Oxaliplatin-induced Peripheral Sensory Neuropathy Research Articles

New diagnostic measures of oxaliplatin-induced peripheral sensory neuropathy

ObjectiveOxaliplatin-induced peripheral neuropathy (OIPN) is an unwanted side effect of oxaliplatin chemotherapy treatment. OIPN manifests in an acute phase that lasts a few days after injection and a persistent phase that may become chronic. Currently, there is no consensus about a clinically applicable, quantitative, and objective measure of OIPN. MethodsSeventeen patients treated with oxaliplatin containing adjuvant chemotherapy for stage III colon cancer, but otherwise healthy, were tested with six quantitative sensory tests (QST) and five large fibre perception threshold tracking (PTT) measures (quantified by, e.g., rheobase and electrotonus threshold) one hour before each of the 12 chemotherapy cycles given at two weeks’ intervals. These measures were repeated at 3, 6, and 12-month follow-ups. The temporal development of OIPN assessed by the Common Terminology Criteria for Adverse Events (CTCAE) scale, QST, and PTT measures was calculated by linear regression. ResultsThe CTCAE score showed a tri-phasic increase during the treatment and remained increased during the follow-up. The vibration threshold (R = 0.25, p<0.001), the cold pain threshold (R = 0.17, p = 0.02), and the rheobase (R = 0.28, p < 0.001) increased during treatment, whereas the cold detection threshold (R=-0.16, p = 0.002) decreased. The cold pain threshold and the rheobase remained increased, and the cold detection and heat pain threshold remained decreased during follow-up. ConclusionsIncreased cold pain sensitivity and decreased large fibre sensitivity (increased rheobase) correlate to the persistent OIPN, whereas the CTCAE score assesses both acute and persistent OIPN. Furthermore, the novel PTT method assessed the nerve excitability changes caused by the oxaliplatin.

Endocannabinoid System Attenuates Oxaliplatin-Induced Peripheral Sensory Neuropathy Through the Activation of CB1 Receptors.

Oxaliplatin-induced neurotoxicity is expressed as a dose-limiting peripheral sensory neuropathy (PSN). Cannabinoid substances have been investigated for the analgesic effect. This study aimed to investigate the role of cannabinoid receptors in oxaliplatin-associated PSN. Swiss male mice received nine oxaliplatin injections (2mg/kg, i.v.). Mechanical and thermal nociceptive tests were performed for 56days. CB1, CB2, and c-Fos expression were assessed in dorsal root ganglia (DRG), spinal cord (SC), trigeminal ganglia (TG), spinal trigeminal nucleus caudalis (Sp5C), and periaqueductal gray (PAG). Iba-1 expression was assessed in DRG and ATF3 in TG. Cannabidiol (10mg/kg, p.o.) or a CB1/CB2 non-selective agonist (WIN 55,212-2; 0.5mg/kg, s.c.) or AM251 (CB1 antagonist) or AM630 (CB2 antagonist) (3mg/kg, i.p.) were injected before oxaliplatin. Oxaliplatin increased CB1 in DRG, SC, TG, Sp5C, and ventrolateral PAG, with no interference in CB2 expression. Cannabidiol increased CB1 in DRG, reduced mechanical hyperalgesia and c-Fos expression in DRG and SC. Additionally, WIN 55,212-2 increased CB1 in DRG, reduced mechanical hyperalgesia, cold allodynia and c-Fos expression in DRG and SC. CB1 blockage hastened the cold allodynia response, but the CB2 antagonist failed to modulate the oxaliplatin-induced nociceptive behavior. Oxaliplatin also increased Iba-1 in DRG, suggesting immune response modulation which was reduced by cannabidiol and enhanced by AM630. The modulation of the endocannabinoid system, through the CB1 receptor, attenuates the oxaliplatin-associated PNS. The activation of the endocannabinoid system could be considered as a therapeutic target for controlling oxaliplatin-associated neuropathy.

