抗抑郁药对抗奥沙利铂诱发的神经病理性疼痛的作用研究

背景与目的:新型铂类化疗药物奥沙利铂是一种治疗多种常见肿瘤的高效化疗药物,但其引起的高发的外周神经性不良反应严重限制了临床应用.传统的镇痛药物对此类化疗药物诱发的神经病理性疼痛效果较差.因此本研究旨在观察抗抑郁药地昔帕明及氟西汀对奥沙利铂诱发的小鼠神经病理性疼痛模型的作用,从而为抗抑郁药缓解化疗药物引起的神经病理性疼痛以及抗肿瘤辅助治疗提供实验依据.方法:一次性腹腔注射奥沙利铂(30 mg/kg)制备神经病理性疼痛小鼠模型;von Frey纤毛法测定小鼠的机械刺激缩足反射(mechanical withdrawal threshold,MWT)阈值,作为神经病理性疼痛模型小鼠痛觉超敏反应的指标;地昔帕明及氟西汀灌胃1 h后观察MWT的变化.结果:地昔帕明及氟西汀均明显升高神经病理性疼痛模型小鼠的MWT值,且此作用可被阿片受体拮抗药纳洛酮阻断.地昔帕明可明显增强吗啡类镇痛药丁丙诺啡升高神经病理性疼痛模型小鼠MWT的作用.结论:抗抑郁药物地昔帕明和氟西汀对化疗药物奥沙利铂诱发的痛觉超敏具抑制作用,可用于缓解化疗药物引起的神经病理性疼痛.联合应用抗抑郁药地昔帕明与吗啡类镇痛药丁丙诺啡具有协同效应.     

Subclinical pretreatment sensory deficits appear to predict the development of pain and numbness in patients with multiple myeloma undergoing chemotherapy

Purpose

Chemotherapy-induced peripheral neuropathy is a major complication in the treatment for cancer, including multiple myeloma (MM). Patients may develop painful and non-painful (e.g., numbness) neuropathy symptoms that impair function and often persist after therapy is terminated. This study tested the hypothesis that baseline subclinical neuropathy, as assessed by sensory thresholds, is related to the development of neuropathy symptoms (e.g., pain and numbness) in patients with MM undergoing treatment with chemotherapy.

Methods

Patients (n = 56) who had undergone two or fewer cycles of induction therapy and who had no evident neuropathy were assessed using quantitative sensory tests to determine multiple-modality sensory thresholds. Patient-reported pain and numbness were assessed through induction therapy (16 weeks) via the MD Anderson Symptom Inventory. A subset of participants (n = 15) continued reporting on their symptoms for an additional 16 weeks (“maintenance phase”).

Results

Patients with sharpness detection deficits at baseline (n = 11, 20 % of sample) reported less severe pain and numbness during induction therapy and less numbness during maintenance therapy (P < 0.05). During the maintenance phase, patients with warmth detection deficits (n = 5, 38 % of sample) reported more severe pain and numbness, and those with skin temperature deficits (n = 7, 47 % of maintenance sample) reported more severe pain (P < 0.05). These deficits were related to patient reported difficulty walking, a common symptom of peripheral neuropathy.

Conclusion

Our results suggest that baseline subclinical sensory deficits may be related to a patient’s risk for developing chemotherapy-induced peripheral neuropathy.     

Use of an alpha lipoic,methylsulfonylmethane and bromelain dietary supplement (Opera<Superscript>®</Superscript>) for chemotherapy-induced peripheral neuropathy management,a prospective study

