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Cetuximab (Erbitux)

Web Resources: Cetuximab (Erbitux)
Latest Research Publications

Web Resources: Cetuximab (Erbitux) (6 links)


Latest Research Publications

Wichmann G, Cedra S, Schlegel D, et al.
Cilengitide and Cetuximab Reduce Cytokine Production and Colony Formation of Head and Neck Squamous Cell Carcinoma Cells Ex Vivo.
Anticancer Res. 2017; 37(2):521-527 [PubMed] Related Publications
BACKGROUND/AIM: To analyze ex vivo effects of combined targeting of the epidermal growth factor-receptor (EGFR) by cetuximab (E) plus αVβ3 and αVβ5 integrins by cilengitide (Cil) on colony formation of epithelial cells (CFec) and release of pro-angiogenetic and pro-inflammatory cytokines in head and neck squamous cell carcinoma (HNSCC) cells.
MATERIALS AND METHODS: Collagenase-IV digests of 43 histopathological confirmed HNSCC cases were seeded into laminin-coated 96-well plates containing E, Cil, or Cil+E in final concentrations of 66.7 μg/ml, 10 μM, and 10 μM+66.7 μg/ml, respectively. Following the FLAVINO-assay protocol, supernatants were harvested after 3 days and adherent cells fixed in ethanol. Counting of CFec was facilitated by FITC-labeled pan-cytokeratin antibodies. Out of 43 HNSCC cases, 39 had adherent growth (mean CFec≥4/well in triplicate controls). Cytokines in supernatants were measured using ELISA were interleukin 6 (IL-6), monocyte chemoattractant protein 1 (MCP-1) and vascular endothelial growth factor A (VEGFA).
RESULTS: CFec on laminin was significantly reduced by Cil, E, and Cil+E. Cytokine measurements also revealed significant suppression of MCP-1, IL-6 and VEGFA. The strongest suppression of CFec, MCP-1 and VEGFA release was exerted by Cil and E combined. Efficacy of Cil+E exceeded those of the solely applied pharmaceutics but failed regarding significant synergism of both treatments as E was unable to significantly boost the effects of Cil. In contrast, IL-6 release was significantly suppressed by E but not by Cil, while their combination strongly reduced it.
CONCLUSION: Combined targeting of EGFR and integrins with E and Cil heightens their suppressive effects regarding CFec as well as release of pro-angiogenetic and pro-inflammatory cytokines.

Tang XM, Chen H, Liu Y, et al.
The cardiotoxicity of cetuximab as single therapy in Chinese chemotherapy-refractory metastatic colorectal cancer patients.
Medicine (Baltimore). 2017; 96(3):e5946 [PubMed] Free Access to Full Article Related Publications
The cardiac safety of cetuximab, particularly as single approach, has not been investigated extensively. This trial was designed to evaluate the cardiac safety of cetuximab as salvage monotherapy in Chinese chemotherapy-refractory metastatic colorectal cancer (mCRC) patients.Cetuximab was administrated at an initial dose of 400 mg/mon day 1 (week 1), followed by a maintenance dose of 250 mg/m on day 1 of each 7-day cycle. Electrocardiograph (ECG), routine laboratory tests, and troponin I (TNI) Ultra were performed at baseline, during, and after the cetuximab therapy. The incidence of abnormal ECGs, elevated TNI Ultra, cardiac events, and noncardiac events were recorded and analyzed.TNI Ultra+ was found in 20 patients (32.3%) during the cetuximab therapy.TNI Ultra+ occurred more frequently in patients with more than 3 organs affected and accepted fourth or above lines of chemotherapy. The most frequent abnormal ECG was ST depression in 24 (38.7%) patients. The elevated TNI Ultra and abnormal ECGs could recover after the cetuximab therapy. The most of cardiac adverse events were mild and transient and the noncardiac adverse events were also consistent with the known safety profile for cetuximab.Cetuximab showed its cardiac safety as a single agent for chemotherapy-refractory mCRC patients. And TNI Ultra and ECG could be sensitive and convenient approaches for the surveillance of adverse events.

Bai L, Wang F, Li ZZ, et al.
Chemotherapy plus bevacizumab versus chemotherapy plus cetuximab as first-line treatment for patients with metastatic colorectal cancer: Results of a registry-based cohort analysis.
Medicine (Baltimore). 2016; 95(51):e4531 [PubMed] Free Access to Full Article Related Publications
The present observational cohort study was designed to elucidate the efficacy and safety profile of bevacizumab or cetuximab with chemotherapy as the first-line treatment in Chinese patients with metastatic colorectal cancer (mCRC). Clinical data were collected from a single-center registry study where mCRC patients received first-line fluoropyrimidine-based chemotherapy combined with either bevacizumab (188 patients with KRAS wild-type or mutated tumors) or cetuximab (101 patients with KRAS wild-type tumors) between January 2009 and December 2013. The Kaplan-Meier method was used for survival analysis. Cox proportional hazards model was used for estimating the prognostic and predictive values of clinicopathological characteristics. No statistically significant difference was observed between the bevacizumab and cetuximab groups in terms of median progression-free survival (PFS) (10.6 vs 8.7 months, P = 0.317), median overall survival (OS) (27.7 vs 28.3 months, P = 0.525), or overall response rate (43.1% vs 53.5%, P = 0.108). For the subset of patients with peritoneal dissemination, bevacizumab-based triplet appears to be superior to cetuximab-based triplet as measured by PFS (9.6 vs 6.1 months) and OS (26.3 vs 12.7 months), but not for patients without peritoneal dissemination (PFS, 10.6 vs 9.1 months; OS, 27.9 vs 30.7 months) (all unadjusted and adjusted interaction P < 0.05). Our study suggests that bevacizumab- or cetuximab-based regimens have similar effectiveness as first-line treatment of mCRC in Chinese population. Patients with peritoneal dissemination were likely to gain more benefit from bevacizumab than cetuximab treatment. Future prospective studies are required to further confirm these results.

