Oxaliplatin-Specific Neurotoxicity Scale Research Articles

Electronic von Frey as an objective assessment tool for oxaliplatin-induced peripheral neuropathy: A prospective longitudinal study.

There is wide discrepancy on how to perform clinical assessment of oxaliplatin-induced peripheral neuropathy. In this scenario, the Electronic von Frey (EVF), which evaluates pain objectively based upon mechanical pain thresholds (MPTs), may be a valuable tool. The present study aims to quantify hyperalgesia in the hands and feet of patients treated with oxaliplatin and to propose a novel method to classify the degree of neurotoxicity using EVF-derived measures as cut-off points. This is a prospective cohort study including 46 patients treated for colorectal cancer with the FLOX regimen. Before each oxaliplatin administration, patients were evaluated with the Acute and Chronic Neuropathy Questionnaire, Oxaliplatin-Specific Neurotoxicity Scale and National Cancer Institute Common Terminology Criteria for Adverse Events scale. Also, objective pain assessment with the EVF was performed. For both upper and lower extremities, EVF was shown to correlate well with patients' symptoms and functional impairment, as assessed by subjective scales. Also, when cut-off MPT variations were determined for diagnosis of neurotoxicity grade 2 or 3, the method showed good sensitivity and specificity. Electronic von Frey is a noninvasive and easy-to-perform objective method with potential to supplement the current assessment tools for oxaliplatin-induced peripheral neuropathy, which are mostly subjective.

FLOX (5-fluorouracil + leucovorin + oxaliplatin) chemotherapy for colorectal cancer leads to long-term orofacial neurotoxicity: a STROBE-guided longitudinal prospective study.

Colorectal carcinoma (CRC) is widely treated by chemotherapy based on an intensely neurotoxic drug: oxaliplatin (OXL). We objective to evaluate prospectively the orofacial neurotoxicity during FLOX (fluorouracil + leucovorin + OXL) chemotherapy. So, 46 patients with CRC were prospectively evaluated during FLOX chemotherapy by 3 cycles (C) of 6weeks (W) each. We weekly applied the orofacial section of the Acute and Chronic Neuropathy Questionnaire of Common Toxicity Criteria for Adverse Events of the National Cancer Institute of the United States of America (Oxaliplatin-specific neurotoxicity scale). Patients were asked the following concerning the severity (scores 0-5) of orofacial symptoms: jaw pain, eyelids drooping, throat discomfort, ear pain, tingling in mouth, difficulty with speech, burning or discomfort of the eyes, loss of any vision, feeling shock/pain down back and problems breathing. We summed the scores (0-50) and evaluated the clinicopathological data. Friedman/Dunn, Chi square and multinomial regression logistic tests were used (SPSS 20.0, p < 0.05). There was a significant increase in sum of orofacial neurotoxicity from baseline to C1.W3, C2.W1 and C3.W5 (p < 0.001) due increase in scores of jaw pain (p < 0.001), eyelids drooping (p = 0.034), throat discomfort (p < 0.001), ear pain (p = 0.034), tingling in mouth (p = 0.015), burning/discomfort of your eyes (p < 0.001), loss of any vision (p < 0.001), feeling shock/pain down back (p < 0.001), problems with breathing (p = 0.045), but not difficulty with speech (p = 0.087). Women (p = 0.021) and young patients (p = 0.027) had significant higher prevalence of orofacial neurotoxicity. FLOX-related orofacial neurotoxicity begins acutely and remains long term with increased incidence in women and younger patients.

Genetic polymorphisms of SCN9A are associated with oxaliplatin-induced neuropathy