Chemotherapy-induced peripheral neuropathy (CIPN) is a major clinical problem associated with a number of cytotoxic agents. OPERA^® (GAMFARMA srl, Milan, Italy) is a new dietary supplement where α-lipoic acid, Boswellia Serrata, methylsulfonylmethane and bromelain are combined in a single capsule. The aim of this prospective study was to determine the efficacy and safety of OPERA^® supplementation in a series of patients affected by CIPN. We selected 25 subjects with CIPN evolving during or after chemotherapy with potentially neurotoxic agents. Patients were enrolled at the first clinical manifestation of neuropathy. CIPN was assessed at the enrollment visit and subsequently repeated every 3 weeks until 12 weeks. Primary endpoint was the evaluation of changes of measured scores after 12 weeks of therapy compared to baseline evaluation. Secondary endpoints were the evaluation of neuropathy reduction at 12 weeks after beginning of therapy with OPERA^®. Analysis of VAS data showed reduction in pain perceived by patients. According to NCI-CTC sensor and motor score, mISS scale and TNSc scale, both pain and both sensor and motor neuropathic impairment decreased after 12 weeks of treatments. Treatment with OPERA supplement was well tolerated; no increase in the toxicity profile of any of the therapeutic regimen that the patients were undergoing was reported. OPERA^® was able to improve CIPN symptoms in a prospective series of patients treated with neurotoxic chemotherapy, with no significant toxicity or interaction. Prospective RCT in a selected patients’ population is warranted to confirm its promising activity.     

Strategies for Managing Chemotherapy-Induced Sensory Neuropathy

Chemotherapy-induced sensory neuropathy occurs in most patients undergoing treatment with oxaliplatin for colorectal cancer. Although the acute form of neurotoxicity is transient, the chronic form, which is correlated with the cumulative dose of oxaliplatin administered over time, may be long lasting in a subset of patients and may have a significant impact on function and quality of life. Because treatment options for established chemotherapy-induced peripheral neuropathy are limited, recent efforts have focused on prevention. This review discusses acute and chronic neurotoxic effects of oxaliplatin, the most recent evidence for decreasing the probability of developing peripheral neuropathy, and the clinical management of existing neuropathy.     

Prophylaxe und Therapie der chemotherapieinduzierten Polyneuropathie

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most disabling side effects of cancer treatment with neurotoxic agents such as platinum compounds, taxanes, vinca-alkaloids, eribulin, and bortezomib. To protect patients from long-term impairments of daily functioning and quality of life, early diagnosis of CIPN via assessment of neuropathic symptoms and patient-reported outcome measures prior to each treatment cycle is desirable. Acute neurotoxicity due to oxaliplatin and taxane-induced acute pain syndrome are predictive for development of cumulative peripheral neurotoxicity. Prompt dose modification of the causal substance can avoid interruption or discontinuation of tumor therapy. Pharmacologic prophylaxis of CIPN has not been established so far. Duloxetine as well as exercise and balance training are promising approaches to CIPN treatment.     

PainVision系统量化评估癌痛及化疗神经毒性的应用分析

背景与目的：癌症相关性疼痛是晚期肿瘤患者的重要临床症状,而化疗常导致周围神经病变,引发疼痛,严重影响患者的生活质量。目前癌痛的评估大都通过患者主观量表来实现,缺乏客观评价手段。本研究借助PainVision系统(PV法)从神经电生理角度定量地进行癌痛评估,检测分析化疗导致的神经病变程度。方法：癌痛患者通过数字疼痛强度量表(numerical rating scale,NRS)主观量表和PV法同时进行疼痛评估,将PV法所得检测值与NRS评分进行相关性分析;对化疗患者进行电流知觉阈值(current perception threshold,CPT)检测,了解化疗对患者CPT水平的影响,尝试PV法进行化疗神经毒性的检测。结果：癌痛患者所测得疼痛比(PainRatio)和患者NRS评分线性相关(Pearson系数为0.849,P＜0.001);伴有神经毒性临床症状的患者CPT水平升高,但接受奥沙利铂、紫杉醇和其他药物化疗后的患者CPT水平未见明显差异。结论：PV法可以定量地进行癌痛评估,有助于相对客观地进行癌痛分析。化疗后有明显神经病变的患者出现CPT升高,提示PV法具有潜在检测与评估化疗导致神经毒性的临床应用价值。     