Koizumi M, Takahashi M, Murata M, et al.
Thrombotic microangiopathy associated with cetuximab, an epidermal growth factor receptor inhibitor
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Clin Nephrol. 2017; 87 (2017)(1):51-54 [PubMed] Related Publications
Cetuximab is a chimeric human-murine monoclonal antibody that binds competitively and with high affinity to the epidermal growth factor receptor (EGFR) and is used to treat advanced squamous cell carcinoma of the head and neck. After receiving a total of six doses of cetuximab, a 72-year-old male presented with pretibial edema, acne-like skin rash, and nephrotic syndrome. The renal biopsy findings revealed features of thrombotic microangiopathy (TMA), with the expansion of the subendothelial zone, reduplication of the glomerular basement, and swelling of the endothelial cells. Nine weeks after the discontinuation of cetuximab, his pretibial edema had disappeared and proteinuria decreased. To our knowledge, this is the first report in which kidney biopsy revealed evidence of TMA due to cetuximab administration. Our report suggests that it may be prudent to monitor patients receiving cetuximab closely for the possible development of nephrotic syndrome.
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Chun SG, Hughes R, Sumer BD, et al.
A Phase I/II Study of Nab-Paclitaxel, Cisplatin, and Cetuximab With Concurrent Radiation Therapy for Locally Advanced Squamous Cell Cancer of the Head and Neck.
Cancer Invest. 2017; 35(1):23-31 [PubMed] Related Publications
Nab-paclitaxel might impact efficacy of radiation for head and neck (H&N) cancer. Nab-paclitaxel, cisplatin, cetuximab, and radiation were evaluated in patients with locally advanced head and neck cancer in this phase I/II trial. Median follow-up was 24 months for 34 patients. The maximum tolerated dose of nab-paclitaxel was 20 mg/m(2) with 20 mg/m(2) cisplatin and 250 mg/m(2) cetuximab. The 2-year progression-free survival (PFS) was 60% (95% confidence interval (CI) 0.42, 0.78), local control 71% (95% CI 0.55, 0.87), and overall survival 68% (95% CI 0.50, 0.86). This is the first study evaluating these agents with radiation in humans, with similar 2-year PFS as historic control.

Azadi S, Tafazzoli-Shadpour M, Omidvar R, et al.
Epidermal growth factor receptor targeting alters gene expression and restores the adhesion function of cancerous cells as measured by single cell force spectroscopy.
Mol Cell Biochem. 2016; 423(1-2):129-139 [PubMed] Related Publications
Loss of cell-cell adhesion function is a common characteristic of many human epithelial carcinomas that is frequently due to loss of E-cadherin expression. In cancer progression, loss of E-cadherin is associated with invasion and metastasis potential, hence restoration of its function may contribute to the metastasis inhibition. This study examined effect of Epidermal Growth Factor Receptor (EGFR/Her1) blockade on the E-cadherin expression, cellular adherence, and cell elasticity in two human epithelial cancer cell lines, MCF7 and A431. EGFR blocking agents as antibodies or small molecules target EGFR directly. Furthermore, due to intracellular signaling pathways they influence cell behavior and activities. The idea here is to investigate the effect of reduced activity of this signaling pathway using anti-EGFR Antibody (Cetuximab) and tyrosine kinase inhibitor (Lapatinib) on cell-cell adhesion and cell mechanical properties. Real-Time PCR analysis demonstrated that treatment of cells with considered drugs increased the expression of E-cadherin gene among samples. The atomic force microscopy-based single cell force spectroscopy technique was used to measure adhesive force of cancerous cells. Results indicated that inhibition of EGFR activity elevated cell-cell adhesion force, accompanied by stiffening of the cell bodies. In summary, Cetuximab and Lapatinib have been found to mediate cell-cell adhesion by restoration of E-cadherin expression and function. Our data suggest possible therapeutic potential for inhibition of metastasis via the blockade of EGFR signaling.

Caroline B, Sundus Y, Dawn D, et al.
Cost analysis of cetuximab (Erbitux) plus radiotherapy (ERT) versus concomitant cisplatin plus radiotherapy (CRT) within an NHS oncology unit (single institution): a pilot study.
Br J Radiol. 2016; 89(1068):20160105 [PubMed] Related Publications
OBJECTIVE: The aim of this feasibility study is to define the resource effectiveness of cetuximab vs cisplatin given concomitantly with radiotherapy for squamous cell carcinoma within a National Health Service clinical oncology unit.
METHODS: 20 patients with Stage 3 or 4 head and neck squamous cell cancers were randomized to receive either cetuximab with radiotherapy (ERT) or cisplatin with radiotherapy concurrent with external beam radiotherapy 70 Gy in 35 fractions on a 1 : 1 basis over a 12-month duration. The study compared the resource utilization of ERT vs cisplatin with radiotherapy taking into account drug costs, clinical management and the costs of managing treatment-related toxicity from first fraction of radiotherapy to 6 months after the completion of therapy. Outcome measures were quality of life (recorded at the entry, end of radiotherapy, 6 weeks post treatment and 6 months post treatment), admissions to hospital, delays to radiotherapy, locoregional control and survival.
RESULTS: Total drug costs including cost of nutritional supplements for patients treated with cetuximab were £7407.45 compared with £3959.07 for patients treated with cisplatin. Unscheduled admissions for toxicity management were significantly more common in the ERT arm. Healthcare personnel spent significantly more time delivering unscheduled outpatient care for patients receiving cisplatin than for those receiving cetuximab (p = 0.01). No significant difference in the quality of life was suggested at baseline, 6 weeks and 6 months. The mean time to removal of percutaneous gastrostomy (PEG) after completion of radiotherapy was 49.7 weeks in the cisplatin arm and 18.5 weeks in the cetuximab arm (p = 0.04). There was a statistically significant difference in patient-reported use of PEG between the cisplatin and cetuximab arms at 6 months following completion of treatment (p = 0.04). At 21 months, overall survival was 80% in the cisplatin arm vs 50% in the cetuximab (p = 0.332), with disease-free survival being 80% in the cisplatin arm vs 40% in the cetuximab (p = 0.097).
CONCLUSION: Cetuximab is still more expensive in simple drug cost terms than cisplatin when delivered with radiotherapy taking into account costs of drugs for toxicity management and nutritional supplements but other resource implications such as inpatient admission, time spent delivering unscheduled care and cost of additional investigations to manage toxicity for patients treated with cisplatin significantly reduce differential. The study suggested significant differences in patient-reported PEG use at 6 months and in time to PEG removal in favour of the cetuximab arm. Advances in knowledge: There is paucity of randomized data on cost analysis for cisplatin vs cetuximab radiotherapy; this trial informs on the cost analysis between the two approaches.

