Cumulative Dose Of Oxaliplatin 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.

Risk Factors for Thrombocytopenia Induced by Capecitabine Plus Oxaliplatin Therapy in Patients With Colorectal Cancer.

Capecitabine plus oxaliplatin (CapeOX) therapy is used as an adjuvant chemotherapy regimen for patients with colorectal cancer (CRC). Although oxaliplatin induces thrombocytopenia, the risk factors for thrombocytopenia in oxaliplatin-treated patients with CRC are not well established. We aimed to investigate the risk factors for thrombocytopenia in CapeOX-treated patients with CRC. In addition, we evaluated platelet counts and non-invasive liver fibrosis indices, specifically the aspartate aminotransferase-to-platelet ratio index (APRI) and the fibrosis-4 index (FIB-4), during CapeOX therapy in these patients. Between July 2017 and June 2020, we enrolled CapeOX-treated patients with high-risk stage II or stage III CRC at seven hospitals collaborating with the Division of Oncology, Aichi Prefectural Society of Hospital Pharmacists (Aichi prefecture, Japan). In this retrospective study, we investigated patients' backgrounds, laboratory data, concomitant medications, number of cycles of CapeOX and oxaliplatin, cumulative dose of oxaliplatin, and administration period. The cut-off values were calculated using receiver operating characteristic analysis of platelet counts and APRI and FIB-4 scores. Fifty-five patients without thrombocytopenia and 44 patients with thrombocytopenia were enrolled. During CapeOX therapy, the thrombocytopenia group showed a significant decrease in platelet count and a significant increase in APRI and FIB-4 scores compared to the non-thrombocytopenia group. Baseline albumin level ≤3.5 g/dl and platelet count ≤238×103/μl were independently associated with ≥grade 2 thrombocytopenia in CapeOX-treated patients. Baseline albumin level and platelet count may be useful for predicting thrombocytopenia in CapeOX-treated patients with high-risk stage II or stage III CRC.

Predictive factors of collateral vessel development induced by oxaliplatin-based chemotherapy.

Oxaliplatin can lead to hepatic sinusoidal injury, called hepatic sinusoidal obstruction syndrome (SOS), resulting in portal hypertension-related complications. This could worsen the clinical course of the patients treated with oxaliplatin. Early diagnosis is challenging. We explored predictive markers of oxaliplatin-induced collateral vessels. Patients who received oxaliplatin-based chemotherapy were retrospectively screened. We evaluated their laboratory findings and spleen size on computed tomography immediately before oxaliplatin-based chemotherapy and after 6months of treatment. The primary outcome was collateral vessel development, as a surrogate marker for oxaliplatin-induced SOS in patients who underwent oxaliplatin-based chemotherapy. The secondary outcome was the identification of factors that predicted the development of collateral vessels. We enrolled 161 patients who received oxaliplatin-based chemotherapy. They had a median age of 69years, and 63.3% were men. Collateral vessels developed in nine (5.6%) patients during the study period. After oxaliplatin-based chemotherapy, the spleen size increased in 104 patients (64.6%), with a ≥ 30% increase in 19.4% of the patients. Univariate analysis showed that the Fibrosis-4 (FIB-4) index (≥ 1.76; OR 9.17), aspartate aminotransferase:platelet ratio index (APRI) (≥ 0.193; OR 9.62), cumulative dose of oxaliplatin (≥ 1000mg; OR 8.43), and increase in spleen size (≥ 30%; OR 6.01) were significant risk factors for collateral vessel development. Multivariate analysis after stepwise selection revealed that the FIB-4 index and spleen size were significant independent predictive factors. A ≥ 1.76 increase in the FIB-4 index and a ≥ 30% increase in spleen size after 6months of oxaliplatin-based chemotherapy were significant predictive markers for collateral vessel development.

Risk factors for oxaliplatin-induced peripheral neuropathy: a systematic review and meta-analysis.