Meet the expert: How I treat chemotherapy-induced peripheral neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent, often irreversible and disabling adverse effect of many commonly used chemotherapeutic agents. Older patients are at particular risk of developing CIPN due to comorbid conditions affecting the health of peripheral nerves. Symptoms of CIPN include paresthesias, dysesthesias, sensory loss, motor weakness, dysautonomia, and falls. Pharmacologic management of CIPN involves use of medications including antidepressants, anticonvulsants, and topical treatments for modulation of neuropathic pain. These medications should be used and monitored carefully in older patients as they may increase the risk of confusion, falls, and drug-drug interactions. Patients with CIPN are at an increased risk of falls and should be considered for supportive care interventions including physical and occupational therapy, assistive devices, and safety evaluations. Surveillance of CIPN during and following treatment is essential. The development of neuropathic symptoms may require dose reduction, drug holiday, or transitioning to another chemotherapeutic agent. Symptoms of CIPN typically improve following exposure to neurotoxic therapy, although in older adults the rate of improvement may be slow, and recovery is often incomplete. Early involvement of a neurologist should be considered in patients with atypical, progressive, motor- or autonomic- predominant presentations of neuropathy. Patients with refractory neuropathic pain or those who cannot tolerate standard symptomatic treatment should be referred to a pain specialist or palliative care.     

Efficacy of lamotrigine in the management of chemotherapy-induced peripheral neuropathy: a phase 3 randomized, double-blind, placebo-controlled trial, N01C3

BACKGROUND: Lamotrigine, an antiepileptic agent, has been reported as being effective in reducing symptoms of neuropathy associated with various etiologies. Based on such data, a multicenter double-blind, placebo-controlled, randomized trial was conducted to evaluate the effect of lamotrigine on pain and other neuropathic symptoms due to chemotherapy-induced peripheral neuropathy (CIPN). METHODS: Patients with symptomatic CIPN with symptom scores of either 1) >3 on a 0-10 Numerical Rating Scale (NRS) or 2) >1 on the 0-3 the Eastern Cooperative Oncology Group (ECOG) neuropathy scale (ENS) were eligible (higher numbers corresponding to greater severity of symptoms in both scales). Patients were randomly assigned to receive lamotrigine (target dose of 300 mg/day) or placebo for 10 weeks. Endpoints were measured biweekly. RESULTS: In all, 131 patients were enrolled. Both groups were well matched at baseline. Over the 10-week period of the trial, the average pain scores (NRS) for the lamotrigine and placebo arms declined in both arms, with no statistically significant difference noted between the changes in the 2 groups (0.3 and 0.5 unit reduction from baseline, respectively; P=.56). Similarly, decreases in the ENS with therapy were not statistically different (0.4 and 0.3, respectively; P=.3). Changes in other subjective symptom scales were also not found to be statistically different between the 2 groups. Toxicities were mild and similar in each group. CONCLUSIONS: The results suggest that lamotrigine is not effective for relieving neuropathic symptoms in patients because of CIPN.     

Examining the Impact of a Web-Based Intervention to Promote Patient Activation in Chemotherapy-Induced Peripheral Neuropathy Assessment and Management

Lack of activation in self-care can compromise a patient’s ability to monitor and manage cancer treatment-related side effects, such as chemotherapy-induced peripheral neuropathy (CIPN). The web-based Carevive® Care Planning System (CPS) was developed to promote evidence-based symptom assessment and treatment by enhancing patients’ involvement in their own care. The purpose of this single-arm, pre-test/post-test, prospective study was to examine whether the CPS can promote patient activation in CIPN symptom assessment and management. Seventy-five women with breast cancer receiving neurotoxic chemotherapy were recruited from a Comprehensive Cancer Center. Using standardized neuropathy measures embedded within the CPS, patients reported their CIPN symptoms over three consecutive clinical visits and completed the Patient Activation Measure (PAM) at the first and third visits. Mean changes in PAM scores between visits were compared using repeated measure analysis of covariance, adjusting for age. At baseline, patients were diagnosed with cancer within the past year (94.7%), highly activated (85% Level III/IV), and had a mean age of 51.3. PAM scores improved significantly from 67.15 (SD = 13.5; range = 47–100) at visit one to 69.29 (SD = 16.18; range = 47–100) (p = 0.02) (n = 62) at visit three. However, patients perceived the CPS to be of minimal value because it solely focused on CIPN and, for many, CIPN was not severe enough to motivate them to seek out symptom management information. Further research is needed to assess the utility of the CPS in promoting activation in the assessment and management of varying cancer treatment-related symptoms.     