BackgroundOxaliplatin is a chemotherapy agent active against digestive tumors. Peripheral neuropathy is one of the most important dose-limiting toxicity of this drug. It occurs in around 60–80% of the patients, and 15% of them develop severe neuropathy. The pathophysiology of oxaliplatin neurotoxicity remains unclear. SCN9A is a gene codifying for a subtype sodium channel (type IX, subunit α) and mutations in this gene are involved in neuropathic perception. In this study we investigated whether SCN9A genetic variants were associated with risk of neurotoxicity in patients diagnosed of cancer on treatment with oxaliplatin.MethodsBlood samples from 94 patients diagnosed of digestive cancer that had received oxaliplatin in adjuvant or metastatic setting were obtained from three hospitals in Madrid. These patients were classified into two groups: “cases” developed oxaliplatin-induced grade 3–4 neuropathy (n = 48), and “controls” (n = 46) had no neuropathy or grade 1. The neuropathy was evaluated by an expert neurologist and included a clinical examination and classification according to validated neurological scales: National Cancer Institute Common Toxicity Criteria (NCI-CTC), Oxaliplatin-Specific Neurotoxicity Scale (OSNS) and Total Neuropathy score (TNS). Genotyping was performed for 3 SCN9A missense polymorphisms: rs6746030 (R1150W), rs74401238 (R1110Q) and rs41268673 (P610T), and associations between genotypes and neuropathy were evaluated.ResultsWe found that SCN9A rs6746030 was associated with protection for severe neuropathy (OR = 0.39, 95% CI = 0.16–0.96; p = 0.041). Multivariate analysis adjusting for diabetes provided similar results (p = 0.036). No significant differences in neuropathy risk were detected for rs74401238 and rs41268673.ConclusionSCN9A rs6746030 was associated with protection for severe oxaliplatin-induced peripheral neuropathy. The validation of this exploratory study is ongoing in an independent series.

Laser acupuncture attenuates oxaliplatin-induced peripheral neuropathy in patients with gastrointestinal cancer: a pilot prospective cohort study.

Oxaliplatin is a platinum compound that is widely used in the treatment of some solid tumours. Oxaliplatin-induced peripheral neuropathy (OIPN) in the upper and lower extremities is the major adverse side effect and represents the main dose-limiting factor of this drug. The aim of this single-arm study was to evaluate the feasibility and effects of laser acupuncture (LA) in the treatment of OIPN in patients with advanced gastrointestinal cancers. 17 gastrointestinal cancer survivors (14 colorectal and 3 gastric cancers), who had been treated with oxaliplatin-based chemotherapies, were recruited. Low-level laser stimulation (50 mW) bilaterally at PC6, PC7, PC8, P9, LU11, SP6, KI3, BL60, KI1, and KI2 was administered for 20 min/point for 12 sessions over 4 weeks. The pain quality assessment scale (PQAS), chemotherapy-induced neurotoxicity questionnaire (CINQ), oxaliplatin-specific neurotoxicity scale (OSNS), quantitative touch-detection threshold (using von Frey filaments), and cold-triggered pain withdrawal latency (using the cold-water immersion test) were measured before and after completion of the 12 treatment sessions. PQAS, CINQ, and OSNS scores, as well as touch-detection threshold and cold-trigger pain withdrawal latency all improved significantly after LA in the cancer patients with OIPN (p<0.05). LA significantly relieved both oxaliplatin-induced cold and mechanical allodynia and also decreased the incidence and severity of neurotoxicity symptoms in the patients' upper and lower extremities and impact on their daily activities (all p<0.05). Following treatment with LA, neurotoxicity symptoms were significantly improved in cancer patients with OIPN. Further randomised controlled trials are needed to evaluate the role of LA as a therapeutic option in the management of OIPN.

Phase III randomized, placebo (PL)-controlled, double-blind study of intravenous calcium/magnesium (CaMg) to prevent oxaliplatin-induced sensory neurotoxicity (sNT), N08CB: An alliance for clinical trials in oncology study.

3501 Background: Cumulative neurotoxicity commonly leads to early discontinuation of oxaliplatin-based therapy. In a relatively small, prematurely-discontinued, randomized study, IV CaMg was associated with reduced oxaliplatin-induced sNT (Grothey, JCO, 2011). N08CB was designed to definitively test whether IV CaMg significantly decreases cumulative oxaliplatin-related sNT. Methods: 353 pts with colon cancer undergoing adjuvant therapy with FOLFOX were randomized to 3 arms: IV CaMg (1g calcium gluconate, 1g magnesium sulfate) before and after oxaliplatin vs PL before and after vs CaMg before and PL after. The primary endpoint was cumulative sNT repeatedly measured by the sensory subscale of the EORTC QLQ-CIPN20. Secondary endpoints, using CTCAE 4.0 and an oxaliplatin specific neurotoxicity scale, were also assessed. Acute neuropathy data were also collected for 5 days following each oxaliplatin dose. The area under the curve (AUC) of the sensory subscale during the treatment cycles was used as summary measures for comparison. The Wilcoxon rank-sum tests were conducted for each treatment versus placebo arm, at 2.5%, adjusting for multiplicity using Bonferroni’s approach. Results: CaMg did not reduce cumulative sNT. Primary and secondary analyses data are summarized in the Table. In addition, there were no significant differences between arms regarding oxaliplatin administered doses or chemotherapy discontinuation rates. Also, there were no substantial differences in acute neuropathy scores or side-effects between study arms. Conclusions: This study does not demonstrate any activity of IV CaMg as a neuroprotectant against oxaliplatin-induced neurotoxicity. Clinical trial information: NCT01099449. [Table: see text]