Yu P, Fan Y, Qu X, et al.
Cbl-b regulates the sensitivity of cetuximab through ubiquitin-proteasome system in human gastric cancer cells.
J BUON. 2016 Jul-Aug; 21(4):867-873 [PubMed] Related Publications
PURPOSE: Cetuximab is a monoclonal antibody against epidermal growth factor receptor (EGFR) and is approved for clinical use in combination with chemotherapy in patients affected by colorectal cancer (CRC), non small cell lung cancer (NSCLC), and head and neck cancer. Compared with these cancers, gastric cancer is relatively resistant to cetuximab and its regulatory mechanism is still unclear.
METHODS: In this study, we assessed whether the ubiquitin- proteasome pathway is involved in regulating cetuximab-induced cells apoptosis in MGC803 and BGC823 gastric cancer cell lines.
RESULTS: The casitas B lineage lymphoma-b (Cbl-b), a kind of E3 ubiquitin ligase, was involved in this process. Specific silenced Cbl-b expression increased the expression of EGFR.
CONCLUSIONS: Our findings lead to a better understanding of the mechanism of cetuximab action, and suggests that Cbl-b increases the sensitivity of cetuximab in gastric cancer cells.

Wu X, Huang J, Liu L, et al.
Cetuximab concurrent with IMRT versus cisplatin concurrent with IMRT in locally advanced nasopharyngeal carcinoma: A retrospective matched case-control study.
Medicine (Baltimore). 2016; 95(39):e4926 [PubMed] Free Access to Full Article Related Publications
To evaluate the treatment efficacies and toxicities of concurrent cetuximab-based bioradiotherapy (BRT) or cisplatin-based chemoradiotherapy (CRT) in locally advanced nasopharyngeal carcinoma. :Patients with previously untreated locally advanced nasopharyngeal carcinoma were matched into pairs, and enrolled into the study. All patients were given either BRT or CRT. Survival outcomes, toxicities, and prognostic factors were evaluated. :A total of 112 patients were enrolled. The 5-year overall survival was 79.3% and 79.5% in CRT and BRT arm, respectively (P = 0.797) and the 5-year DFS was 73.5% and 74.6%, respectively (P = 0.953). In toxicity analysis, CRT arm had more significant decrease in white blood cell, platelet, hemoglobin, and severe vomiting, while more severe skin reactions and mucositis were shown in BRT arm. :BRT was not less efficacious than traditional CRT. They lead to different aspects of toxicities. If patients cannot stand more severe toxicities caused by CRT, BRT could be an ideal alternative.

Rachar V, Czejka M, Kitzmueller M, et al.
Assessment of Pharmacokinetic Interaction Between Capecitabine and Cetuximab in Metastatic Colorectal Cancer Patients.
Anticancer Res. 2016; 36(9):4715-23 [PubMed] Related Publications
AIM: This study focuses on the plasma disposition and metabolic activation of capecitabine (CCB) when administered alone or when combined with cetuximab (CTX).
PATIENTS AND METHODS: Twenty-four chemo-naïve patients with KRAS wild-type colorectal cancer were randomized into two arms and received either CCB alone (1,000 mg/m(2) bid p.o.), followed by CCB plus CTX (loading dose (LD)=400 mg/m(2) followed by 250 mg/m(2) weekly i.v. maintenance dose) (Arm A; n=12 patients (patients)) or CCB plus CTX followed by CCB alone (Arm B; n=12 patients). Plasma samples were collected from the cubital vein and CCB, 5'-desoxy-5-fluorocytidine (5'-DFCR) and 5'-desoxy-5 fluorouridine (5'-DFUR) were quantified by a sensitive, selective reversed phase high-performance liquid chromatography (HPLC) assay. Non-compartment pharmacokinetic parameters have been calculated by Phoenix WinNonlin.
RESULTS: No clinically relevant impact of CTX on CCB pharmacokinetic parameters and metabolic conversion could be detected in both arms after statistical evaluation (ANOVA).
CONCLUSION: From the pharmacokinetic point of view, co-administration of CTX to CCB seems to be safe.

Holubec L, Polivka J, Safanda M, et al.
The Role of Cetuximab in the Induction of Anticancer Immune Response in Colorectal Cancer Treatment.
Anticancer Res. 2016; 36(9):4421-6 [PubMed] Related Publications
Monoclonal antibodies binding the epidermal growth factor receptor (EGFR), such as cetuximab or panitumumab, are widely used targeted therapeutics for the treatment of patients with colorectal cancer. The clinical significance of these drugs has so far been associated with combined chemotherapy or radiation. It has been shown that these treatment strategies have their clinical limitations and do not fully exploit the immunomodulatory effect of these drugs. In this review, we discuss the mechanisms of immunomodulation together with the anticancer immune response to the monoclonal antibodies targeted to the EGFR. The combination of anti-EGFR monoclonal antibodies with other immunotherapeutic treatment modalities certainly brings new opportunities for targeted therapy in patients with colorectal cancer.