Oxaliplatin-induced neuropathy is a significant complication of cancer therapy. We aimed at investigating the risk factors of oxaliplatin-induced neuropathy (OIPN) and providing evidence to enhance its prevention. PubMed, Medline, Web of Science, Embase, China Knowledge Resource Integrated Database, and the Wanfang Database were searched comprehensively for observational studies investigating the prevalence and risk factors of OIPN from inception to November 30, 2021. The Newcastle-Ottawa Scale was used by two independent reviewers to assess methodological quality. When applicable, we used meta-analysis to determine mean differences and odds ratios for continuous and nominal scaled data. We included 20 studies involving 10,900 participants for analysis. Factors associated with OIPN risk identified by meta-analysis were age, gender, diabetes, anemia, hypomagnesaemia, alcohol consumption, body mass index, body surface area, cumulative oxaliplatin dose and the number of chemotherapy cycles. Factors not associated with OIPN risk included smoking history and chemotherapy regimen. This meta-analysis identified multiple variables associated with OIPN. The recognition of modifiable risk factors is an urgent priority to improve prevention and treatment outcomes.

Oxaliplatin in metastatic colorectal cancer: Does hepatic arterial infusion reduce sensitive neuropathy compared to the intravenous route?

95 Background: Oxaliplatin, a major drug in metastatic colorectal cancer (MCRC), is responsible for a cumulative and limiting peripheral neuropathy (PN). Hepatic arterial infusion (HAI) chemotherapy, which makes sense in cases of exclusive or predominant liver metastases, increases the intratumor concentration of the administered drug(s) to improve efficacy and limit systemic toxicity. Methods: We compared the frequency and severity of NP in oxaliplatin-naive patients with MCRC included in trials that evaluated treatment with oxaliplatin administered either by HAI (CHOICE, OSCAR, and PACHA-01 trials) or by intravenous (IV) route (FFCD 2000-05 trial). The primary endpoint was the occurrence of clinically significant NP (grade 2-4) according to the cumulative dose of oxaliplatin received. The secondary endpoints were the occurence of severe NP (grade 3-4) and time to onset of NP. Results: 342 patients were included (IV oxaliplatin: 300; HAI: 42). 180 patients in the IV group (60%) and 24 patients in the HAI group (57%) developed clinically significant NP, with no significant difference between the 2 groups (p = 0.85). 95 patients in the IV group (32%) and 8 patients in the HAI group (19%) developed severe NP, with no significant difference between the 2 groups (p = 0.082). NP appeared earlier in the HAI group, with more treatment discontinuations for neurotoxicity. Conclusions: The administration of oxaliplatin HAI rather than IV in the treatment of MCRC does not seem to reduce the incidence, precocity and severity of NP.

Dorsal Root Ganglion Morphometric Changes Under Oxaliplatin Treatment

PurposeMagnetic resonance neurography (MRN) can detect dorsal root ganglia (DRG) hypertrophy in patients with oxaliplatin-induced peripheral neuropathy (OXIPN) but is difficult to apply in clinical daily practice. Aims of this study were (i) to assess whether DRG volume is reliably measurable by routine computed tomography (CT) scans, (ii) to measure longitudinal changes in DRG during and after oxaliplatin administration and (iii) to assess correlation between DRG morphometry and individual oxaliplatin dose.MethodsFor comparison of MRN and CT measurements, CT scans of 18 patients from a previous MRN study were analyzed. For longitudinal assessment of DRG size under treatment, 96 patients treated with oxaliplatin between January and December 2014 were enrolled retrospectively. DRG volumetry was performed by analyzing routine CT scans, starting with the last scan before oxaliplatin exposure (t0) and up to four consecutive timepoints after initiation of oxaliplatin therapy (t1–t4) with the following median and ranges in months: 3.1 (0.4–4.9), 6.2 (5.3–7.8), 10.4 (8.2–11.9), and 18.4 (12.8–49.8).ResultsDRG volume measured in CT showed a moderately strong correlation with MRN (r = 0.51, p < 0.001) and a strong correlation between two consecutive CTs (r = 0.77, p < 0.001). DRG volume increased after oxaliplatin administration with a maximum at timepoint t2. Higher cumulative oxaliplatin exposure was associated with significantly higher absolute DRG volumes (p = 0.005). Treatment discontinuation was associated with a nonsignificant trend towards lower relative DRG volume changes (p = 0.08).ConclusionCT is a reliable method for continuous DRG morphometry; however, since no standardized assessment of OXIPN was performed in this retrospective study, correlations between DRG size, cumulative oxaliplatin dose and clinical symptoms in future prospective studies are needed to establish DRG size as a potential OXIPN biomarker.

