Overexpression of epidermal growth factor type-1 receptor (EGF-R1) in cervical cancer: implications for Cetuximab-mediated therapy in recurrent/metastatic disease

OBJECTIVES: To evaluate and compare epidermal growth factor type-1 receptor (EGF-R1) expression in short term and established cervical cancer cell lines generated from primary and metastatic/recurrent sites of disease. To evaluate the sensitivity of cervical cancer cell lines to treatment with a chimeric MAb against EGFR-1 (Cetuximab). METHODS: EGFR-1 expression was evaluated by flow cytometry on 22 cervical cancer cell lines including 14 primary cervical cancer cell lines obtained from cervical biopsies (11 patients) and recurrent sites of disease (three patients) as well as eight established cell lines. Tumor cell lines were tested for sensitivity to Cetuximab-mediated complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) in 51Cr release assays. Finally, Cetuximab-mediated inhibition of cell proliferation was also tested. RESULTS: Fourteen out of fourteen (100%) primary tumors and seven out of eight (87.5%) established cervical cancer cell lines expressed EGFR-1 by flow cytometry. Cell lines from recurrent/metastatic sites of disease expressed higher levels of EGFR-1 when compared to those obtained from primary sites (p>0.05). Minimal CDC was detected in the majority of cervical cancer cell lines exposed to complement+/-Cetuximab in the absence of peripheral blood lymphocytes (PBL). In contrast, cervical tumor cell lines were found highly sensitive to Cetuximab-mediated ADCC when challenged with PBL from either healthy donors or cervical cancer patients. Importantly, ADCC was further increased in the presence of complement. Finally, tumor proliferation was significantly inhibited by Cetuximab in all cervical tumors tested. CONCLUSIONS: EGFR-1 is highly expressed in primary and recurrent cervical tumors. Cetuximab might be a novel and attractive therapeutic strategy in patients harboring chemotherapy-resistant, recurrent, or metastatic cervical cancer.     

Targeted therapy in advanced colorectal cancer, an update

The introduction of inhibitors of signal transduction pathways has increased the therapeutic arsenal for patients with advanced colorectal cancer (ACC). Bevacizumab, a monoclonal vascular endothelial growth factor antibody, is currently part of the standard first-line treatment in combination with fluoropyrimidine-based chemotherapy. Cetuximab, a chimeric monoclonal antibody against the epidermal growth factor receptor, has shown efficacy in irinotecan-refractory ACC patients. Several experimental targeted agents, including small molecules that inhibit receptor tyrosine kinase activity, are currently being tested. We review the mechanism of action as well as the current status of targeted therapy in ACC.     

Combining targeted therapies

Therapeutics in oncology are rapidly changing, with the advent of the so-called “targeted drugs.” A clear example is trastuzumab, an anti-HER2 monoclonal antibody, and its role in the treatment of breast cancer. Trastuzumab was followed by other monoclonal antibodies like cetuximab (anti-EGFR) and bevacizumab (anti-VEFG) and by tyrosine kinase inhibitors such as imatinib, gefitinib (anti-EGFR) and others. The complex biology of the cancer cell leads us to search combination strategies to act simultaneously in different points of signals transduction pathways to enhance the anticancer effect. Here we review various clinical trials and also experimental data exploring these new drugs in combination. Combination with chemotherapy is beyond the scope of this review. For this review, we have selected the following agents: cetuximab, trastuzumab, bevacizumab, panitumumab, imatinib, erlotinib, gefitinib, sorafenib, sunitinib, and lapatinib.     