Zhou J, Zhao R, Wen F, et al.
Economic evaluation study (CHEER-compliant): Cost-effectiveness analysis of RAS screening for treatment of metastatic colorectal cancer based on the CALGB 80405 trial.
Medicine (Baltimore). 2016; 95(27):e3762 [PubMed] Free Access to Full Article Related Publications
Cetuximab (Cetux)/Bevacizumab (Bev) treatments have shown considerably survival benefits for patients with metastatic colorectal cancer (mCRC) in the last decade. But they are costly. Currently, no data is available on the health economic implications of testing for extended RAS wild-type (wt) prior to Cetux/Bev treatments of patients with mCRC. This paper aimed to evaluate the cost-effectiveness of predictive testing for extended RAS-wt status in mCRC in the context of targeting the use of Cetux/Bev.Markov model 1 was conducted to provide evidence evaluating the cost-effectiveness of predictive testing for KRAS-wt or extended RAS-wt status based on treatments of chemotherapy plus Cetux/Bev. Markov model 2 assessed the cost-effectiveness of FOLFOX plus Cetux/Bev or FOLFIRI plus Cetux/Bev in extended RAS-wt population. Primary base case data were identified from the CALGB 80405 trial and the literatures. Costs were estimated from West China Hospital, Sichuan University, China. Survival benefits were reported in quality-adjusted life-years (QALYs). The incremental cost-effectiveness ratio (ICER) was calculated.In analysis 1, the cost per QALY was $88,394.09 for KRAS-Cetux, $80,797.82 for KRAS-Bev, $82,590.72 for RAS-Cetux, and $75,358.42 for RAS-Bev. The ICER for RAS-Cetux versus RAS-Bev was $420,700.50 per QALY gained. In analysis 2, the cost per QALY was $81,572.61, $80,856.50, $80,592.22, and $66,794.96 for FOLFOX-Cetux, FOLFOX-Bev, FOLFIRI-Cetux, and FOLFIRI-Bev, respectively. The analyses showed that the extended RAS-wt testing was less costly and more effective versus KRAS-wt testing before chemotherapy plus Cetux/Bev. Furthermore, FOLFIRI plus Bev was the most cost-effective strategy compared with others in extended RAS-wt population.It was economically favorable to identify patients with extended RAS-wt status. Furthermore, FOLFIRI plus Bev was the preferred strategy in extended RAS-wt patients.

Bibault JE, Morelle M, Perrier L, et al.
Toxicity and efficacy of cetuximab associated with several modalities of IMRT for locally advanced head and neck cancer.
Cancer Radiother. 2016; 20(5):357-61 [PubMed] Related Publications
PURPOSE: Intensity-modulated radiation therapy (IMRT) has shown its interest for head and neck cancer treatment. In parallel, cetuximab has demonstrated its superiority against exclusive radiotherapy. The objective of this study was to assess the acute toxicity, local control and overall survival of cetuximab associated with different IMRT modalities compared to platinum-based chemotherapy and IMRT in the ARTORL study (NCT02024035).
PATIENTS AND METHOD: This prospective, multicenter study included patients with epidermoid or undifferentiated nasopharyngeal carcinoma, epidermoid carcinoma of oropharynx and oral cavity (T1-T4, M0, N0-N3). Acute toxicity, local control and overall survival were compared between groups (patients receiving cetuximab or not). Propensity score analysis at the ratio 1:1 was undertaken in an effort to adjust for potential bias between groups due to non-randomization.
RESULTS: From the 180 patients included in the ARTORL study, 29 patients receiving cetuximab and 29 patients treated without cetuximab were matched for the analysis. Ten patients (34.5%) reported acute dermal toxicity of grade 3 in the cetuximab group versus three (10.3%) in the non-cetuximab group obtained after matching (P=0.0275). Cetuximab was not significantly associated with more grade 3 mucositis (P=0.2563). There were no significant differences in cutaneous or oral toxicity for patients treated with cetuximab between the different IMRT modalities (P=1.000 and P=0.5731, respectively). There was no significant difference in local relapse-free survival (P=0.0920) or overall survival (P=0.4575) between patients treated with or without cetuximab.
CONCLUSION: Patients treated with cetuximab had more cutaneous toxicities, but oral toxicity was similar between groups. The different IMRT modalities did not induce different toxicity profiles.

Nishimura G, Taguchi T, Takahashi M, et al.
Phase II trial of concurrent bio-chemoradiotherapy using docetaxel, cisplatin, and cetuximab for locally advanced head and neck squamous cell carcinoma.
Cancer Chemother Pharmacol. 2016; 77(6):1315-9 [PubMed] Related Publications
PURPOSE: Although locally advanced head and neck squamous cell carcinoma (HNSCC) can be effectively treated using chemoradiotherapy (CRT) with docetaxel (DTX), and cisplatin (CDDP) plus 5-fluorouracil (TPF-CRT), severe adverse events (especially neutropenia) can limit treatment adherence. Therefore, we evaluated the safety and efficacy of a new chemotherapy regimen that consisted of DTX and CDDP plus cetuximab (Cmab) with concurrent radiotherapy.
METHODS: Bio-chemoradiotherapy (B-CRT) using DTX, CDDP, and Cmab was administrated to patients with locally advanced HNSCC, and its safety and efficacy were evaluated.
RESULTS: Interim analysis of nine patients revealed severe neutropenia in five patients (56 %) and leukopenia in seven patients (78 %); hence, the study was terminated. One patient experienced disease-free survival using only B-CRT.
CONCLUSIONS: Neutropenia was equally severe for B-CRT, compared to TPF-CRT. Based on the limited sample size, it is impossible to conclude that B-CRT has non-inferior efficacy, compared to TPF-CRT.

Wang L, Ding Y, Wei L, et al.
Recurrent Olfactory Neuroblastoma Treated With Cetuximab and Sunitinib: A Case Report.
Medicine (Baltimore). 2016; 95(18):e3536 [PubMed] Free Access to Full Article Related Publications
Olfactory neuroblastoma (ONB) is a rare cancer originating in the olfactory epithelium of the nasal vault. The recurrence rate of ONB is high, as the standard treatment of surgery followed by radiotherapy and/or chemotherapy is usually unsuccessful. The use of targeted therapy based on individual genomic variations after cancer relapse has not been reported. Here, we present the case of a 44-year-old man who was diagnosed with recurrent ONB and treated with a regimen developed using whole exome sequencing. Potential targets were first identified and then matched to appropriate drugs. Gene mutations in the genes encoding EGFR, FGFR2, KDR, and RET were discovered in the patient's tumor tissue by whole exome sequencing and the patient was treated with a combination of the targeted drugs cetuximab and sunitinib. Five days after treatment, enhancement magnetic resonance imaging showed a 65% reduction in tumor size, and the Visual analog scale headache scores went down to 2/10 from 10/10. Repeat imaging at 1 month showed a complete response.This study represents the first demonstration of an effective personalized treatment of ONB by targeted drugs, and sheds light on how precision medicine can be used to treat recurrent ONB that fails to respond to routine tumor resection, radiotherapy, and/or chemotherapy.