Population pharmacokinetics of peritoneal,plasma ultrafiltrated and protein-bound oxaliplatin concentrations in patients with disseminated peritoneal cancer after intraperitoneal hyperthermic chemoperfusion of oxaliplatin following cytoreductive surgery: correlation between oxaliplatin exposure and thrombocytopenia

Purpose

First, to evaluate the peritoneal (IP), plasma ultrafiltrated (UF) and protein-bound (B) pharmacokinetics (PK) of oxaliplatin after intraperitoneal hyperthermic chemoperfusion (HIPEC) following cytoreductive surgery. Second, to evaluate the relationship between oxaliplatin exposure and observed toxicity.

Methods

IP, UF, and B concentrations from 75 patients treated by 30-min oxaliplatin-based HIPEC procedures were analysed according to a pharmacokinetic modelling approach using NONMEM. Oxaliplatin was administered in a 5 % dextrose solution (2 L/m²) at 360 (n = 58) or 460 mg/m² (n = 17). The most frequently observed toxicities were related to the peritoneal, systemic exposures and to the parameters corresponding to the oxaliplatin absorption from peritoneal cavity into plasma.

Results

IP (n = 536), UF (n = 669) and B (n = 661) concentrations were simultaneously described according to a five-compartment PK model with irreversible nonlinear binding from UF to B according to a Michaelis–Menten equation. The mean (±SD) maximum fraction of dose absorbed and elimination half-life from the peritoneum was 53.7 % (±8.5) and 0.49 h (±0.1), respectively. The mean (±SD) ratio AUC_IP/AUC_UF was 5.3 (±2) confirming the pharmacokinetic advantage of the procedure. Haemoperitoneum (22.7 %), neuropathy (18.7 %), grade 3/4 thrombocytopenia (13.3 %) were the most frequently reported toxicities. AUC_UF accounts for approximately 12 % of the variation in the maximum percentage of platelet decrease (r = 0.35, p = 0.002). Thrombocytopenia was correlated with higher AUC_UF, partly dependent on the extent and rate of oxaliplatin absorption.

Conclusions

Despite a common dose administered, variability in peritoneal and systemic oxaliplatin exposures are observed, leading to differences in haematological toxicity between patients.     

文拉法辛对奥沙利铂诱发神经病理性疼痛的抑制作用及机制

目的观察文拉法辛对抗奥沙利铂诱发神经病理性疼痛效果并探索其可能机制,进而为化疗相关神经病理性疼痛的治疗及预防提供实验数据和理论基础。方法Sprague–Dawley大鼠经侧尾静脉给予奥沙利铂4 mg/kg,每周2次,连续4周,共给药8次,建立奥沙利铂诱发神经病理性疼痛大鼠模型;von Frey纤维丝测定大鼠的机械刺激缩足反射阈值（mechanical withdrawal threshold,MWT）作为神经病理性疼痛大鼠模型痛觉反应指标;观察分别给予0.9%氯化钠溶液、文拉法辛7.5 mg/kg、文拉法辛15 mg/kg连续4周,每天一次灌胃后测MWT动态变化,并通过免疫组织化学法测定第五腰椎背根神经节μ、κ、δ阿片受体表达差异。结果文拉法辛明显升高神经病理性疼痛模型大鼠的MWT值,文拉法辛7.5及15 mg/kg组较0.9%氯化钠溶液组μ、κ、δ阿片受体高表达（P＜0.05）。结论文拉法辛可有效抑制奥沙利铂诱发神经病理性疼痛,其作用机制可能与诱导μ、κ、δ阿片受体表达升高有关。     

Prevalence of Oxaliplatin-induced Chronic Neuropathy and Influencing Factors in Patients with Colorectal Cancer in Iran

Background: The chemotherapeutic agent oxaliplatin can cause acute and chronic forms of peripheral neuropathy. The aim of this study was to evaluate the incidence of chronic neuropathy and its risk factors in colorectal cancer (CRC) patients treated with FOLFOX or XELOX regimens in the Oncology Ward of Hazrate- Rasoul Hospital in Tehran. Materials and Methods: A total of 130 patients with CRC were entered into our study, aged over 18 years, without history of receiving other neurotoxic agents or other predisposing factors such as diabetes or neurologic diseases and kidney and liver dysfunction. For the FOLFOX regimen, patients received oxaliplatin, 85 mg/m2, every 2 weeks for 12 courses and with the XELOX regimen, oxaliplatin was 130mg/m2, every 3 weeks for 8 courses. Based on Common Toxicity Criteria (CTC or NCI-CTC v.3), the patients were divided into 5 groups (grades) based on the severity of their symptoms. Results: Fifty-seven patients (43.8%) were male and 73(56.2%) female. Some 19 patients (14.7%) had BMI<20, 97(74.6%) were between 20-25 and 14 (10.8%) ≥25. In 105 patients (80.7%) neuropathy was found. There was significant correlation between BMI, hypomagnesaemia and especially, severity of anemia in patients with neuropathy compared to those without. Conclusions: Oxaliplatin regimens can induce chronic neuropathy in CRC patients, with anemia, high BMI and hypomagnesaemia as risk factors that can predispose to this kind of neurotoxicity.     