Impact of Dose, Sex, and Strain on Oxaliplatin-Induced Peripheral Neuropathy in Mice.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common, dose limiting, and long-lasting side effect of chemotherapy treatment. Unfortunately, no treatment has proven efficacious for this side effect. Rodent models play a crucial role in the discovery of new mechanisms underlying the initiation, progression, and recovery of CIPN and the potential discovery of new therapeutics. However, there is limited consistency in the dose, the sex, age, and genetic background of the animal used in these studies and the outcome measures used in evaluation of CIPN rely primarily on noxious and reflexive measures. The main objective of this study was to provide a comprehensive and systematic characterization of oxaliplatin-induced peripheral neuropathy in mice by using a battery of behavioral, sensory, electrophysiological, and morphometric measures in both sexes of the two widely used strains of mice, C57BL/6J and BALB/cJ. Mice received intraperitoneal injections of 3 or 30 mg/kg cumulative doses of oxaliplatin over the course of 2 weeks. Both doses induced long-term and time-dependent mechanical and cold hypersensitivity. Our results show that 30 mg/kg oxaliplatin reduced the locomotor activity in C57BL/6J mice, and C57BL/6J females showed anxiety-like behavior one-week post completion of treatment. In the same dose group, BALB/cJ males and females sustained a larger decrease in sucrose preference than either male or female C57BL/6J mice. Both strains failed to show significant changes in burrowing and nesting behaviors. Two clinically relevant assessments of changes to the peripheral nerve fibers, nerve conduction and intraepidermal nerve fiber density (IENFD) were evaluated. Only BALB/cJ females showed significant reduction in the nerve conduction amplitude 1 week after 30 mg/kg oxaliplatin regimen. Moreover, this dose of the chemo agent reduced the IENF density in both sexes and strains. Our findings suggest that mouse strain, sex, and assay type should be carefully considered when assessing the effects of oxaliplatin and potential therapeutic interventions.

P-10 Prevalence and risk factors of chronic neuropathy in 225 colorectal cancer patients treated with oxaliplatin-based regimens in Tunisia

Oxaliplatin is largely used in colorectal cancers (CRC). A major side effect is acute and chronic peripheral neuropathy. The aim of our study was to evaluate the prevalence and risk factors of oxaliplatin-induced chronic neuropathy and to study the consequences on treatment observation. We conducted a retrospective study including patients with CRC treated in the oncology department of the military hospital of Tunis between January 2013 and December 2020. Patients were treated with oxaliplatin-based regimens: FOLFOX, FOLOFORINOX, and XELOX. Evaluation of neuropathy was done according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE V4). 225 patients were included. Median age was 58 years. Sex ratio was 1.32. 54% were aged above 60 years. 33% had diabetes. 64% presented neuropathy: 57% grade 1, 29% grade 2 and 14% grade 3. The average cumulative dose leading to the occurrence of neurotoxicity (all grades) was 510.32 mg/m2. We noted a correlation between diabetes, cumulative dose of oxaliplatin, and the incidence of chronic neuropathy. No correlation was found between sex, age, high BMI, chronic renal dysfunction, and neuropathy incidence. Neuropathy required a dose adjustment (a 25% decrease in the initial dose of oxaliplatin) in 32% of cases. Patients had to delay their treatment in 14.5% of cases. The discontinuation of oxaliplatin was decided in 16% of cases. The most prescribed treatment for neuropathy was pregabalin (74%), followed by carbamazepine (11.8%). Medication was not sufficient to stop neuropathy in 77.7% of cases. The incidence of chronic oxaliplatin-induced neuropathy was high and contributed to treatment delay and modification in many cases. Diabetes and cumulative dose of oxaliplatin were associated with chronic neuropathy.