The single-nucleotide polymorphism T&gt;C rs4353229 in CASP7 gene and mir-224 as new biomarkers of oxaliplatin-induced neurotoxicity in advanced colorectal cancer.

513 Background: Oxaliplatin represents a central component of colorectal (CCR) cancer treatment. It is known that the ways in which oxaliplatin is neurotoxic include not only DNA damage, but also the modulation of specific molecules, such as caspases 3 and 7, involved in regulating the cellular equilibrium between apoptotic death and the cell cycle. MiRNAs are non-coding RNAs that can block mRNA traslation. Recent evidences indicate that variations in miRNA binding sites may contribute to the susceptibility to CCR. However, the effect of these SNPs on miRNA-target interaction remains to be determined. The SNP T&gt;C rs4353229 in CASP7 gene is binding site of miR-224. We hypothesize that miR-224 and the SNP T&gt;C rs4353229 could be new predictive biomarkers of oxaliplatin-induced neurotoxicity in advanced colorectal cancer. Methods: We examined the SNP T&gt;C rs4353229 in CASP7 gene in 62 patients with advanced CCR. All patients had received first line of chemotherapy based in fluoropirimidines plus oxaliplatin. The Oxaliplatin-Specific Neurotoxicity Scale was utilized to assess oxaliplatin-related symptoms. Time to progresion (TTP) and objetive response rate (ORR) were calculated. Genomic DNA was extracted from peripheral blood and genotyped by allelic discrimination. We explored the possible correlation of rs4353229 with neurotoxicity, DCR and TTP using and Chi-cuadrado test and Kaplan-Meier model (log rank) respectively. Results: SNP distribution was 3,2% (ancestral homozygous CC), 46,7% (variant homocygous TT) and 43,7% (heterocygous CT). Median TTP was 10 months (IC95%: 7,4-12,5); regarding CASP7 polymorphism, there were not differences (p=0,41; log rank). ORR was 64,5% and there are not differences between CC, CT and TT patients (p=0,50). Fifteen patients experienced neurotoxicity grade III/IV (24,19%) and it was correlated significantly with ancestral homoygous CC patients (p=0,003). Conclusions: The SNP T&gt;C rs4353229 in CASP7 gene and miR-224 may be new candidates predictor of oxaliplatin-induced neurotoxicity. Further characterization of CASP7 SNPs and miR-224 may open new avenues for the study of cancer and therapeutic interventions.

Efficacy of venlafaxine for the prevention and relief of oxaliplatin-induced acute neurotoxicity: results of EFFOX, a randomized, double-blind, placebo-controlled phase III trial

Oxaliplatin neurosensory toxicity is dose limiting and may present as acute symptoms and/or cumulative peripheral neuropathy. From October 2005 to May 2008, patients with oxaliplatin-induced acute neurotoxicity were randomized into a double-blind study, to receive either venlafaxine 50 mg 1 h prior oxaliplatin infusion and venlafaxine extended release 37.5 mg b.i.d. from day 2 to day 11 or placebo. Neurotoxicity was evaluated using numeric rating scale (NRS) for pain intensity and experienced relief under treatment, the Neuropathic Pain Symptom Inventory and the oxaliplatin-specific neurotoxicity scale. The primary end point was the percentage of patients with a 100% relief under treatment. Forty-eight patients were included (27 males, median age: 67.6 years). Most patients had colorectal cancer (72.9%). Median number of cycles administered at inclusion was 4.5 (mean cumulative oxaliplatin dose: 684.6 mg). Twenty out of 24 patients in arm A (venlafaxine) and 22 out of 24 patients in arm B (placebo) were assessable for neurotoxicity. Based on the NRS, full relief was more frequent in the venlafaxine arm: 31.3% versus 5.3% (P=0.03). Venlafaxine side-effects included grade 1-2 nausea (43.1%) and asthenia (39.2%) without grade 3-4 events. Venlafaxine has clinical activity against oxaliplatin-induced acute neurosensory toxicity.