Oxaliplatin rechallenge in metastatic colorectal cancer patients after prior oxaliplatin treatment

Because the number of cytotoxic agents available for the treatment of metastatic colorectal cancer (mCRC) is limited, rechallenge with the same chemotherapy agents can provide a continuum of treatment. This study investigated the efficacy and feasibility of oxaliplatin rechallenge in mCRC patients who had been previously exposed to oxaliplatin-based chemotherapy. Patients were included if they had mCRC and evaluable disease, had remained disease-free or progression-free for at least 6 months after the last dose of prior oxaliplatin-based therapy, and were retreated with oxaliplatin therapy. Between January 2009 and May 2014, 110 patients were retreated with oxaliplatin-based regimens; of these, 42 (38.2%) had received prior oxaliplatin as adjuvant chemotherapy and 68 (61.8%) as palliative chemotherapy. The overall response rate to oxaliplatin rechallenge was 30.9% (34/110), and the disease control rate was 68.2% (75/110), with one patient achieving complete response, 33 achieving partial response, and 41 having stable disease. Median progression-free survival and overall survival following oxaliplatin rechallenge were 5.9 months (95% confidence interval [CI], 4.4–7.4 months) and 18.5 months (95% CI, 14.0–23.0 months), respectively. Sixteen patients experienced grade 2 or 3 neuropathy. Ten patients experienced any grade hypersensitivity reaction within four cycles of treatment, including six who stopped treatment due to grade 3 or 4 hypersensitivity reactions. Rechallenge with oxaliplatin-based therapy may be an option for patients who achieve at least 6 months of disease-free or progression-free survival with prior oxaliplatin-based chemotherapy. However, neurotoxicity and hypersensitivity reactions should be carefully monitored in this setting.     

Peripheral neuropathy induced by combination chemotherapy of docetaxel and cisplatin.

Docetaxel, a new semisynthetic taxoid that has demonstrated promising activity as an antineoplastic agent, was administered in combination with cisplatin to 63 patients in a dose-escalating study. As both drugs were known to be potentially neurotoxic, peripheral neurotoxicity was prospectively assessed in detail. Neuropathy was evaluated by clinical sum-score for signs and symptoms and by measurement of the vibration perception threshold (VPT). The severity of neuropathy was graded according to the National Cancer Institute''s ''Common Toxicity Criteria''. The docetaxel-cisplatin combination chemotherapy induced a predominantly sensory neuropathy in 29 (53%) out of 55 evaluable patients. At cumulative doses of both cisplatin and docetaxel above 200 mg m(-2), 26 (74%) out of 35 patients developed a neuropathy which was mild in 15, moderate in ten and severe in one patient. Significant correlations were present between both the cumulative dose of docetaxel and cisplatin and the post-treatment sum-score of neuropathy (P < 0.01) as well as the post-treatment VPT (P < 0.01). The neurotoxic effects of this combination were more severe than either cisplatin or docetaxel as single agent at similar doses.     

Efficacy and safety of capecitabine as maintenance treatment after first-line chemotherapy using oxaliplatin and capecitabine in advanced gastric adenocarcinoma patients: a prospective observation