Using randomized trial data to estimate effects of complex treatment regimens in real-world patients.

e18706 Background: Real-world patients often differ from trial participants in prognostic factors such as age, sex, and cancer substage. New methods combine covariate data from real-world patients (the “target population”) with outcome and covariate data from a trial to estimate treatment effects in the target population that take these differences into account. With some assumptions, these methods can also estimate outcomes under treatment regimens not studied in the trial such as “what if we only gave six cycles of chemotherapy?” or “what if patients all perfectly followed a protocol?” Methods: Data from the MOSAIC trial of 5-fluorouracil (5FU) vs oxaliplatin + 5FU (FOLFOX) were combined with covariate data from a target population of stage III colon cancer patients in the US Oncology Network meeting trial eligibility criteria. We used weighting and G-computation to estimate five-year mortality and treatment-related paresthesia risk in the target population for four regimens: treatment with up to 12 cycles of 5FU, if providers used their discretion on dose reductions and delays (5FU-MD); up to 12 cycles of FOLFOX with similar physician discretion (FOLFOX-MD); up to 6 cycles of FOLFOX, with providers perfectly following a strict and specific protocol of dose reductions and delays (6-cycle FOLFOX-P, “P” for “per protocol”); and up to 12 cycles of FOLFOX, following the same strict protocol (12-cycle FOLFOX-P). Results: Tablepresents five-year all-cause mortality and paresthesia risk under each regimen in the stage III target population estimated from the models built in trial participants. Paresthesia risk increased with cumulative oxaliplatin dose. Estimated 5-year mortality was lowest with 12-cycle FOLFOX-P. Conclusions: In a target population of US Oncology Network patients with stage III colon cancer, strict protocols of 12 cycles of FOLFOX were predicted to improve survival compared to strict 6-cycle FOLFOX regimens or less strict 12-cycle FOLFOX and 5FU regimens at the cost of substantial increases in side effects. While estimates of risk differences in 5-year mortality were imprecise, combining trial and real-world data and then using weights and G-computation allowed estimation of benefits and harms of multiple regimens in a clinically relevant patient population.[Table: see text]

Comparing FOLFOX delivery in trial and real-world populations using longitudinal cumulative dose.

1521 Background: Patterns of chemotherapy delivery are likely to differ between trial and real-world populations. Typical measures used to compare these patterns are calculated at treatment completion, potentially missing key differences in the timing and trajectory of delays and dose reductions. We used a new measure, longitudinal cumulative dose (LCD), to compare treatment delivery over time in trial and real-world populations. Methods: We compared chemotherapy delivery in patients with stage II-III colon cancer enrolled in the MOSAIC trial of 5-fluorouracil (5FU) vs oxaliplatin + 5FU (FOLFOX4) to patients treated from 2008-2019 in the US Oncology Network with FOLFOX4, FOLFOX6, or mFOLFOX6. For each patient, we computed oxaliplatin LCD as the cumulative oxaliplatin dose received at a given timepoint (t) divided by the final standard oxaliplatin dose. We then estimated the median and 25th and 75th percentiles for oxaliplatin LCD within each regimen at day 68 (before the standard timing of the 7th dose), 168 (two weeks after the standard end of treatment), and 250. Results: The table shows the number of patients receiving each treatment regimen and the median and interquartile range for oxaliplatin LCD at each time. Higher LCDs in the trial show delivery closer to standard treatment, meaning fewer delays, dose reductions, and discontinuations. Differences between the medians, 25th percentiles, and 75th percentiles of LCD in each regimen were small at day 68 but grew considerably by days 168 and 250. Conclusions: Divergence from the standard dosing schedule was larger in real-world versus trial settings and varied by oxaliplatin regimen. LCD, as a longitudinal measure, showed that differences in delivery between trial and real-world populations grew substantially over time (even after 168 days and the standard end of treatment) possibly as real-world patients experienced more side effects and barriers to treatment than trial participants. These discrepancies in LCD may cause poorer outcomes in real-world settings than expected based on randomized trials.[Table: see text]