Improving Chemotherapy-Induced Peripheral Neuropathy in Patients with Breast or Colon Cancer after End of (Neo)adjuvant Therapy: Results from the Observational Study STEFANO

Introduction: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect persisting after completion of neurotoxic chemotherapies. This observational study was designed to evaluate the effectiveness of the dietary supplement OnLife® (patented mixture of specific fatty acids and palmitoylethanolamide) in improving symptoms of CIPN in breast and colon cancer patients. Methods: Improvement of CIPN was evaluated in adult patients, previously treated with (neo)adjuvant paclitaxel- (breast cancer) or oxaliplatin-based (colon cancer) therapies, receiving OnLife® for 3 months after completion of chemotherapy. The primary endpoint was to compare the severity of peripheral sensory neuropathy (PSN) and peripheral motor neuropathy (PMN) before and at the end of OnLife® treatment. Secondary endpoints included the assessment of patient-reported quality of life and CIPN symptoms as assessed by questionnaires. Results: 146 patients (n = 75 breast cancer patients and n = 71 colon cancer patients) qualified for analysis; 31.1% and 37.5% of breast cancer patients had an improvement of PSN and PMN, respectively. In colon cancer patients, PSN and PMN improved in 16.9% and 20.0% of patients, respectively. According to patient-reported outcomes, 45.9% and 37.5% of patients with paclitaxel-induced PSN and PMN, and 23.9% and 22.0% of patients with oxaliplatin-induced PSN and PMN experienced a reduction of CIPN symptoms, respectively. Conclusion: OnLife® treatment confirmed to be beneficial in reducing CIPN severity and in limiting the progression of neuropathy, more markedly in paclitaxel-treated patients and also in patients with oxaliplatin-induced CIPN.

Management of Oxaliplatin-Induced Peripheral Sensory Neuropathy.

Oxaliplatin-induced peripheral neurotoxicity (OIPN) is a severe and potentially permanent side effect of cancer treatment affecting the majority of oxaliplatin-treated patients, mostly with the onset of acute symptoms, but also with the establishment of a chronic sensory loss that is supposed to be due to dorsal root ganglia neuron damage. The pathogenesis of acute as well as chronic OIPN is still not completely known, and this is a limitation in the identification of effective strategies to prevent or limit their occurrence. Despite intense investigation at the preclinical and clinical levels, no treatment can be suggested for the prevention of OIPN, and only limited evidence for the efficacy of duloxetine in the treatment setting has been provided. In this review, ongoing neuroprotection clinical trials in oxaliplatin-treated patients will be analyzed with particular attention paid to the hypothesis leading to the study, to the trial strengths and weaknesses, and to the outcome measures proposed to test the efficacy of the therapeutic approach. It can be concluded that (1) prevention and treatment of OIPN still remains an important and unmet clinical need, (2) further, high-quality research is mandatory in order to achieve reliable and effective results, and (3) dose and schedule modification of OHP-based chemotherapy is currently the most effective approach to limit the severity of OIPN.

Amifostine protects from the peripheral sensory neuropathy induced by oxaliplatin in mice

Sensory neuropathy is a dose-limiting side effect of oxaliplatin-based cancer treatment. This study investigated the antinociceptive effect of amifostine and its potential neuroprotective mechanisms on the oxaliplatin-related peripheral sensory neuropathy in mice. Oxaliplatin (1 mg/kg) was injected intravenously in Swiss albino male mice twice a week (total of nine injections), while amifostine (1, 5, 25, 50, and 100 mg/kg) was administered subcutaneously 30 min before oxaliplatin. Mechanical and thermal nociceptive tests were performed once a week for 49 days. Additionally, c-Fos, nitrotyrosine, and activating transcription factor 3 (ATF3) immunoexpressions were assessed in the dorsal root ganglia. In all doses, amifostine prevented the development of mechanical hyperalgesia and thermal allodynia induced by oxaliplatin (P<0.05). Amifostine at the dose of 25 mg/kg provided the best protection (P<0.05). Moreover, amifostine protected against neuronal hyperactivation, nitrosative stress, and neuronal damage in the dorsal root ganglia, detected by the reduced expression of c-Fos, nitrotyrosine, and ATF3 (P<0.05 vs the oxaliplatin-treated group). In conclusion, amifostine reduced the nociception induced by oxaliplatin in mice, suggesting the possible use of amifostine for the management of oxaliplatin-induced peripheral sensory neuropathy.

Skin platinum deposition in colorectal cancer patients following oxaliplatin-based therapy.

