In vivo and in vitro antitumor activity of oxaliplatin in combination with cetuximab in human colorectal tumor cell lines expressing different level of EGFR

This study aimed to assess the effect of cetuximab (C225, Erbitux, a chimeric anti-epidermal growth factor receptor (EGFR) monoclonal antibody) in combination with oxaliplatin in vitro and in vivo on four colon cancer cell lines (HCT-8; HT-29, SW620, HCT-116) expressing different levels of EGFR. In vitro, cetuximab combined with oxaliplatin significantly decreased the IC50 values of oxaliplatin in HCT-8 (EGF-R moderate) and HT-29 (EGF-R weak) cell lines, while SW620 (EGF-R negative) and HCT-116 (EGFR strong) cell lines remained unresponsive. This combination was synergistic in HCT-8 and HT-29 cell lines while cetuximab induced no major modification of the IC50 of oxaliplatin in HCT-116 or SW620 cell lines. We then determined the effect of cetuximab on the EGF-induced EGFR phosphorylation and we highlight a correlation between the basal level of phospho-EGFR and the response to the combination. In vivo, the combination of cetuximab plus oxaliplatin significantly inhibited tumor growth of HCT-8 and HT-29 (tumor delay or Td = 21.6+/-2.9 and 18.0+/-2.9 days respectively, synergistic effect) compared to either oxaliplatin (Td=12.6+/-2.3 and 14.4+/-3.2 days respectively) or cetuximab (Td=13.4+/-2.9 and 14.5+/-2.4 days, respectively) alone in xenograft models. The combination had no effect on HCT-116 and SW-620 cell lines. The observed responses are strictly dependent on the cell type, and are not correlated with the level of EGFR expression but related to the basal level of phospho-EGFR. This study provides promising preclinical results for a possible clinical investigation of the combination of oxaliplatin plus cetuximab in chemorefractory colorectal tumors.     

Phase I trial of cetuximab in combination with capecitabine, weekly irinotecan, and radiotherapy as neoadjuvant therapy for rectal cancer

PURPOSE: To establish the feasibility and efficacy of chemotherapy with capecitabine, weekly irinotecan, cetuximab, and pelvic radiotherapy for patients with locally advanced rectal cancer. METHODS AND MATERIALS: Twenty patients with rectal cancer (clinical Stage uT3-T4 or N+) received a standard dosing regimen of cetuximab (400 mg/m(2) on Day 1 and 250 mg/m(2) on Days 8, 15, 22, and 29) and escalating doses of irinotecan and capecitabine according to phase I methods: dose level I, irinotecan 40 mg/m(2) on Days 1, 8, 15, 22, and 29 and capecitabine 800 mg/m(2) on Days 1-38; dose level II, irinotecan 40 mg/m(2) and capecitabine 1000 mg/m(2); and dose level III, irinotecan 50 mg/m(2) and capecitabine 1000 mg/m(2). Radiotherapy was given to a dose of 50.4 Gy (45 Gy plus 5.4 Gy). Resection was scheduled 4-5 weeks after termination of chemoradiotherapy. RESULTS: On dose level I, no dose-limiting toxicities occurred; however, Grade 3 diarrhea affected 1 of 6 patients on dose level II. Of 5 patients treated at dose level III, 2 exhibited dose-limiting toxicity (diarrhea in 2 and nausea/vomiting in 1). Therefore, dose level II was determined as the recommended dose for future studies. A total of 10 patients were treated on dose level II and received a mean relative dose intensity of 100% of cetuximab, 94% of irinotecan, and 95% of capecitabine. All patients underwent surgery. Five patients had a pathologically complete remission and six had microfoci of residual tumor only. CONCLUSION: Preoperative chemoradiotherapy with cetuximab, capecitabine, and weekly irinotecan is feasible and well tolerated. The preliminary efficacy is very promising. Larger phase II trials are ongoing.     