Janmaat VT, Bruno MJ, Polinder S, et al.
Cost-Effectiveness of Cetuximab for Advanced Esophageal Squamous Cell Carcinoma.
PLoS One. 2016; 11(4):e0153943 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Costly biologicals in palliative oncology are emerging at a rapid pace. For example, in patients with advanced esophageal squamous cell carcinoma addition of cetuximab to a palliative chemotherapy regimen appears to improve survival. However, it simultaneously results in higher costs. We aimed to determine the incremental cost-effectiveness ratio of adding cetuximab to first-line chemotherapeutic treatment of patients with advanced esophageal squamous cell carcinoma, based on data from a randomized controlled phase II trial.
METHODS: A cost effectiveness analysis model was applied based on individual patient data. It included only direct medical costs from the health-care perspective. Quality-adjusted life-years and incremental cost-effectiveness ratios were calculated. Sensitivity analysis was performed by a Monte Carlo analysis.
RESULTS: Adding cetuximab to a cisplatin-5-fluorouracil first-line regimen for advanced esophageal squamous cell carcinoma resulted in an the incremental cost-effectiveness ratio of €252,203 per quality-adjusted life-year. Sensitivity analysis shows that there is a chance of less than 0.001 that the incremental cost-effectiveness ratio will be less than a maximum willingness to pay threshold of €40,000 per quality-adjusted life-year, which is representative for the threshold used in The Netherlands and other developed countries.
CONCLUSIONS: Addition of cetuximab to a cisplatin-5-fluorouracil first-line regimen for advanced esophageal squamous cell carcinoma is not cost-effective when appraised according to currently accepted criteria. Cost-effectiveness analyses using outcome data from early clinical trials (i.c. a phase II trial) enable pharmaceutical companies and policy makers to gain early insight into whether a new drug meets the current eligibility standards for reimbursement and thereby potential admittance for use in regular clinical practice.

Wang X, Jiang R, Cui EH, et al.
N1-guanyl-1,7-diaminoheptane enhances the chemosensitivity of NSCLC cells to cetuximab through inhibition of eukaryotic translation initiation factor 5A2 activation.
Eur Rev Med Pharmacol Sci. 2016; 20(7):1244-50 [PubMed] Related Publications
OBJECTIVE: N1-guanyl-1, 7-diaminoheptane (GC7), an inhibitor of deoxyhypusine synthase has been shown to exhibit significant anti-cancer activity. However, the biological role of eukaryotic translation initiation factor 5A2 activation (EIF5A2) and GC7 on drug resistance in non-small cell lung cancer (NSCLC) has not been investigated. In this study, we aimed to investigate the therapeutic effect of GC7 combined with cetuximab in NSCLC therapy.
MATERIALS AND METHODS: The current study used cell viability assays, EdU incorporation assays, and western blot to detect that the GC7 exhibited synergistic cytotoxicity with cetuximab in NSCLC.
RESULTS: CCK-8 assays showed that combined treatment with GC7 and cetuximab significantly inhibited the viabilities in three NSCLC cell lines. In addition, EdU incorporation assays also indicated that GC7 co-treatment remarkably enhanced the cetuximab sensitivity in NSCLC cells. Nevertheless, down-regulation of EIF5A2 diminished the regulatory role of GC7 in cetuximab cytotoxicity. Western blot showed that transfection of EIF5A2 siRNA significantly suppressed the protein expression of EIF5A2 in NSCLC cells.
CONCLUSIONS: These findings demonstrate that combined treatment with GC7 could enhance cetuximab sensitivity by inhibiting EIF5A2 in NSCLC cells, implying the potential clinical application of GC7 in cetuximab-based chemotherapy for NSCLC patients.

Tai CJ, Huang MT, Wu CH, et al.
Combination of Two Targeted Medications (Bevacizumab Plus Cetuximab) Improve the Therapeutic Response of Pancreatic Carcinoma.
Medicine (Baltimore). 2016; 95(15):e3259 [PubMed] Free Access to Full Article Related Publications
The objective of this study is to evaluate the efficacy and safety profiles of the targeted medications, bevacizumab and cetuximab, in combination with cytostatic drugs in patients with locally advanced or metastatic pancreatic cancer. In this retrospective phase 2 study, a total of 59 patients with pancreatic cancer were recruited and received conventional (gemcitabine, cisplatin, and fluorouracil) or targeted regimen (conventional plus bevacizumab and cetuximab for the first cycle) in 2-week intervals for four cycles. The primary end-point for this study was the overall response rate. Secondary end-points were progression-free survival and the safety profiles of the combined therapy. The median time-to-progression and overall survival were 3 and 7 months, respectively, in the conventional treatment group as well as 11 and 13 months, respectively, in the targeted medications treatment group. The most common adverse events in both treatment groups were nausea and vomiting. Moderate (Grade 2) nausea and vomiting were more common in the conventional group than the targeted group but severe (Grade 3) nausea and vomiting were more common in the targeted group. Bevacizumab and cetuximab in combination with gemcitabine, cisplatin, and fluorouracil may help lengthen overall survival up to six months for patients with pancreatic cancer.

