-specific primers and SYBR green in real-time polymerase chain reaction. All patients had received adjuvant oxalipla-tin-based chemotherapy. The severity of OXLIPN was defined by means of the clinical total neuropathy score. Following the discontinuation of treatment, 36/62 patients (58.1%) developed OXLIPN. Grade I neurotoxicity was revealed in 14 (38.9%) patients and grade II neurotoxicity in 22 (61.1%) patients. Results: From patients without OXLIPN (n = 26), 80.8% (n = 21) were homozygous for G, 19.2% (n = 5) were heterozygous (AG) and none was homozygous for A. The corresponding percentages for patients developing any grade of OXLIPN (n = 36) were similar. Likewise, among patients experiencing OXLIPN, insignificant differences in R19K genotypes were revealed between those with grade I versus grade II neurotoxicity. Conclusion: Our study failed to provide evidence to support a causal relationship between the SCN2A R19K polymorphism and OXLIPN.

Incidence and characteristics of peripheral neuropathy during oxaliplatin-based chemotherapy for metastatic colon cancer

Aim. The current prospective study sought to trace the incidence and severity of oxaliplatin-induced peripheral neuropathy (OXLIPN) and to determine its clinical and electrophysiological pattern. Patients and methods. Twenty-five adult patients scheduled to be treated with 12 courses of the oxaliplatin-based regimen, FOLFOX-4, for metastatic colon cancer participated in this study. Patients were clinically and electrophysiologically monitored at baseline and followed-up during chemotherapy. The severity of OXLIPN was summarized by means of a modified Total Neuropathy Score (TNS). Results. Evidence of OXLIPN was disclosed in 16 of the 25 patients (64%). The mean TNS values for patients manifesting some grade of OXLIPN were 13.9±5.8 (range 7–28). All longitudinal comparisons concerning the motor conduction parameters failed to reach significance. By contrast, comparisons of the median changes at baseline and each of the follow-up studies revealed significant decrease in all sensory action potentials examined. Conclusion. Our results indicate that the majority of patients treated with the FOLFOX-4 regimen would manifest an axonal, predominately sensory peripheral neuropathy, of mild to moderate severity.