a Department of Immunology, Genetics and Pathology , Uppsala University , Uppsala , Sweden.
b Clinic for Gastroenterology and Hepatology of Military Medical Academy of Serbia , Belgrade , Serbia.
Acta Oncol. 2018 Mar;57(3):393-402. doi: 10.1080/0284186X.2017.1398836. Epub 2017 Nov 15.
Oxaliplatin causes disabling acute and chronic peripheral neuropathy. We explored the preventive effects of calmangafodipir, mimicking the mitochondrial enzyme manganese superoxide dismutase, thereby protecting cells from oxidative stress, in a placebo-controlled, double-blinded randomised phase II study (ClinicalTrials.gov.NCT01619423) in patients with metastatic colorectal cancer (mCRC).
mCRC patients treated with modified FOLFOX-6 (folinic acid 200 mg/m, 5-fluorouracil bolus 400 mg/m, oxaliplatin 85 mg/m and 5-fluorouracil 2400 mg/m continuous infusion for 46 h) every fortnight for 8 cycles in first or second line were eligible. Calmangafodipir was given in a phase I dose-finding and in a phase II placebo-controlled study, as a 5-min infusion 10 min prior to oxaliplatin. Neurotoxicity was evaluated by the physician using the Oxaliplatin Sanofi Specific Scale and by the patient using the cold allodynia test and the Leonard scale.
Eleven patients were included in phase I without any detectable toxicity to calmangafodipir. In the phase II study, 173 patients were randomised to placebo (n = 60), calmangafodipir 2 µmol/kg (n = 57) and calmangafodipir 5 µmol/kg (n = 45, initially 10 µmol/kg, n = 11). Calmangafodipir-treated patients (all three doses pooled) had less physician graded neurotoxicity (odds ratio (90% confidence interval one-sided upper level) 0.62(1.15), p = .16), significantly less problems with cold allodynia (mean 1.6 versus 2.3, p < .05) and significantly fewer sensory symptoms in the Leonard scale (cycle 1-8 mean 1.9 versus 3.0, p < .05 and during follow-up after 3 and 6 months, mean 3.5 versus 7.3, p < .01). Response rate, progression-free and overall survival did not differ among groups.
Calmangafodipir at a dose of 5 µmol/kg appears to prevent the development of oxaliplatin-induced acute and delayed CIPN without apparent influence on tumour outcomes.
奥沙利铂可引起严重的急性和慢性周围神经病变。我们通过一项安慰剂对照、双盲随机 2 期临床试验（ClinicalTrials.gov.NCT01619423），探索了钙镁黄嘌呤（一种模仿线粒体酶锰超氧化物歧化酶的药物）的预防作用，该药物可以保护细胞免受氧化应激，该试验纳入转移性结直肠癌（mCRC）患者。
接受改良 FOLFOX-6（亚叶酸钙 200mg/m2、5-氟尿嘧啶推注 400mg/m2、奥沙利铂 85mg/m2、5-氟尿嘧啶 2400mg/m2 持续输注 46 小时）治疗的 mCRC 患者，每两周一次，共 8 个周期，可入组一线或二线治疗。钙镁黄嘌呤在剂量递增的 1 期和安慰剂对照的 2 期研究中，在奥沙利铂之前 10 分钟给予 5 分钟的输注。神经毒性由医生使用奥沙利铂 Sanofi 特异性量表，以及由患者使用冷感觉异常测试和 Leonard 量表进行评估。
在没有检测到钙镁黄嘌呤毒性的情况下，11 例患者入组 1 期研究。在 2 期研究中，173 例患者被随机分配至安慰剂组（n=60）、钙镁黄嘌呤 2μmol/kg 组（n=57）和钙镁黄嘌呤 5μmol/kg 组（n=45，最初剂量为 10μmol/kg，n=11）。钙镁黄嘌呤治疗组（所有三种剂量合并）的医生分级神经毒性更低（优势比（90%置信区间单侧上限）0.62（1.15），p=0.16），冷感觉异常的问题明显减少（平均 1.6 对 2.3，p<0.05），Leonard 量表的感觉症状明显减少（第 1-8 周期平均 1.9 对 3.0，p<0.05，在 3 个月和 6 个月后的随访期间，平均 3.5 对 7.3，p<0.01）。各组之间的缓解率、无进展生存期和总生存期无差异。
钙镁黄嘌呤 5μmol/kg 剂量似乎可预防奥沙利铂引起的急性和迟发性 CIPN，而对肿瘤结局无明显影响。
