British Columbia Cancer Agency, Vancouver, BC, Canada.
Invest New Drugs. 2011 Aug;29(4):680-7. doi: 10.1007/s10637-010-9396-4. Epub 2010 Feb 12.
Cetuximab is a chimeric monoclonal antibody targeting the epidermal growth factor receptor (EGFR). The recommended dosage is an initial load of 400 mg/m² intravenously (IV) followed by a weekly maintenance dose of 250 mg/m². It has been reported retrospectively that cetuximab efficacy was correlated with dose-related severity of skin rash. This study was prospectively designed to examine the safety and feasibility of escalating weekly doses of cetuximab, testing the hypothesis of the relationship of dose-dependent skin toxicity and efficacy. Methods Four dose levels were tested: Cetuximab 400 mg/m² IV loading dose and 250, 300, 350, 400 mg/m² weekly IV maintenance. There was no intra-patient dose escalation. Standard dose limiting toxicity criteria were used. Rash was evaluated using two additional validated dermatology methods: global acne grading scale (GAGS) and acne lesion counting (ALC). Tumor specimens and blood samples were obtained for correlative analyses.
Twenty seven patients with solid tumors were enrolled: five head and neck, three pancreas, four gall bladder, two each of prostate, breast, colorectal, lung, and esophagus, and five others. Planned dose escalation was completed without reaching dose-limiting toxicity (DLT) or the maximum tolerated dose (MTD). The highest dose level was expanded to a total of 17 patients. Gr 3/4 toxicities included: lymphopenia (2), fatigue (2), and hypomagnesemia (2). One patient experienced a grade 3 rash (350 mg/m²). Sixty five percent of pts had a ≥ Gr 2 rash that was not dose dependent. In 22 evaluable patients, there was one partial response (PR) in a patient with cholangiocarcinoma (400 mg/m²) and seven patients had stable disease (SD). ALC and GAGS demonstrated no correlation with dose or response. Correlative studies evaluating k-ras, EGFR FISH status and immunologic correlatives were conducted on available tumor samples.
Cetuximab administered at 400 mg/m² IV as a loading dose with weekly maintenance dose of 400 mg/m² is feasible and well tolerated. There was no direct correlation of the grade of rash with dose in this group of patients with heterogenous solid tumors.
西妥昔单抗是一种针对表皮生长因子受体（EGFR）的嵌合单克隆抗体。推荐剂量为初始负荷剂量 400mg/m² 静脉注射（IV），随后每周维持剂量 250mg/m²。据回顾性报道，西妥昔单抗的疗效与皮疹的严重程度呈剂量相关。本研究前瞻性设计旨在检查西妥昔单抗每周剂量递增的安全性和可行性，检验剂量依赖性皮肤毒性与疗效的相关性假设。
共测试了 4 个剂量水平：西妥昔单抗 400mg/m² IV 负荷剂量和 250、300、350、400mg/m² 每周 IV 维持剂量。无患者内剂量递增。使用标准剂量限制毒性标准。皮疹采用两种额外验证的皮肤病学方法进行评估：全球痤疮分级量表（GAGS）和痤疮病变计数（ALC）。采集肿瘤标本和血液样本进行相关分析。
共纳入 27 例实体瘤患者：5 例头颈部、3 例胰腺、4 例胆囊、2 例前列腺、2 例乳腺、2 例结直肠、2 例肺和 5 例其他部位。计划的剂量递增完成，未达到剂量限制毒性（DLT）或最大耐受剂量（MTD）。最高剂量水平扩展至共 17 例患者。3/4 级毒性包括：淋巴细胞减少症（2）、疲劳（2）和低镁血症（2）。1 例患者出现 3 级皮疹（350mg/m²）。65%的患者出现≥2 级皮疹，但与剂量无关。在 22 例可评估患者中，1 例胆管癌患者（400mg/m²）有部分缓解（PR），7 例患者有稳定疾病（SD）。ALC 和 GAGS 与剂量或反应无相关性。对可获得的肿瘤样本进行了相关研究，评估了 k-ras、EGFR FISH 状态和免疫相关性。
西妥昔单抗 400mg/m² IV 负荷剂量联合每周 400mg/m² 维持剂量是可行且耐受良好的。在这组异质性实体瘤患者中，皮疹的严重程度与剂量之间没有直接的相关性。