西妥昔单抗联合化疗治疗消化系统肿瘤的临床研究

目的观察西妥昔单抗联合化疗治疗消化系统肿瘤的疗效及不良反应。方法回顾性分析17例接受西妥昔单抗联合化疗治疗的消化系统肿瘤患者的资料,对其进行疗效评价及安全性分析。合并的化疗方案主要有以奥沙利铂或伊立替康为主的联合化疗以及伊立替康单药化疗。结果全组可评价疗效者13例,有效率（RR）为46.2%,疾病控制率（DCR）为76.9%,中位疾病进展时间（TTP）4.0个月。一线治疗6例,RR为66.7%,DCR为83.3%,中位TTP 4.8个月。13例有8例为结直肠癌,RR为50%,DCR为87.5%,中位TTP 5.0个月,其中一线治疗3例全部获得PR。痤疮样皮疹发生率为52.9%,但未显示出皮疹与有效率的相关性。结论西妥昔单抗联合化疗治疗消化系统肿瘤安全有效,尤其一线治疗效果更佳,值得进一步扩大样本研究。     

西妥昔单抗急性输液反应的临床对策

目的：本研究分析临床应用西妥昔单抗中急性输液反应的临床表现和处理经验，探讨预防和治疗的方法。方法：分析24例晚期胃癌和结直肠癌化疗联合西妥昔单抗治疗中急性输液反应的临床表现和处理方法。结果：在24例晚期胃癌和结直肠癌的治疗中，4例出现Ⅰ～Ⅱ度的急性输液反应，发生率为16．7％。均出现在首次输注后5～10min，表现为寒战、胸部紧迫感，约0．5h后出现低热，均为37～38．5℃，持续1～2h后自行缓解。待症状缓解后减慢输注速度，在严密监测下继续应用西妥昔单抗，4例均未再出现输液反应。结论：西妥昔单抗出现Ⅰ～Ⅱ度输液反应后不需停药，减慢输注速度和在严密监测生命体征下可继续应用西妥昔单抗治疗并可有效地预防急性输液反应再次出现，但出现Ⅲ或Ⅳ度输液反应的患者将终生停止应用西妥昔单抗治疗。     

A phase 1/2 of a combination of Cetuximab and Taxane for “triple negative” breast cancer patients

50–70% of tumors of the so called “triple negative” subtype of breast cancer express EGFR. We hypothesized that addition of anti EGFR to Taxanes will result in increased effectiveness in EGFR expressing tumors. Here we set out to obtain data regarding the safety, tolerability and also the effectivity of the combination of weekly Taxane treatments with Cetuximab -an anti EGFR antibody in this subgroup of breast cancer. 18 triple negative breast cancer patients were treated with weekly Cetuximab and Taxane therapy. Addition of Cetuximab resulted in controllable Dermatologic toxicity in most patients –with grade 3 in two patients. Some impressive results were noted including one CR, one near CR and regression of chemotherapy and radiation resistance skin metastasis. Median TTF -and overall survival −6 and 12 months. Administration of Taxane Cetuximab weekly therapy for triple negative breast cancer patients is feasible. Use of anti EGFR-Taxane combinations should be assessed in larger clinical trials in this patient population perhaps in a similar manner to the lung cancer patients only in those with strong EGFR expression.     

Role of chemotherapy and novel biological agents in the treatment of elderly patients with colorectal cancer

Patients older than 65 years are the fastest growing segment of the cancer population. It is estimated that within 20 years over 75% of cases and 85% of deaths from colorectal cancer （CRC） will be in this setting. Concerns about cancer treatment in the elderly relate to comorbidities, which increase proportionally with age, physiological changes associated with aging which may influence drug metabolism and toxicity, and diminishing life expectancy, which particularly impacts decisions surrounding the benefits of adjuvant therapies. Over the last 10 years, significant improvements in the treatment of advanced CRC with combination therapy have been made. The randomized trials which have defined these improvements did not exclude elderly patients. However, the median age of patients in these trials has generally been approximately 60 years. Thus, it appears that some degree of selection is involved with younger and presumably fitter patients being the subjects in most of the pivotal trials. The availability of new molecularly targeted agents and newly improved existing agents has expanded the range of treatment options available. This variety gives greater flexibility in dealing with different subsets of patients, such as the elderly. However, some fit elderly patients seem to tolerate combination therapy reasonably well, while studies on unfit elderly subjects are needed.     