Optimize the dose of oxaliplatin for locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy followed by radical surgery and adjuvant chemotherapy

BackgroundAddition of oxaliplatin to capecitabine remains controversial for locally advanced rectal cancer (LARC). And cumulative oxaliplatin dose (COD) varied among clinical trials showing different therapeutic effects of this regimen. The objective of this study was to explore how COD affected tumor metastasis and patient survival.MethodsTotally 388 patients diagnosed with stage cII-III rectal cancer and treated with neoadjuvant chemoradiotherapy followed by radical surgery plus adjuvant chemotherapy were consecutively enrolled into this study and retrospectively reviewed. After grouping by total chemotherapy cycle (TCC), influences of COD on adverse effects and patients’ survivals were analyzed in each group. Univariate and multivariate survival analyses were performed through Kaplan-Meier approach and COX proportional hazards model, respectively. Age, gender, anemia, differentiation, carcinoembryonic antigen, carbohydrate antigen 19–9, pretreatment clinical stage and postsurgical pathologic stage were used as covariates.ResultsCOD < 460 mg/m2 emerged as an independent predictor of poorer overall, metastasis-free and disease-free survivals, in patients treated with TCC ≤ 7. The hazard ratios were 1.972, 1.763 and 1.637 (P values were 0.021, 0.028 and 0.041), respectively. But it was note-worthy that COD ≥460 mg/m2 increased incidence of acute toxicities from 38.4 to 70.8% (P < 0.001). And in patients treated with TCC ≥ 8, COD failed to be a prognosticator.ConclusionsFor LARC patients treated with insufficient TCC (≤ 7), oxaliplatin of ≥460 mg/m2 might be needed to improve survival, though it might resulted in more acute toxicities.

Oxaliplatin-induced peripheral neuropathy risk factors and management in Tunisian population.

The most important limits of oxaliplatin treatment is its peripheral neurotoxicity. The aim of our study was to evaluate the oxaliplatin-induced peripheral neuropathy, its impact on treatment and its management. One hundred chemo-naive patients treated with oxaliplatin-based regimen in the medical oncology department of the military hospital of Tunis between 2012 and 2017 were recruited retrospectively. Evaluation of neuropathy was done according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE V4). Fifty-six patients were aged more than 60 years. The sex-ratio was 1.56. Twenty-seven patients were overweight, 17 were obese and 56 had a BMI inferior to 25 kg/m2. Two patients were consuming alcohol. Twenty-three patients had diabetes. Sixty-four patients developed chronic peripheral neuropathy because of oxaliplatin (grade 1-2 in 58 cases and grade 3 in 6 cases). Sex, BMI, diabetes and alcohol consumption were not associated with the development of peripheral neuropathy. No association was found between grades of neuropathy and sex, alcohol consumption and diabetes. The median cumulative dose of oxaliplatin that induced neuropathy was 432.4 mg/m2. The most prescribed treatment was gabapentin (81%) and carbamazepine (16.8%). The treatment was not sufficient to stop neuropathy in 82.6% of cases. Dose reduction was done in 64.2% of cases, treatment delay in 10.7% of cases and treatment interruption in 10.7% of cases. We didn't find any association between known risk factors and peripheral neuropathy. The cumulative dose is interesting to define or to predict the timing of neurotoxicity.

Splenomegaly in Colon Cancer During Adjuvant Oxaliplatin-based Chemotherapy.