Oxaliplatin is widely used in the treatment of gastrointestinal malignancies. One of the most common and dose-limiting side effects of oxaliplatin is the chronic peripheral sensory neuropathy. The mechanism of this neurotoxicity is poorly understood and there are no effective preventive or treatment strategies, other than oxaliplatin dose interruption or reduction. Colorectal cancer patients who completed FOLFOX at least 6months prior to enrollment were eligible. EORTC QLQ-CIPN20 questionnaire was used for assessing self-reported neuropathic symptom. Blood samples and skin biopsies were obtained and analyzed for platinum. Twelve patients were enrolled. The mean cumulative dose of oxaliplatin was 818 ± 54mg/m2, and the median time from last dose of oxaliplatin was 38.7months (range: 7.2-65.6months). The QLQ-CIPN20 sensory score was 18 or less in 10 patients and 19 and 25, respectively, in 2 patients. Platinum was detectable in plasma from 4/12 patients up to 63.3months after the completion of FOLFOX. In all six patients with skin biopsies, platinum was present in the skin with imaging mass cytometry. QLQ-CIPN20 scores and plasma platinum concentrations were not related to cumulative doses of oxaliplatin or interval from the last dose of oxaliplatin. Platinum was readily detectable in skin biopsies more than 60months post-completion of FOLFOX. This is the first demonstration of platinum deposition in skin post-oxaliplatin treatment and it provides a possible mechanism for oxaliplatin-induced peripheral sensory neuropathy and its persistence.

Metformin reduces c-Fos and ATF3 expression in the dorsal root ganglia and protects against oxaliplatin-induced peripheral sensory neuropathy in mice

Oxaliplatin is a third-generation platinum drug commonly used as the first line treatment of metastatic colorectal cancer. Oxaliplatin-based anticancer regimens course with dose-limiting neurotoxicity. The pharmacological strategies used to manage such side effect are not totally effective. Metformin is an anti-diabetic drug that is described to negatively modulate painful diabetic neuropathy. Then, this study aimed to assess the effect of metformin in the oxaliplatin-induced peripheral sensory neuropathy in mice. For that purpose, Swiss male mice were injected with oxaliplatin (1, 2 or 4 mg/kg, i.v., twice a week with a total of nine injections) alone or in combination with daily administration of metformin (250 mg/kg, p.o.). Thermal and mechanical nociceptive tests were performed once a week for five weeks. Then, the animals were euthanized on day 35 post-first injection of oxaliplatin and the dorsal root ganglia were harvested for the assessment of c-Fos and ATF3 expressions. Oxaliplatin caused a nociceptive response accompanied by the increased expression of c-Fos and ATF3 in the dorsal root ganglia and spinal cord. In addition, the oxaliplatin-associated nociception was significantly attenuated by metformin (P < 0.05), which also reduced the expression of c-Fos and ATF3 (P < 0.05). Therefore, metformin protected from the peripheral sensory neuropathy induced by oxaliplatin, which was confirmed by the reduction of c-Fos and ATF3 expression, two known neuronal activation and damage markers, respectively.

Involvement of Endothelin Receptors in Peripheral Sensory Neuropathy Induced by Oxaliplatin in Mice.

The aim of this study was to evaluate the participation of the endothelin ETA and ETB receptors and the effects of bosentan in oxaliplatin-induced peripheral sensory neuropathy (OIN) in mice. Adult male Swiss mice received 1mg/kg of oxaliplatin intravenously, twice a week for 5weeks. Dorsal root ganglia (DRG) and spinal cords were removed for evaluation of the endothelin ETA and ETB receptor expression. Afterwards, selective (BQ-123 and BQ-788; 10nmol in 30μL, intraplantarly) and non-selective (bosentan, 100mg/kg, orally) antagonists were administered in order to evaluate the involvement of the endothelin receptors in OIN. Mechanical and thermal nociception tests were performed once a week for 56days. Oxaliplatin induced mechanical and thermal hypersensitivity and increased the endothelin ETA receptor expression in both the DRG and spinal cord (P < 0.05). Endothelin ETB receptor expression was increased in the DRG (P < 0.05) but not in the spinal cord. Both endothelin ETA and ETB receptor selective antagonists partially prevented mechanical hyperalgesia in mice with OIN (P < 0.05). Moreover, bosentan prevented mechanical and thermal hypersensitivity in oxaliplatin-treated mice (P < 0.05). In conclusion, both endothelin ETA and ETB receptors seem to be involved in the OIN in mice and they should be considered possible targets for the management of this clinical feature.