Predictors of oxaliplatin-induced peripheral neuropathy in patients with advanced colorectal cancer (CRC).

619 Background: Chemotherapy-induced neuropathy (CINP) is one of the major dose-limiting toxicities of oxaliplatin. The purpose of this study was to identify early predictors of CIPN and investigate the feasibility of using nerve conduction studies (NCS) to monitor CINP. Methods: Under IRB-approved protocol, we systematically examined patient-reported symptoms, neurological tests and bilateral NCS of the peroneal, superficial peroneal and sural nerves every 3 weeks before each dose of oxaliplatin (75-130 mg/m2) in 12 CRC patients receiving 8 to 13 cycles of XELOX. The severity of neuropathy was graded by the NCI Common Toxicity Criteria (CTC v.4.0) and the Oxaliplatin-Specific Neurotoxicity Scale (OSNS). Results: At the end of chemotherapy three of 12 patients developed peripheral sensory neuropathy CTC grade 3, five had grade 2, and four had grade 1 (3 of them had no self-reported symptoms with loss of Achilles tendon reflexes). At the eighth cycle test only 4 patients experienced CTC grade 2 criteria, but 7 of 12 patients had paresthesias persisting between the cycles of chemotherapy (OSNS grade 2 or higher). Development of grade 2 CINP by CTC or OSNS criteria by the eights cycle of chemotherapy was not associated with the total dose of oxaliplatin received (ANOVA p = 0.86 and 0.78 accordingly), but was significantly associated with administration of concomitant medication (Spearman correlation = 0.62, p = 0.03 for OSNS and 0.6, p = 0.04 for CTC grade 2 CINP). Presence of grade 2 or higher sensory neuropathy before the 8th cycle of oxaliplatin was significantly associated with development of grade 3 CINP by the time of chemotherapy completion (Spearman correlation = 0.8, p = 0.001). The maximal CINP grade that patients have reached during chemotherapy was also significantly associated with concomitant medication use (Spearman correlation = 0.76, p = 0.004). Conclusions: Concomitant administration of medications was the only factor significantly associated with severity of CINP in our study cohort. Further study is needed to verify if it is associated with altered bioavailability of oxaliplatin. No significant financial relationships to disclose.

Measures of oxaliplatin-induced neutrotoxicity in 187 patients with FOLFOX4

14552 Background: Oxaliplatin-based regimen (FOLFOX regimen) for patients with colorectal cancer have improved survival. Neurotoxicity is the most frequent dose-limiting toxicity of oxaliplatin. Various strategies and pharmacologic agents are currently under investigation to prevent or treat oxaliplatin-induced neurotoxicity. One of them is Stop-and-Go strategy based on the observation of reversibility of the neurotoxic symptoms after discontinuation of oxaliplatin. Stop-and-Go concept will prolong the time of oxaliplatin-based therapy as long as antitumor efficacy is still maintained. Methods: Patients with a histologically verified advanced colorectal carcinoma were eligible for the study. From April 2005 to March 2006 at Cancer Institute Hospital, 187 patients whom treated with bimonthly oxaliplatin-based regimen (FOLFOX4) were enrolled. An oxaliplatin specific neurotoxicity scale are distinct from the National Cancer Institute common toxicity criteria classification (CTC-AE vol. 3). This study was performed to carefully assess the onset and duration to recovery of oxaliplatin neurotoxicity and resumption rate of FOLFOX4. Results: Neurotoxicity was observed in 72 patients with Grade 1, 56 patients with Grade 2 and 33 patients with Grade 3. Oxaliplatin-induced cumulative neurotoxicity develops progressively. The median cumulative doses of oxaliplatin were 170 mg/m2 with Gr. 1; 845.8 mg/m2 with Gr. 2; and 850 mg/m2 with Gr. 3. The median time to onset were 16 days with Gr. 1; 174 days with Gr. 2; and 177 days with Gr. 3. The median time to recovery after stopping the therapy and the median time to progression during the discontinuation of oxaliplatin were 56 and 59 days, respectively, in patients allocated to Gr. 2 compared with 106 and 73 days, respectively, in patients allocated to Gr. 3. The recovery time during the discontinuation showed a statistically significant reduction of the values in the Gr. 2 but not in Gr. 3 (p = 0.0024). The resumption rates of oxaliplatin were 73.7% with Gr. 2 and 46.4% with Gr. 3. Conclusions: Our results may focus to manage time course of Stop-and-Go strategy in clinical practice. No significant financial relationships to disclose.

