Hematology-Oncology and Head and Neck Cancer Program, and Radiation Oncology, University of Pittsburgh, Pittsburgh, PA, USA.
Clin Cancer Res. 2011 Sep 1;17(17):5755-64. doi: 10.1158/1078-0432.CCR-11-0861. Epub 2011 Jul 12.
A phase I clinical trial and molecular correlative studies were conducted to evaluate preclinical evidence for combinatorial activity of the proteasome inhibitor bortezomib, the epidermal growth factor receptor (EGFR) inhibitor cetuximab, and radiation therapy.
Patients with radiotherapy-naive stage IV or recurrent squamous cell carcinoma of the head and neck (SCCHN) were studied. Escalating doses of bortezomib (0.7, 1.0, and 1.3 mg/m²) were given intravenously twice weekly on days 1, 4, 8, and 11, every 21 days, with weekly cetuximab beginning 1 week prior and concurrently with intensity-modulated radiotherapy, delivered in 2 Gy fractions to 70 to 74 Gy. Molecular effects were examined in serial serum and SCCHN tumor specimens and the cell line UMSCC-1.
Seven patients were accrued before the study was terminated when five of six previously untreated patients with favorable prognosis oropharyngeal SCCHN progressed within 1 year (progression-free survival = 4.8 months; 95% CI, 2.6-6.9). Three patients each received bortezomib 0.7 or 1.0 mg/m², without dose-limiting toxicities; one patient treated at 1.3 mg/m² was taken off study due to recurring cetuximab infusion reaction and progressive disease (PD). Expected grade 3 toxicities included radiation mucositis (n = 4), dermatitis (n = 4), and rash (n = 1). SCCHN-related cytokines increased in serial serum specimens of patients developing PD (P = 0.029). Bortezomib antagonized cetuximab- and radiation-induced cytotoxicity, degradation of EGFR, and enhanced prosurvival signal pathway activation in SCCHN tumor biopsies and UMSCC-1.
Combining bortezomib with cetuximab and radiation therapy showed unexpected early progression, evidence for EGFR stabilization, increased prosurvival signaling, and SCCHN cytokine expression, warranting avoidance of this combination.
进行了一项 I 期临床试验和分子相关性研究，以评估蛋白酶体抑制剂硼替佐米、表皮生长因子受体（EGFR）抑制剂西妥昔单抗和放射治疗联合应用的临床前证据。
研究对象为未经放疗的 IV 期或复发性头颈部鳞状细胞癌（SCCHN）患者。每周两次静脉注射硼替佐米（0.7、1.0 和 1.3mg/m²），于第 1、4、8 和 11 天给药，每 21 天一次，在开始前 1 周和调强放疗同时每周给予西妥昔单抗，70 至 74Gy 时以 2Gy 分次给予。在连续的血清和 SCCHN 肿瘤标本以及 UMSCC-1 细胞系中检测分子效应。
在研究因 6 例先前未经治疗的预后良好的口咽 SCCHN 患者在 1 年内进展（无进展生存期=4.8 个月；95%CI，2.6-6.9）而终止之前，共入组了 7 例患者。3 例患者分别接受了 0.7 或 1.0mg/m²的硼替佐米治疗，没有出现剂量限制毒性；1 例接受 1.3mg/m²治疗的患者因反复发生西妥昔单抗输注反应和疾病进展（PD）而退出研究。预期的 3 级毒性包括放射性黏膜炎（n=4）、皮炎（n=4）和皮疹（n=1）。在发生 PD 的患者的连续血清标本中，SCCHN 相关细胞因子增加（P=0.029）。硼替佐米拮抗了西妥昔单抗和放射诱导的细胞毒性、EGFR 降解以及增强了 SCCHN 肿瘤活检和 UMSCC-1 中的 prosurvival 信号通路激活。
硼替佐米联合西妥昔单抗和放射治疗显示出出乎意料的早期进展，EGFR 稳定的证据，增加了 prosurvival 信号，以及 SCCHN 细胞因子表达，这表明应避免这种联合治疗。