The risk factors for oxaliplatin-induced peripheral sensory neuropathy and thrombocytopenia in advanced gastric cancer.

Peripheral sensory neuropathy (PSN) and thrombocytopenia are the main dose-limiting toxicities of oxaliplatin for the treatment of advanced gastric cancer (AGC). Because the risk factors for those toxicities in practice have not been clarified, we conducted this prospective study. AGC patients who received oxaliplatin-based therapy at any of seven institutions participating in the Kyushu Medical Oncology Group were assessed after we obtained written informed consent. A total of 60 patients including 39 males and 21 females were examined. The median age was 66years. The numbers of patients receiving oxaliplatin as the first, second, or third and later lines of therapy were 39, 16, and 5, respectively. An initial dose of 130, 100, or < 100mg/m2 oxaliplatin was administered to 12, 39, and 9 patients, respectively. S-1 or capecitabine as a concomitant drug was administered in 54 and 6 patients, respectively. In multivariate analysis, the comorbidity of diabetes mellitus was associated with ≥ grade 2 thrombocytopenia (p = 0.035). No significant risk factor was associated with ≥ grade 2 PSN. However, the accumulated dose of oxaliplatin exhibited a strong correlation with ≥ grade 2 PSN (p = 0.0043), and the predicted accumulated dose of oxaliplatin in which 10% of patients developed ≥ grade 2 PSN was 800mg/m2. The frequency of PSN in subsequent paclitaxel therapy in patients with ≥ grade 2 or worse PSN in oxaliplatin-based chemotherapy did not increase compared to those with none or grade 1 PSN in oxaliplatin. Thrombocytopenia in AGC patients with diabetes mellitus should be carefully monitored during oxaliplatin-based therapy.

Platinum deposition in skin as a possible mechanism for peripheral sensory neuropathy (PSN) in patients (pts) with colorectal cancer (CRC) following oxaliplatin-based therapy.

685 Background: Oxaliplatin plus fluorouracil (FOLFOX) is a standard treatment for CRC pts. One of the most common and dose-limiting side effects of oxaliplatin is PSN. The mechanism of this phenomenon is poorly understood. Previous studies suggested that higher serum platinum levels were related to more severe neuropathy in testicular cancer pts. Methods: CRC pts who completed adjuvant FOLFOX at least 6 months prior to enrollment are eligible. Baseline demographic and treatment information were collected. EORTC CIPN20 (with EORTC QLQ-C30) questionnaire was used for self-reported PSN symptom assessment. Peripheral blood samples were collected for total/free platinum concentrations using high-performance liquid chromatography with tandem mass spectrometry (HPLC/MS-MS). Skin biopsies were obtained from the lower leg of consented pts. Imaging mass cytometry (IMC) was used to visualize platinum deposition (195Pt) and intra-epidermal nerve fiber (IENF) (PGP9.5-154Sm) in formalin-fixed paraffin embedded (FFPE) skin biopsy samples stained with a metal-conjugated antibody cocktail. Results: Nine patients were enrolled. Median age was 51.8 yr (range: 34.5-69.4 yr); male/ female: 5/4; mean cumulative dose of oxaliplatin was 800.7 ± 188.2 mg/m2; median time from last dose of oxaliplatin to enrollment was 48 months (range: 7.2-65.6 months). The mean sensory score from CIPN20 was 15.4 ± 4.3 (range: 10-25). Platinum was undetectable in plasma samples collected from all 9 patients. In skin samples, IMC showed significant platinum depositions and IENF. Conclusions: Severity of PSN was not related to cumulative dose of oxaliplatin or interval from last dose of oxaliplatin. Although platinum was undetectable in plasma in these patients, platinum was readily detectable in skin biopsies up to 65.6 months post completion of FOLFOX. This is the first demonstration of platinum deposition in skin post oxaliplatin treatment and it provides a possible mechanism for oxaliplatin-induced PSN.