Patient-reported neurotoxicity with FULV versus FLOX in patients with stage II or III carcinoma of the colon: Results of NSABP Protocol C-07

3564 Background: NSABP Phase III Protocol C-07 compared the efficacy of FULV versus FLOX in patients with stage II or III colon cancer. The definitive analysis revealed an increase in 3-year disease-free survival from 71.6% to 76.5% (HR=0.79, p=0.004) in favor of FLOX. The present study compares patient-reported neurotoxicity between the treatment groups. Methods: Patients were randomized to either FULV (5-FU, 500 mg/m2 iv bolus weekly x 6; LV, 500 mg/m2 iv weekly x 6, each 8-week cycle x 3) or FLOX (FULV with oxaliplatin 85 mg/m2 iv administered on weeks 1, 3 and 5 of each 8-week cycle x 3). A subset of patients (planned sample size 400) at select institutions completed the validated FACT/GOG Oxaliplatin-Specific Neurotoxicity Scale (NTX-12) at baseline, week 4 of cycle 2, and at 6, 12 and 18 months. Mean NTX-12 scores were compared between treatments at 18 months using a t-test and longitudinally with mixed effects modeling. Item responses were compared between treatments with logistic regression. Results: From February 2000 to July 2001, 395 patients with follow-up (206 FULV, 189 FLOX) were enrolled in the neurotoxicity study. They were comparable by disease stage and site, age, and sex to the 759 concurrently accrued C-07 patients not in the sub-study (data not shown). NTX-12 form submission rates were high (with a low of 77% at 12 months). Mean neurotoxicity was higher in the oxaliplatin arm throughout the period of study (p&lt;0.0001) and remained higher at 18 months (p=0.009). During therapy, FLOX patients experienced significant increases in hand/foot neuropathy and overall weakness, and an improvement in hearing ( Table ). At 18 months, hand neurotoxicity resolved, but patients who received oxaliplatin experienced ringing in the ears and continued foot discomfort. Conclusions: This presentation provides the first public review of the severity and persistence of neurotoxicity associated with oxaliplatin in this study. [Table: see text] [Table: see text]

Survey of oxaliplatin-associated neurotoxicity using an interview-based questionnaire in patients with metastatic colorectal cancer

BackgroundNew chemotherapy regimens for patients with colorectal cancer have improved survival, but at the cost of clinical toxicity. Oxaliplatin, an agent used in first-line therapy for metastatic colorectal cancer, causes acute and chronic neurotoxicity. This study was performed to carefully assess the incidence, type and duration of oxaliplatin neurotoxicity.MethodsA detailed questionnaire was completed after each chemotherapy cycle for patients with metastatic colorectal cancer enrolled in a phase I trial of oxaliplatin and capecitabine. An oxaliplatin specific neurotoxicity scale was used to grade toxicity.ResultsEighty-six adult patients with colorectal cancer were evaluated. Acute neuropathy symptoms included voice changes, visual alterations, pharyngo-laryngeal dysesthesia (lack of awareness of breathing); peri-oral or oral numbness, pain and symptoms due to muscle contraction (spasm, cramps, tremors). When the worst neurotoxicity per patient was considered, grade 1/2/3/4 dysesthesias and paresthesias were seen in 71/12/5/0 and 66/20/7/1 percent of patients. By cycles 3, 6, 9, and 12, oxaliplatin dose reduction or discontinuation was needed in 2.7%, 20%, 37.5% and 62.5% of patients.ConclusionOxaliplatin-associated acute neuropathy causes a variety of distressing, but transient, symptoms due to peripheral sensory and motor nerve hyperexcitability. Chronic neuropathy may be debilitating and often necessitates dose reductions or discontinuation of oxaliplatin. Patients should be warned of the possible spectrum of symptoms and re-assured about the transient nature of acute neurotoxicity. Ongoing studies are addressing the treatment and prophylaxis of oxaliplatin neurotoxicity.