IntroductionOxaliplatin-based chemotherapy is the standard treatment in stage III colon cancer. Oxaliplatin may cause sinusoidal damage and sinusoidal obstruction syndrome (SOS) in the liver. Clinical reflections of SOS are splenomegaly and thrombocytopenia. This study aimed to investigate the frequency of splenomegaly development in patients receiving oxaliplatin-based chemotherapy and thrombocytopenia incidence rates related to this condition. Materials and methodsFiles of 50 patients having received fluorouracil and oxaliplatin (mFOLFOX6) regimen for stage 3 colon cancer between 2015 and 2017 were retrospectively reviewed. Spleen volumes (SV) of the patients were calculated using pre-and post-chemotherapy tomographic examinations. A 50% increase in the SV after chemotherapy (SV ≥1.5 change) was accepted as chemotherapy-associated splenomegaly. The patients were divided into two groups as having or not having splenomegaly after chemotherapy. Complete blood count was evaluated prior to each treatment cycle, and on the third month of treatment, termination was used for thrombocyte values. ResultsSplenomegaly was determined in 50% of the patients. Cumulative oxaliplatin dosage was found higher in those who developed splenomegaly (p = 0.003). Chemotherapy dose reduction was higher in patients who did not develop splenomegaly (p = 0.015). Thrombocytopenia was confirmed higher in patients who developed splenomegaly compared to those who did not (p = 0.047). Lower thrombocyte counts were found in the complete blood count of the patients having developed splenomegaly which was performed during and 3 months after chemotherapy when compared to those that did not develop splenomegaly (p-values, respectively, as 0.005, 0.038). Upon multivariate logistic regression analysis, cumulative oxaliplatin dose was the single independent factor related to splenomegaly (OR: 7.55 (1.90-31.61); p = 0.004).ConclusionThrombocytopenia was confirmed to be higher in colon cancer patients receiving adjuvant mFOLFOX6 and developing splenomegaly during the post-treatment period. Moreover, splenomegaly was shown to be associated with the cumulative oxaliplatin doses received. Thrombocytopenia seen in patients receiving oxaliplatin for colon cancer should be a warning in terms of splenomegaly and SOS development.

Ameliorative effects of aqueous extract of Forsythiae suspensa fruits on oxaliplatin-induced neurotoxicity in vitro and in vivo

BackgroundThe dried fruits of Forsythia suspensa has generally been used to clear heat and detoxify in traditional Korean and Chinese medicine. Oxaliplatin is a first-line treatment chemotherapeutic agent for advanced colorectal cancer, but it induces peripheral neuropathy as an adverse side effect affecting the treatment regimen and the patient’s quality of life. The present study was conducted to evaluate the neuroprotective effects of an aqueous extract of F. suspensa fruits (EFSF) on oxaliplatin-induced peripheral neuropathy.MethodsThe chemical components from EFSF were characterized and quantified using the ultra-high performance liquid chromatography-diode array detector system. The cytotoxicities of anticancer drugs in cancer cells and PC12 cells were assessed by the Ez-Cytox viability assay. To measure the in vitro neurotoxicity, the neurite outgrowth was analyzed in the primary dorsal root ganglion (DRG) cells, and neural PC12 cells that were differentiated with nerve growth factor. To evaluate the in vivo neuroprotective activity, the von Frey test was performed in six-week-old male mice (C57BL/6) receiving EFSF (60–600 mg/kg) in the presence of 20–30 mg/kg cumulative doses of oxaliplatin. Thereafter, the mice were euthanized for immunohistochemical staining analysis with an antibody against PGP9.5.ResultsEFSF attenuated the cytotoxic activities of the various anticancer drugs in neural PC12 cells, but did not affect the anticancer activity of oxaliplatin in human cancer cells. Oxaliplatin remarkably induced neurotoxicities including cytotoxicity and the inhibited neurite outgrowth of DRG and neural PC12 cells. However, the co-treatment of EFSF (100 μg/ml) with oxaliplatin completely reversed the oxaliplatin-induced neurotoxicity. Forsythoside A, the major component of EFSF, also exerted remarkable neuroprotective effects against the oxaliplatin-induced neurotoxicity. In addition, EFSF (60–200 mg/kg) significantly alleviated the oxaliplatin-induced mechanical allodynia and loss of intra-epidermal nerve fiber to the levels of the vehicle control in the mouse peripheral neuropathy model.ConclusionsEFSF could be considered a useful herbal medicine for the treatment of peripheral neuropathy in cancer patients receiving chemotherapy with oxaliplatin.

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.

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.