Neurotoxic effect of oxaliplatin: Comparison with its oxalate-free analogue cis-[PtII(1R,2R-DACH)(3-acetoxy-1,1-cyclobutanedicarboxylato)] (LLC-1402) in mice

Studies suggest that oxalate is involved in the development oxaliplatin-induced peripheral sensory neuropathy (OPSN). This study aimed to compare the neurotoxic effects of oxaliplatin with its oxalate-free cytotoxic analogue cis-[PtII(1R,2R-DACH)(3-acetoxy-1,1-cyclobutanedicarboxylato)] (LLC-1402) in mice. Oxaliplatin and LLC-1402 were intravenously injected in male Swiss mice with a total of nine injections. Oxalate was intraperitoneally injected in other animals. The development of OPSN was evaluated using mechanical and thermal sensitivity tests. Dorsal root ganglia of the mice were removed to evaluate c-Fos, ATF3 and iNOS expression and a sample of blood was collected for leukocyte count and hepatic and renal biochemical function tests. Oxaliplatin and LLC-1402 decreased the mechanical and thermal nociceptive threshold, whilst oxalate lead to a partial and later increase in the mechanical sensitivity (P<0.05). c-Fos, ATF3 and iNOS expressions were increased in neuronal cells during and after the end of the injections in animals treated with oxaliplatin and LLC-1402 (P<0.05), even though oxaliplatin lead to an earlier increase. Only c-Fos expression was elevated during the period of injections in the oxalate group (P<0.05), but this expression reduced after the end of the treatment. c-Fos expression was also shown in glial satellite cells only in the oxaliplatin-treated animals. Oxaliplatin and LLC-1402 reduced leukocyte count (P<0.05), but did not change renal and liver functions. In conclusion, oxalate may contribute to an earlier development of peripheral sensory neuropathy. However, the antitumor cytotoxic mechanism of oxaliplatin seems to be the main responsible by its neurotoxic effect.

P-304 - Incidence of oxaliplatin-induced peripheral sensory neuropathy in patients with colorectal cancer treated by FOLFOX regimen at a regional community hospital in Québec

P-304 - Incidence of oxaliplatin-induced peripheral sensory neuropathy in patients with colorectal cancer treated by FOLFOX regimen at a regional community hospital in Québec

P-066 New methods of detecting oxaliplatin-induced peripheral sensory neuropathy in patients undergoing adjuvant treatment with 5-fluorouracil and oxaliplatin for colon cancer

P-066 New methods of detecting oxaliplatin-induced peripheral sensory neuropathy in patients undergoing adjuvant treatment with 5-fluorouracil and oxaliplatin for colon cancer

Incidence and evolution of oxaliplatin-induced peripheral sensory neuropathy in diabetic patients with colorectal cancer: a pooled analysis of three phase III studies

BackgroundThe purpose of this study was to determine whether the presence of diabetes mellitus (DM) influences the incidence, severity, and/or course of peripheral sensory neuropathy (PSN) after oxaliplatin (FOLFOX) therapy in patients with colorectal cancer (CRC). MethodsA retrospective pooled analysis incorporating three phase III studies was conducted: Multicenter International Study of Oxaliplatin, 5-Fluorouracil, and Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) (adjuvant treatment; stage II/III colon cancer), EFC4584 (second-line treatment; metastatic CRC), and EFC2962 (first-line treatment; metastatic CRC). Patients were ineligible for the studies if they had known PSN (EFC4584) or PSN grade ≥1 (MOSAIC and EFC2962) at baseline. The incidence of PSN was evaluated retrospectively in patient subgroups with or without DM at baseline that received FOLFOX. Kaplan–Meier curves were used to assess the probability of PSN with increasing cumulative oxaliplatin dose. ResultsOf 1587 patients enrolled across the three studies, 135 (8.5%) had DM at baseline. The incidence of PSN (non-DM/DM) was 45.0%/46.7% (grade 1), 28.6%/26.7% (grade 2), and 13.0%/12.6% (grade 3). The probability of PSN by cumulative dose of oxaliplatin was similar in DM and non-DM patients. ConclusionsThis retrospective analysis indicates that oxaliplatin-based therapy does not influence the incidence, severity, or time to onset of PSN in asymptomatic DM patients with CRC who meet eligibility criteria for clinical trials.