The value of maintenance therapy after first-line chemotherapy has been verified in lung cancer and colorectal cancer, however, in gastric cancer, the role of maintenance therapy is still waiting for an answer. The aim of this study is to evaluate the efficacy and safety of capecitabine as maintenance treatment after first-line chemotherapy in advanced gastric adenocarcinoma patients in China. Specimens of patients with advanced gastric adenocarcinoma who were given 6 cycles of oxaliplatin and capecitabine (Xelox for short) as first-line chemotherapy, without disease progression and with grade 2 or higher neuropathy, were collected for analysis. Among them, 64 patients received capecitabine as maintenance (group A) and 222 patients without maintenance as group B. Survival analysis was performed with a Cox regression model. Grades 3–4 adverse events were uncommon; hematologic toxicity was infrequent (5 %) and consistently mild in the phase of maintenance treatment. The median progression-free survival (PFS) was 11.4 months [95 % confidence interval (CI), 10.2–12.6 months] for group A patients, while it was 7.1 months (95 % CI, 6.1–8.0 months) for patients in group B, P?<?0.001. The multivariated analysis showed that the maintenance treatment was an independent prognostic factor in advanced gastric adenocarcinoma patients. The style of first-line treatment-maintenance therapy (Xelox-X) was active and feasible for advanced gastric adenocarcinoma patients who had suffered from grade 2 or higher level of neuropathy.     

Goshajinkigan reduces oxaliplatin-induced peripheral neuropathy without affecting anti-tumour efficacy in rodents

Oxaliplatin is a key drug in the treatment of colorectal cancer, but it causes acute and chronic neuropathies in patients. Goshajinkigan (GJG) is a Kampo medicine that is used for the treatments of several neurological symptoms including pain and numbness. More recently, GJG has been reported to prevent the oxaliplatin-induced peripheral neuropathy in clinical studies. No experimental study, however, has been conducted to date to determine the effect of GJG on pain behaviour in a rat model of oxaliplatin-induced neuropathy. Moreover, the impact on the anti-tumour effect of oxaliplatin remains unknown. In the present study, we examined the effects of GJG on the peripheral neuropathy and anti-tumour activity of oxaliplatin in rodents. Repeated administration of oxaliplatin caused cold hyperalgesia from days 3 to 37 and mechanical allodynia from days 21 to 28. Repeated administration of GJG prevented the oxaliplatin-induced cold hyperalgesia but not mechanical allodynia and axonal degeneration in rat sciatic nerve. Single administration of GJG reduced both cold hyperalgesia and mechanical allodynia after the development of neuropathy. In addition, GJG did not affect the anti-tumour effect of oxaliplatin in the tumour cells or tumour cells-implanted mice. These results suggest that GJG relieves the oxaliplatin-induced cold hyperalgesia and mechanical allodynia without affecting anti-tumour activity of oxaliplatin, and, therefore, may be useful for the oxaliplatin-induced neuropathy in clinical practice.     

天麻素对化疗痛模型大鼠脊髓IL-1β和TNFα表达的影响

目的 观察天麻素对长春新碱致大鼠神经病理性疼痛的治疗作用,观察大鼠脊髓腰段IL-1β和TNF α表达的变化,探讨其在脊髓水平的作用机制。方法 用长春新碱隔日腹腔注射制作大鼠化疗痛模型,模型成功制备后腹腔注射天麻素治疗,用电子Von Frey测痛仪测定大鼠机械性痛阈,热辐射仪测定大鼠热刺激痛阈值;采用ELISA方法检测脊髓腰段IL-1β和TNFα表达情况。结果 实验第8天化疗痛大鼠模型成功建立,用不同剂量天麻素治疗模型大鼠1周后,治疗组大鼠的机械和热刺激痛阈值与模型组比较均有不同程度的提高 (P<0.01, P<0.05);与模型组比较,治疗组大鼠的IL-1β和TNFα的表达明显降低（P<0.01）。结论 天麻素可减轻长春新碱诱导的大鼠化疗痛反应,其机制可能与抑制化疗痛大鼠脊髓IL-1β和TNFα的表达有关。     

Predictors of duloxetine response in patients with oxaliplatin‐induced painful chemotherapy‐induced peripheral neuropathy (CIPN): a secondary analysis of randomised controlled trial – CALGB/alliance 170601