Cumulative dose of oxaliplatin in adjuvant therapy for stage III colon cancer patients: Impact on survival.

e15671Background: The oxaliplatin-based therapy administerated over 6 months remains the standard of adjuvant treatment for stage III colon cancer patients.The IDEA study demonstrated that in certa...

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.

High-dose 8% capsaicin patch in treatment of chemotherapy-induced peripheral neuropathy: single-center experience

High-dose capsaicin patch is effective in treatment of neuropathic pain in HIV-associated neuropathy and diabetic neuropathy. There are no studies assessing effectiveness of high-dose capsaicin patch in treatment of chemotherapy-induced peripheral neuropathy. We sought to determine the effectiveness of treatment of pain associated with chemotherapy-induced peripheral neuropathy with high-dose capsaicin patch. Our study group consisted of 18 patients with clinically confirmed oxaliplatin-induced neuropathy. Baseline characteristic including underling disease, received cumulative dose of neurotoxic agent, neuropathic symptoms, prior treatment and initial pain level were recorded. Pain was evaluated with Numeric Rating Scale prior to treatment with high-dose capsaicin and after 1.8 day and after 8 and 12 weeks after introducing treatment. Patients were divided into two groups accordingly to the amount of neurotoxic agent that caused neuropathy (high sensitivity and low sensitivity group). Most frequent symptoms of chemotherapy-induced neuropathy were: pain (88.89%), paresthesis (100%), sock and gloves sensation (100%) and hypoesthesis (100%). Initial pain level was 7.45 ± 1.14. Mean cumulative dose of oxaliplatin after which patients developed symptoms was 648.07 mg/m2. Mean pain level after 12 weeks of treatment was 0.20 ± 0.41. When examined according to high and low sensitivity to neurotoxic agent patients with low sensitivity had higher pain reduction, especially after 8 days after introducing treatment (69.55 ± 12.09 vs. 49.40 ± 20.34%; p = 0.02) and after 12 weeks (96.96 ± 5.56 vs. 83.93 ± 18.59%; p = 0.04). High-dose capsaicin patch is an effective treatment for pain associated with chemotherapy-induced neuropathy in patients treated with oxaliplatin. Patients with lower sensitivity to neurotoxic agents have better response to treatment and pain reduction.

Oxaliplatin-Induced Peripheral Neuropathy and Identification of Unique Severity Groups in Colorectal Cancer

ContextOxaliplatin-induced peripheral neuropathy (OIPN) is a dose-limiting toxicity of oxaliplatin and affects most colorectal cancer patients. OIPN is commonly evaluated by patient symptom report, using scales to reflect impairment. They do not discriminate between unique grouping of symptoms and signs, which impedes prompt identification of OIPN. ObjectiveThe objective of this study was to identify clusters of symptoms and signs that differentiated underlying clinical severity and segregated patients within our population into OIPN subgroups. MethodsChemotherapy-naive colorectal cancer patients (N = 148) receiving oxaliplatin were administered the Total Neuropathy Score clinical (TNSc©), which includes symptom report (sensory, motor, autonomic) and sensory examination (pin sense, vibration, reflexes). The TNSc was administered before chemotherapy initiation (T0) and after cumulative doses of oxaliplatin 510–520 mg/m2 (T1) and 1020–1040 mg/m2 of oxaliplatin (T2). Using mean T2 TNSc scores, latent class analysis grouped patients into OIPN severity cohorts. ResultsLatent class analysis categorized patients into four distinct OIPN groups: low symptoms and low signs (n = 54); low symptoms and intermediate signs (n = 44); low symptoms and high signs (n = 21); and high symptoms and high signs (n = 29). No differences were noted among OIPN groups on age, sex, chemotherapy regimen, or cumulative oxaliplatin dose. ConclusionWe identified OIPN patient groups with distinct symptoms/signs, demonstrating variability of OIPN presentation regardless of cumulative oxaliplatin dose. Over half of the sample had positive findings on OIPN examination despite little or no symptoms. Sensory examination of all patients receiving oxaliplatin is indicated for timely identification of OIPN, which will allow earlier symptom management.