Li W, Ji YH, Li CX, et al.
Evaluation of therapeutic effectiveness of (131)I-antiEGFR-BSA-PCL in a mouse model of colorectal cancer.
World J Gastroenterol. 2016; 22(14):3758-68 [PubMed] Free Access to Full Article Related Publications
AIM: To investigate the biological effects of internal irradiation, and the therapeutic effectiveness was assessed of (131)I-labeled anti-epidermal growth factor receptor (EGFR) liposomes, derived from cetuximab, when used as a tumor-targeting carrier in a colorectal cancer mouse model.
METHODS: We described the liposomes and characterized their EGFR-targeted binding and cellular uptake in EGFR-overexpressing LS180 colorectal cancer cells. After intra-tumor injections of 74 MBq (740 MBq/mL) (131)I-antiEGFR-BSA-PCL, we investigated the biological effects of internal irradiation and the therapeutic efficacy of (131)I-antiEGFR-BSA-PCL on colorectal cancer in a male BALB/c mouse model. Tumor size, body weight, histopathology, and SPECT imaging were monitored for 33 d post-therapy.
RESULTS: The rapid radioiodine uptake of (131)I-antiEGFR-BSA-PCL and (131)I-BSA-PCL reached maximum levels at 4 h after incubation, and the (131)I uptake of (131)I-antiEGFR-BSA-PCL was higher than that of (131)I-BSA-PCL in vitro. The (131)I tissue distribution assay revealed that (131)I-antiEGFR-BSA-PCL was markedly taken up by the tumor. Furthermore, a tissue distribution assay revealed that (131)I-antiEGFR-BSA-PCL was markedly taken up by the tumor and reached its maximal uptake value of 21.0 ± 1.01 %ID/g (%ID/g is the percentage injected dose per gram of tissue) at 72 h following therapy; the drug concentration in the tumor was higher than that in the liver, heart, colon, or spleen. Tumor size measurements showed that tumor development was significantly inhibited by treatments with (131)I-antiEGFR-BSA-PCL and (131)I-BSA-PCL. The volume of tumor increased, and treatment rate with (131)I-antiEGFR-BSA-PCL was 124% ± 7%, lower than that with (131)I-BSA-PCL (127% ± 9%), (131)I (143% ± 7%), and normal saline (146% ± 10%). The percentage losses in original body weights were 39% ± 3%, 41% ± 4%, 49% ± 5%, and 55% ± 13%, respectively. The best survival and cure rates were obtained in the group treated with (131)I-antiEGFR-BSA-PCL. The animals injected with (131)I-antiEGFR-BSA-PCL and (131)I-BSA-PCL showed more uniform focused liposome distribution within the tumor area.
CONCLUSION: This study demonstrated the potential beneficial application of (131)I-antiEGFR-BSA-PCL for treating colorectal cancer. (131)I-antiEGFR-BSA-PCL suppressed the development of xenografted colorectal cancer in nude mice, thereby providing a novel candidate for receptor-mediated targeted radiotherapy.

Liu J, Zhou Q, Xu J, et al.
Detection of EGFR expression in patients with colorectal cancer and the therapeutic effect of cetuximab.
J BUON. 2016 Jan-Feb; 21(1):95-100 [PubMed] Related Publications
PURPOSE: This study was designed to detect the expression of epidermal growth factor receptor (EGFR) in tumor specimens of patients with colorectal cancer (CRC); moreover, the relationship between EGFR expression and clinical factors as well as prognosis were analyzed to provide a basis for individualized treatment of CRC.
METHODS: This study used paraffin-embedded tumor specimens of 70 CRC patients who were treated with cetuximab. Immunohistochemistry (IHC) was used to detect the expression of EGFR in CRC tumor specimens. The patient clinical features and treatment administered were recorded and then, the therapeutic effect of cetuximab was evaluated. Progression-free survival (PFS) and overall survival (OS) were assessed.
RESULTS: The positive expression rate of EGFR was 64% (45/70), while 18 patients had negative expression. Twenty-two cases had weak positive expression, 15 cases positive expression and another 15 strongly positive expression. Of 70 specimens, 27 (38.6%) had high EGFR expression belonging to 20 (50%) males and 7 (23%) females (p<0.05). However, age, Karnofsky performance status (KPS), tumor site, grade of differentiation and clinical stage showed no significant difference in relation to EGFR expression (p>0.05). No patient achieved complete remission (CR), 15 (21.4%) had partial remission (PR), 12 (17.1%) were in stable state (SD) and 40 (57.1%) patients had disease progression (PD). Disease control rate (DCR) was 39.02% (16/41) in the group with low EGFR expression and 48.28% (14/29) in the group with high EGFR expression (p>0.05).
CONCLUSION: EGFR expression in CRC tissue is correlated with patient gender. In the group with higher EGFR expression, the effectiveness of cetuximab was significantly higher than that in the low EGFR expression group, indicating correlation between the high expression of EGFR and the short-term effect of cetuximab.

Pantelic A, Markovic M, Pavlovic M, Jancic S
Cetuximab in third-line therapy of patients with metastatic colorectal cancer: A single institution experience.
J BUON. 2016 Jan-Feb; 21(1):70-9 [PubMed] Related Publications
PURPOSE: Cetuximab, an IgG1 chimeric monoclonal antibody (MAB) against epidermal growth factor receptor (EGFR) has activity against metastatic colorectal cancers (mCRC) that express EGFR. The purpose of this study was to demonstrate the efficacy and safety of cetuximab administered to patients with EGFR-positive mCRC.
METHODS: 72 patients with wild-type KRAS mCRC were enrolled. All of them had previously been treated with a fluoropyrimidine, oxaliplatin and irinotecan-based chemotherapy. Patients received cetuximab as monotherapy or in combination with irinotecan-based chemotherapy. All patients were to be treated until the occurrence of disease progression or unacceptable toxicity.
RESULTS: All patients were evaluated for progression free survival (PFS), overall survival (OS) and safety. The median PFS was 4.77 months (95% CI: 4.08-5.45), with an actuarial 47.22% without progression at 3 months and 16.67% at 6 months. The median OS was 11.35 months (95% CI: 9.64-13.06), with 79.17% of the patients being alive at 6 months and 30.56% at 12 months. PFS was significantly higher in patients with skin toxicity as compared to those without skin toxicity (5.31 vs 2.61 months, p<0.001) and with smaller number of metastatic organs vs greater number of metastatic organs (p=0.05). OS was significantly higher in patients with good performance status (p=0.004), with skin toxicity (p=0.013) and with smaller number of metastatic organs (p<0.001). Superior survival rates with higher grades of skin toxicity were noticed. As for patient characteristics, there were no significant differences in age, gender, and primary site localization.
CONCLUSION: Cetuximab improved PFS, OS and preserved the quality of life in patients with mCRC whose previous treatments had failed.