Duloxetine is an effective treatment for oxaliplatin‐induced painful chemotherapy‐induced peripheral neuropathy (CIPN). However, predictors of duloxetine response have not been adequately explored. The objective of this secondary and exploratory analysis was to identify predictors of duloxetine response in patients with painful oxaliplatin‐induced CIPN. Patients (N = 106) with oxaliplatin‐induced painful CIPN were randomised to receive duloxetine or placebo. Eligible patients had chronic CIPN pain and an average neuropathic pain score ≥4/10. Duloxetine/placebo dose was 30 mg/day for 7 days, then 60 mg/day for 4 weeks. The Brief Pain Inventory‐Short Form and the EORTC QLQ‐C30 were used to assess pain and quality of life, respectively. Univariate and multiple logistic regression analyses were performed to identify demographic, physiologic and psychological predictors of duloxetine response. Higher baseline emotional functioning predicted duloxetine response (≥30% reduction in pain; OR 4.036; 95% CI 0.999–16.308; p = 0.050). Based on the results from a multiple logistic regression using patient data from both the duloxetine and placebo treatment arms, duloxetine‐treated patients with high emotional functioning are more likely to experience pain reduction (p = 0.026). In patients with painful, oxaliplatin‐induced CIPN, emotional functioning may also predict duloxetine response. ClinicalTrials.gov, Identifier NCT00489411     

Transient severe hyperbilirubinemia after hepatic arterial infusion of oxaliplatin in patients with liver metastases

Purpose

We have observed severe, but rapidly reversible, hyperbilirubinemia in patients receiving hepatic arterial infusion (HAI) of oxaliplatin. We performed a retrospective analysis to characterize this unusual phenomenon.

Methods

We reviewed the electronic medical records of 113 consecutive patients receiving HAI oxaliplatin to describe the associated hyperbilirubinemia.

Results

Four of 113 patients (3.5 %) presented with transient, severe (grade 3/4) hyperbilirubinemia post-HAI oxaliplatin. Peak levels of total bilirubin within 10–16 h of starting HAI oxaliplatin were 4.6, 12.2, 12.8, and 21.2 mg/dL and declined rapidly (within 24 after stopping treatment). One out of four patients experienced severe abdominal pain, and another patient had an infusion reaction (hypertension and hypoxemia) that reversed after discontinuation of infusion. Total bilirubin was predominantly direct. No significant decline in hemoglobin or increase in alkaline phosphatase occurred. Increase in liver transaminases post-infusion was mild to moderate (grades 1–3) and was seen after HAI oxaliplatin regardless of the emerged hyperbilirubinemia.

Conclusions

Severe hyperbilirubinemia is a rare but rapidly reversible adverse effect of HAI oxaliplatin and may be accompanied by an abdominal pain syndrome or infusion reaction. Treating physicians should be aware for the potential of this reaction. The mechanism of this unusual reaction merits further investigation.     

Overcoming oxaliplatin hypersensitivity: different strategies are needed according to the severity and previous exposure

Purpose

This study investigated the characteristics of oxaliplatin-related hypersensitivity reactions (HSR) and evaluated the efficacy of premedication and desensitization administration for controlling HSR in patients with gastrointestinal malignancy.

Methods

This retrospective study includes oxaliplatin hypersensitivity cases reported to our in-hospital, adverse drug reaction monitoring system between May 2008 and April 2012. We analyzed administration histories of oxaliplatin and premedication treatments, chemotherapy cycle and severity of the initial HSR, and prophylactic measures and their outcomes in subsequent chemotherapy cycles.

Results

One hundred and seventy-three patients showed hypersensitivity to oxaliplatin-based chemotherapy. Oxaliplatin HSR developed after mean chemotherapy cycle 6.3 ± 0.3. Specifically, while HSR occurred at cycle 7.6 ± 0.3 in the case of patients previously unexposed to oxaliplatin-containing chemotherapy, it occurred at cycle 2.6 ± 0.3 in previously exposed patients. Of the 173 patients who exhibited HSR, premedication was administered in 134 patients and 71.6 % of them succeeded in preventing HSR. Desensitization was attempted in 38 patients, including 20 patients in whom premedication administration was unsuccessful, and 89 % of desensitized patients successfully underwent oxaliplatin chemotherapy without HSR. As severity of HSR increased, the success rate by premedication decreased and the percentage of patients that underwent desensitization increased.

Conclusions

Attention should be paid to patients with any prior exposure to oxaliplatin, especially during early chemotherapy cycles. Given the high success rate of preventing HSR by desensitization administration and its apparent safety profile, we suggest that desensitization be considered as the first option for the treatment of grades 3 and 4 HSR cases.