Randomized double blind (DB) placebo (Plcb) controlled phase III study assessing the efficacy of xaliproden (X) in reducing the cumulative peripheral sensory neuropathy (PSN) induced by the oxaliplatin (Ox) and 5-FU/LV combination (FOLFOX4) in first-line treatment of patients (pts) with metastatic colorectal cancer (MCRC)

3507 Background: X, an orally administered non-peptide neurotrophic agent developed by sanofi-aventis, was shown in vitro to minimize neuritic damage induced by Ox (co-culture of Schwann cells and dorsal roots ganglia explant). The probability of occurrence of Grade (Gr) 3–4 PSN at a cumulative dose of Ox of 1000 mg/m2, was consistently reported to be of 18–20%. Methods: First line MCRC pts were randomized to receive, in a DB fashion, FOLFOX4 and either Plcb or X 1mg daily. X was administered from the 1st day of chemotherapy till 15 days post last Ox cycle. Co-primary objectives were reduction in the risk of occurrence of Gr 3–4 PSN relative to cumulative dose of Ox (Kaplan-Meier method) and non-inferiority in response rate (RR). Secondary endpoints included evaluation of sensory action potential (SAP) and safety. Results: From July 2002 to May 2004, 649 pts were randomized (324 Plcb, 325 X). Pts characteristics were well balanced across arms, median number of Ox cycles was 12 in both arms, median relative dose intensity (%) was 83.8 (Plcb) and 85.2 (X). A significant risk reduction of 39% in the probability of Grade 3–4 PSN in favor of X was reported (hazard ratio [95% CI] = 0.61 [0.40; 0.93], p= 0.0203). Overall RR [95 % CI] was: Plcb 42.6% [37.1; 48.2] and X 44.9% [39.4; 50.6]. As prospectively defined in the protocol, the lower bound of the CI of the RR ratio above 0.8 confirms noninferiority in RR (1.055 [0.88; 1.26]). In both arms the mean % of change in SAP worsens as a function of PSN severity. 17.3 (Plcb) and 13.5% (X) of the pts discontinued Ox because of PSN. Severe toxicities (% Gr 3–4), reported with a ≥2% difference between arms, were (plcb vs X): diarrhea 10.9 vs 13.0, pulmonary embolism 0.9 vs 3.1, fatigue 3.7 vs 1.5, neutropenia 43.0 vs 37.8. Conclusion: X was shown to be efficient in reducing the risk of Grade 3–4 oxaliplatin-induced PSN without impacting FOLFOX4 antitumor activity. No significant financial relationships to disclose.

Prevention of Oxaliplatin-Induced Peripheral Sensory Neuropathy by Carbamazepine in Patients with Advanced Colorectal Cancer

Oxaliplatin plays a key role in the treatment of advanced colorectal cancer. The dose-limiting side effect of this platinum analogue is neurotoxicity. Significant efforts have been undertaken in an attempt to prevent and/or circumvent the development of neurotoxicity. Sodium channel inactivation kinetics on rat sensory sural nerve preparations are altered after exposure to oxaliplatin. Carbamazepine antagonizes this effect in vitro. Results from preliminary clinical studies indicate that the sodium channel blockers carbamazepine and gabapentin may be effective in preventing neurotoxicity. The role of amifostine is not yet clear. Randomized clinical studies are necessary to confirm the potential benefit of carbamazepine and other sodium channel blockers in preventing and/or overcoming the development of oxaliplatin-induced neurotoxicity.

An overview of chemotherapy-induced peripheral sensory neuropathy, focusing on oxaliplatin.

When treating patients for metastatic cancer, there is always a balance between the benefits of treatment and resulting side-effects. Peripheral sensory neuropathy (PSN) is a side-effect of many anticancer agents used in routine practice. Oxaliplatin is a relatively new agent currently licensed in over 50 countries including France, Germany and the UK for the treatment of metastatic colorectal cancer. Although it is a new agent, it is from the same family of drugs as cisplatin, an agent that has been used for many years. PSN is the most commonly discussed side-effect associated with oxaliplatin. Oxaliplatin-induced PSN is characterized by two distinct syndromes: a transient acute dysaesthesia and a cumulative distal neurotoxicity. Importantly, both are generally reversible after stopping treatment. Oxaliplatin-induced acute PSN is triggered and exacerbated by cold and can be greatly reduced in affected patients simply by avoiding cold conditions. Oxaliplatin-induced cumulative PSN may also be managed by temporary cessation of treatment.