van Dommelen SM, van der Meel R, van Solinge WW, et al.
Cetuximab treatment alters the content of extracellular vesicles released from tumor cells.
Nanomedicine (Lond). 2016; 11(8):881-90 [PubMed] Related Publications
AIM: Extracellular vesicles (EVs) are attractive candidates for biomarker research, because their content reflects the parental cell status. This study aimed to examine whether tumor cell derived EVs mirrored the cellular changes caused by treatment with cetuximab, a therapeutic antibody that blocks activation of EGF receptor (EGFR).
MATERIALS & METHODS: A-431 cells were treated with cetuximab for 48 h. EVs were isolated using differential centrifugation and protein content was analyzed using western blotting.
RESULTS: EV levels of EGFR and phospho-EGFR were reduced after cetuximab treatment, reflecting similar changes in the parental cells. In addition, cetuximab was found associated with EVs.
CONCLUSION: EVs could serve as biomarkers to monitor cetuximab treatment. Association of cetuximab with EVs might influence its behavior.

Zhang X, Du L, Zhao F, et al.
A Phase II Clinical Trial of Concurrent Helical Tomotherapy plus Cetuximab Followed by Adjuvant Chemotherapy with Cisplatin and Docetaxel for Locally Advanced Nasopharyngeal Carcinoma.
Int J Biol Sci. 2016; 12(4):446-53 [PubMed] Free Access to Full Article Related Publications
PURPOSE: The present clinical trial was designed to evaluate the efficacy and safety of concurrent helical tomotherapy (HT) with cetuximab followed by adjuvant chemotherapy with docetaxel and cisplatin (TP) in the treatment of patients with locoregionally advanced nasopharyngeal carcinoma.
MATERIALS AND METHODS: This phase II clinical trial included 43 patients with Stage III/IV LANC (33 Stage III and 10 Stage IV). The treatment consisted of concurrent HT with cetuximab (400 mg/m(2) loading dose and weekly 250mg/m(2)), followed by four cycles of chemotherapy [docetaxel (70 mg/m(2) on Day 1) and cisplatin (40 mg/m(2) on Days 1 and 2 every 3 weeks). Side effects were evaluated with CTCAE criteria (Common Terminology Criteria for Adverse Events 3.0).
RESULTS: The median follow-up duration was 48.0 months [95% confidence interval (CI) 41.7-58.0 months], the 2-year locoregional failure-free rate (LFFR), progression-free survival (PFS), distant failure-free rate (DFFR) and overall survival (OS) were 95.2%, 79.1%, 88.1% and 93.0% respectively; the 3-year LFFR, DFFR, PFS and OS were 92.7%, 85.6%, 72.0% and 85.7% respectively. The most common grade 3 toxicities were oropharyngeal mucositis (81.4%) and RT-related dermatitis (7.0%). No patients had more than grade 3 radiation related toxicities and no patients required nasogastric feeding. One patient experienced grade 3 osteonecrosis at 18 months after treatment.
CONCLUSIONS: Concurrent HT with cetuximab followed by adjuvant chemotherapy with TP is an effective strategy for the treatment of LANC with encouraging survival rates and minimal side effects.

Marinello E, Pastorelli D, Alaibac M
A case of psoriasis pustolosa palmaris induced by cetuximab.
BMJ Case Rep. 2016; 2016 [PubMed] Related Publications
Cetuximab is a monoclonal antibody that competitively inhibits the epidermal growth factor receptor (EGFR). It is used for the treatment of metastatic colorectal cancer after first-line therapy. We report the first case of a pustular psoriasiform drug eruption induced by cetuximab in a patient with colorectal cancer. This paradoxical side effect could be the result of an imbalance in downstream molecular pathways due to the EGFR signal blockade that could, in selected patients, induce alternative signalling pathways related to keratinocyte proliferation.

Weiss J, Grilley Olson J, Deal AM, et al.
Using the galactose-α-1,3-galactose enzyme-linked immunosorbent assay to predict anaphylaxis in response to cetuximab.
Cancer. 2016; 122(11):1697-701 [PubMed] Related Publications
BACKGROUND: Cetuximab is a monoclonal antibody against epidermal growth factor receptor with activity against head and neck cancer and colorectal cancer. Anaphylaxis in response to cetuximab is a significant clinical problem in the Southeastern United States with a grade 3/4 infusion reaction rate of 14%. Previous retrospective data have suggested that the presence of preformed immunoglobulin E antibodies against galactose-α-1,3-galactose in serum can predict anaphylaxis in response to cetuximab.
METHODS: Sixty patients were prospectively screened as part of the entry criteria for a phase 2 study of neoadjuvant carboplatin, nab-paclitaxel, and cetuximab. Patients were recruited at 2 academic medical centers known to have high anaphylaxis rates: the University of North Carolina and Vanderbilt. Only patients with a negative laboratory result were treated on the clinical protocol.
RESULTS: No patient experienced anaphylaxis; the negative predictive value was thus 100%. Other than smoking history, the demographics were similar for assay-positive subjects and assay-negative subjects.
CONCLUSIONS: Subjects with a negative test result can be safely treated with cetuximab. Further research is required regarding the optimal cutoff for positivity and the positive predictive value. Cancer 2016;122:1697-701. © 2016 American Cancer Society.