原发性肝癌患者外周血KRAS基因水平及其对西妥昔单克隆抗体治疗疗效的影响

目的 观察应用表皮生长因子受体（EGFR）靶向药物西妥昔单克隆抗体（C225）治疗原发性肝癌（PLC）患者的临床疗效及其影响疗效的因素。方法 2014年8月~2017年8月我院收治的96例PLC患者,在吉西他滨和顺铂化疗的基础上给予C225治疗。采用PCR法检测外周血KRAS基因突变。采用Logistic单因素和多因素回归分析影响疗效的独立因素。结果 在治疗8 w末,在96例PLC患者中,PR 59例（61.5%）,SD 22例（22.9%）,PD 15例（15.6%）;在PR/SD组,血KRAS突变率为9.9%,显著低于PD组的40.0%（P<0.05）;PD组GGT-GAT、GGT-GTT和GGC-GAC突变率分别为13.3%、6.7%和6.7%,显著高于PR/SD组的0.0%、0.0%和0.0%（P<0.05）;多因素Logistic回归分析显示,除肝功能Child分级和肿瘤类型外,PKRAS基因突变亦为C225治疗PLC患者疗效的独立影响因素（P<0.05）。结论 EGFR靶向药物C225治疗晚期PLC患者有一定的疗效,检测血KRAS基因突变对选择患者和判断疗效可能有帮助。     

Patterns of Use and Tolerance of Anti–Epidermal Growth Factor Receptor Antibodies in Older Adults With Metastatic Colorectal Cancer

BackgroundLimited data are available regarding the tolerance of anti–epidermal growth factor receptor (EGFR) antibodies among elderly patients with metastatic colorectal cancer (mCRC). We retrospectively reviewed our experience of treating elderly patients with mCRC with these agents between 2004 and 2011.MethodsPatients with mCRC ≥ 65 years treated with anti-EGFR agents were included in this analysis. We recorded demographic and disease characteristics, treatment regimen and duration, KRAS status, and overall survival (OS). Toxicity evaluation included common hematologic and nonhematologic toxicities seen with these agents.ResultsOne hundred seventeen patients were included, with a median age at treatment initiation of 73 years (range, 65-86 years), 59% of male sex, 82% with colon primary tumors, and 51% with metastatic disease at presentation. Median time on anti-EGFR treatment was 2.4 months. Older age at treatment initiation was associated with use of anti-EGFR antibody as monotherapy versus combination therapy (P = .0009). Worse performance status (PS) at treatment initiation was associated with a shorter overall survival (OS) (P = .013) and shorter treatment duration (P = .01). The incidence of hematologic/nonhematologic grade ≥ 3 was 36% and 15%, respectively. No association was found between age and presence of grade ≥ 3 toxicity. Longer treatment duration and better PS at treatment initiation were the only factors associated with higher incidence of grade 3 toxicity.ConclusionOur data demonstrate that anti-EGFR antibodies can be used in older patients with mCRC, with toxicity profiles similar to those reported in large phase III studies of younger patients. Advanced age was associated with receipt of anti-EGFR agents as monotherapy but did not impact treatment outcomes in this population.     

Pulsed High-Intensity Focused Ultrasound Therapy Enhances Targeted Delivery of Cetuximab to Colon Cancer Xenograft Model in Mice

Our aim was to evaluate whether pulsed high-intensity focused ultrasound (HIFU) therapy enhances the effect of an epidermal growth factor receptor–targeted chemotherapeutic drug, cetuximab, in treating human colon cancer xenografts in a mouse model. Balb/c nude mice with subcutaneous xenografts of HT-29 cells were randomly categorized into control (n = 9), pulsed HIFU alone (n = 10), cetuximab monotherapy (n = 8) or combined pulsed HIFU and cetuximab therapy (n = 9) group. Cetuximab, pulsed HIFU therapy, or both were administered three times per week starting from day 8 after tumor cell injection. Based on tumor growth curves up to 34 days, the combination therapy group showed more suppressed tumor growth than all other groups (p < 0.05). The final relative tumor volumes were 5.4 ± 2.1, 5.2 ± 1.3, 4.8 ± 1.8, and 3.1 ± 0.9 for control, pulsed HIFU alone, cetuximab monotherapy, and combination therapy groups, respectively. In conclusion, pulsed HIFU therapy appears to enhance the anti-tumor effect of epidermal growth factor receptor–targeted cetuximab on human colon cancer xenograft models in mice.     

靶向治疗晚期结直肠癌新进展

结直肠癌是消化道常见的恶性肿瘤之一,其治疗方法主要以手术切除为主,辅助进行化疗和放疗,但是这些治疗方法都不能达到满意的疗效。近年来分子靶向治疗逐渐成为研究热点。有关表皮生长因子受体和血管内皮因子受体等与结直肠癌的发生、发展和转移的关系及其信号传导机制的研究也有了很大进展。因此,分子靶向药物导向治疗有望成为治疗结直肠癌的有效手段。