Lessons learned: Pregabalin is a medication that can decrease neuronal hyperexcitability, relieve neuropathic pain, and reach stable plasma levels after a titration period of only a few days.Its use during oxaliplatin infusions was not able to decrease the incidence of chronic, oxalipaltin-related neuropathic pain, compared with placebo.
Background: Patients with colorectal cancer (CRC) receiving oxaliplatin (OXA) develop acute and chronic painful oxaliplatin-induced peripheral neuropathy (OXAIPN). Acute and chronic OXA-related neuropathies have different pathophysiological bases, but both lead to a common phenomenon: central sensitization (CS) of nociceptive neuronal networks, leading to increased sensitivity (hyperlgesia, allodynia) in the somatosensory system, the common ground of chronic neuropathic pain. Because CS is related to increased risk of painful OXAIPN, we hypothesized that preemptive use of the anti-hyperalgesic drug pregabaline (known to decrease CS) during OXA infusions would decrease the incidence of chronic OXAIPN.
Methods: Pain-free, chemotherapy-naïve CRC patients receiving at least one cycle of modified-FLOX [5-FU(500 mg/m2)+leucovorin(20 mg/m2)/week for] 6 weeks+oxaliplatin(85 mg/m2) at weeks 1-3-5 every 8 weeks] were randomized (1:1) into the study. Patients received either pregabalin or placebo for 3 days before and 3 days after each OXA infusion and were followed for up to 6 months. Clinical assessments were performed at baseline, at the end of chemotherapy, and after the follow-up period. The main outcome was average pain at the last visit assessed by the visual analogic scale (0-10) item of the Brief Pain Inventory (BPI). Secondary endpoints were presence of neuropathic pain according to the Douleur Neuropathique-4 (DN-4), pain dimensions (short- form McGill Pain Questionnaire [MPQ]), Neuropathic Pain Symptom Inventory (NPSI), and changes in nerve conduction studies (NCS) and side effect profile.
Results: One hundred ninety-nine patients (57.0 ± 10.7 years old, 98 female, 101 male) were randomized. Data from 56 patients were not included in the analyses (as they did not receive at least one full cycle of modified FLOX). Data from 78 patients in the pregabalin group and 65 patients in the placebo group were retained for analyses. At the last visit, pain intensity in the pregabalin group was 1.03 (95% confidence interval [CI] = 0.79-1.26), and 0.85 (95% CI = 0.64-1.06) in the placebo group, which did not reach significance. Scores from the BPI, MPQ, DN-4, NPSI, and NCS and side-effect profiles and incidence of death did not differ between groups. Quality of life (QoL) score did not differ between groups (placebo = 76.9 ± 23.1, pregabalin group 79.4 ± 20.6). Mood scores were not significantly different between groups (placebo 9.7 [8.1-11.2]; pregabalin 6.8 [5.6-8.0]).
Conclusion: The preemptive use of pregabalin during OXA infusions was safe, but did not decrease the incidence of chronic pain related to OXAIPN.
经验总结
• 普瑞巴林可减轻神经元过度兴奋和缓解神经性疼痛, 仅滴定几天后即可达到稳定的血浆水平。
• 与安慰剂相比, 在奥沙利铂输注给药期间使用普瑞巴林无法降低与奥沙利铂相关的慢性神经性疼痛的发生率。
摘要
背景.黑色素瘤衍生的热休克蛋白（HSP）和HSP‐肽复合物可以引发保护性抗肿瘤反应。粒细胞‐巨噬细胞集落刺激因子（GM‐CSF）趋化因子也可促进专职抗原呈递细胞（APC）的摄取和加工处理。在此基础上, 我们设计了一项经皮热消融初步研究, 据此诱导热休克蛋白疫苗与GM‐CSF, 以确定这种联合的安全性和初步抗肿瘤效果。
材料和方法.本研究旨在评估经皮消融联合GM‐CSF用于不可切除的转移性黑色素瘤（包括葡萄膜和粘膜型）的总体安全性。所有患者首先接受热休克治疗（42°C, 30分钟）, 然后接受以下三种治疗方法之一：（a）病灶内GM‐CSF（500 mcg标准剂量）；（b）射频消融（RFA）+GM‐CSF；或（c）冷冻消融联合GM‐CSF。研究的主要终点是诱导内源性HSP70和黑色素瘤特异性细胞毒性T淋巴细胞（CTL）。
结果.入组了九名患者（每个研究组三名）。按照方案规定, 未观察到剂量限制性毒性。所有患者均发生了疾病进展, 并继续接受替代治疗。中位总生存期（OS）为8.2个月[95％置信区间（CI）2‐17.2]。该研究的把握度不足以检出治疗组间临床结局的差异。
结论.经皮热消融联合GM‐CSF具有良好的耐受性且在技术上可行, 其不良事件特征被证实可接受并且与常规RFA和冷冻消融相似。HSP70在治疗后被诱导, HSP70升高程度与临床结局或诱导的CTL应答无关。虽然在未来的研究中可以考虑联合使用经皮热消融与GM‐CSF（包括检查点抑制剂）, 但GM‐CSF的使用仍然是实验性的, 并且是在临床试验范围内使用。
Trial registration: ClinicalTrials.gov NCT01450163.
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