Feasibility of cetuximab and chemoradiotherapy combination in Chinese patients with unresectable stage Ⅲ non-small cell lung cancer:a preliminary report

Objective:In recent years,the combination of cetuximab and chemoradiotherapy（CRT） has been used to treat stage III non-small cell lung cancer（NSCLC）;however,limited data are available for Chinese patients.Herein,we report preliminary data from a phase Ⅰ/Ⅱ study testing the combination of cetuximab with inductive chemotherapy,followed by concurrent CRT（CCRT） in Chinese patients with stage HI NSCLC.Methods:Eligibility criteria were Zubrod performance status（PS） 0-1,forced expiratory volume in 1 second（FEVl） >1.2 L and adequate organ function.Enrolled patients received weekly cetuximab（initial dose of400 mg/m² on day 1 of week 1 and a maintenance dose of 250 mg/m² on week 2 to the end of CCRT） with cisplatin/vinorelbine（NP） chemotherapy(every 3 weeks for 2 cycles from week 2,followed by two cycles of concomitant NP chemotherapy and intensity-modulated thoracic radiotherapy（TRT）（60-66 Gy/2 Gy）.The primary endpoints were toxicity and feasibility.All patients received positron emission tomographycomputerized tomography（PET-CT） scans within the 2 weeks prior to enrollment.Univariate analyses were used to assess the correlation between SUV-T,SUV-N,SUV-TOTAL,gender,age,histology,tumor-nodemetastasis（TNM） stage,PS and smoking status and survival.Survival curves were generated for different populations using the Kaplan-Meier method and compared using a log-rank test.Results:Seventeen patients were enrolled and 16 completed the full regime.The overall response rate（ORR）was 58.8%and 82.3%after the induction and CCRT phases,respectively.With a median follow-up duration of 27.6 months,the median survival was 27.6 months[95%confidence interval（CI）:11.3-43.9 months]with 1-and 2-year survival rates of 88.2%（95%CI,60.6-96.9%） and 58.8%（95%CI,60.6-77.8%）,respectively.Three patients remain progression-free to date,and the median progression-free survival（PFS） was 13.5 months（95%CI,6.8-20.2 months）.No treatment-related death occurred;however,76%of the patients experienced grade3+ adverse events（AEs）,including nausea/vomiting,intestinal obstruction,and esophagitis（<6%）,while other AEs were mostly of hematological nature（71%）.The cut-off values for SUV-T and SUV-TOTAL were 11 and20,respectively.Univariate analyses revealed SUV-TOTAL（P=0.027）,SUV-T（P=0.025）,and PS（P=0.006） as potential survival predictors,with a hazard ratio（HR） of 3.4,3.7,and 9.9,respectively.Conclusions:The combination of cetuximab with induction chemotherapy followed by CCRT appears feasible and promising.Local and locoregional maximal SUVs,defined by ¹⁸F-FDG PET-CT scanning,may represent a prognostic indicator for long-term survival for these patients,which warrants further study.     

西妥昔单抗联合放疗在恶性肿瘤治疗中的研究进展

放疗是治疗恶性肿瘤的重要方法,但对中、晚期恶性肿瘤的疗效仍然较差。因此,寻找新的方法联合治疗以增加放疗效果、降低治疗不良反应势在必行。研究显示,分子靶向药物与放疗联合应用于恶性肿瘤的治疗可增加一些肿瘤细胞的放射敏感性,提高放疗疗效。西妥昔单抗是目前临床上应用最广泛的抗表皮生长因子受体（EGFR）药物之一,也是对联合放疗研究较多的靶向治疗药物之一。笔者拟就西妥昔单抗联合放疗的理论机制及其在恶性肿瘤治疗上的应用,进行综述。