Lu HJ, Lin JK, Chen WS, et al.
Primary tumor location is an important predictive factor for wild-type KRAS metastatic colon cancer treated with cetuximab as front-line bio-therapy.
Asia Pac J Clin Oncol. 2016; 12(3):207-15 [PubMed] Related Publications
INTRODUCTION: Left- and right-sided colon cancers were significantly different in epidemiologic, clinical and histological parameters. However, the impact of primary tumor location in metastatic colon cancer treated with front-line targeted triplet regimens is unclear, particularly in Asian populations.
METHODS: A total of 121 patients with KRAS exon 2 codon 12/13 wild-type metastatic colon cancer were enrolled between January 2007 and December 2013. All patients received one target agent, such as cetuximab or bevacizumab, as a front-line targeted triplet regimen. The impact of primary tumor location for cetuximab and bevacizumab groups was analyzed, respectively.
RESULTS: In cetuximab group, left-sided metastatic colon cancer was superior to right-sided metastatic colon cancer in objective response rate (70.1% vs 33.3%, P = 0.024), progression-free survival (15.0 vs 5.3 months, P < 0.001) and overall survival (35.8 vs 14.4 months, P = 0.031). Primary tumor location was an independent prognostic factor for progression-free survival (hazard ratio 0.240, 95% confidence interval 0.114-0.508, P < 0.001). However, in the bevacizumab group, there were no differences in outcomes for either side. Primary tumor location was insignificant for progression-free survival and overall survival in univariate analysis.
CONCLUSION: Left-sided primary tumors were favored in cetuximab-based front-line targeted triplet regimen for metastatic colon cancer.

Bonetta A, Bandera L, Roviello G, et al.
Neoadjuvant chemotherapy and radical radiotherapy associated with cetuximab for laryngeal cancer in a pancreas and renal recipient.
Anticancer Drugs. 2016; 27(5):470-3 [PubMed] Related Publications
The oncological treatment for advanced stage head and neck cancer is based on a combination of cisplatin and cetuximab, and radiotherapy. However, very few data are available on this multimodal approach for this type of cancer in pancreas and renal recipients. We report the case of a pancreas and renal recipient being treated with combined chemoradiotherapy for a locally advanced squamous cancer of the larynx. The patient was under treatment with ciclosporin-based immunosuppressive therapy at the time of cancer diagnosis, which was then replaced by everolimus. After 4 years of follow-up, the patients is still free from disease, with a local complete response, only mild residual dysphonia, and with edema of the chin. Cetuximab plus radiation could be an adequate option for cancer treatment in solid organ transplant recipients affected by locally advanced head and neck cancer; the concomitant use of mammalian target of rapamycin pathway inhibitors may have a synergistic effect in enhancing tumor control in these patients; however, further dedicated studies are warranted.

Yoshimatsu K, Osawa G, Yokomizo H, et al.
Hepatic Arterial Infusion Chemotherapy for Life Threatening Patients due to Liver Metastases from Colorectal Cancer with Cetuximab.
Hepatogastroenterology. 2015; 62(139):612-4 [PubMed] Related Publications
BACKGROUND/AIMS: This retrospective report evaluated the safety and efficacy of hepatic arterial infusion chemotherapy (HAIC) for life threatening patients with unresectable hepatic metastases.
METHODOLOGY: Seven life threatening patients with hepatic metastases who were treated with HAIC up to September 2011 were retrospectively analyzed. As HAIC regimen, 5-FU (1000mg/m2) was administered weekly via continuous 5-hour infusion using a continuous-infusion device. After improvement of liver dysfunction, cetuximab was administered simultaneously by the same dose of single administration. Treatment was repeated weekly until progression of hepatic lesion or discontinuity by unacceptable toxicity or patients' proposal.
RESULTS: In 5 patients with hepatic metastasis related complaints, 3 patients improved after the initiation of HAIC. Three out of 4 patients with PS 2 or 3 were improved by the initiation of HAIC. The median OS was 9.5 months. No severe adverse toxicities and no treatment death related to HAIC were observed. The most severe non-hematologic adverse events were ALP in 3 patients, transaminase and bilirubin in 1 patient with grade 3.
CONCLUSION: HAIC may be considered to perform when the hepatic metastases progress as life threatening status even though those are refractory to standard systemic chemotherapy.

Gulec SA
Y-90 Radiomicrosphere Therapy for Colorectal Cancer Liver Metastases.
Semin Nucl Med. 2016; 46(2):126-34 [PubMed] Related Publications
At present, the systemic treatment of unresectable colorectal cancer liver metastases involves oxaliplatin and irinotecan-based chemotherapy regimens combined with targeted therapies such as bevacizumab (Avastin) and cetuximab (Erbitux). Radiation therapy, traditionally, is not considered a viable treatment modality owing to its unacceptably high hepatic toxicity, and still steering traditional wisdom or dogma that chemoradiation cannot be an oncological strategy for a stage IV disease. Selective internal radiation treatment with yttrium-90 (Y-90) radiomicrospheres has emerged as an effective liver-directed therapy with a favorable therapeutic ratio. Since its early clinical trials, it has demonstrated improved response rates when used in conjunction with systemic or regional chemotherapy. This article reviews the clinical role for Y-90 radiomicrosphere therapy in the contemporary management of colorectal cancer liver metastases. All the structured clinical trials, to date, are summarized, including those that studied the value of combined Y-90 radiomicrosphere therapy and current chemotherapy protocols.

Rosati G, Aprile G, Cardellino GG, Avallone A
A review and assessment of currently available data of the EGFR antibodies in elderly patients with metastatic colorectal cancer.
J Geriatr Oncol. 2016; 7(2):134-41 [PubMed] Related Publications
Although the number of elderly patients is increasing each year, this population has been under-represented in clinical trials. At the same time, the survival of patients with metastatic colorectal cancer has been improving, not only because of improvements in chemotherapy, but especially because of the addition of monoclonal antibodies (bevacizumab, cetuximab and panitumumab). Therefore, it is necessary to define the role of these new drugs in the elderly population, a group that is heterogeneous and consists of those who are fit and able to tolerate all therapies equally as well as younger patients and unfit individuals who should only given best supportive care or therapies specifically modulated for them. Today, although data from phase II-III studies have helped to establish the role of bevacizumab in the elderly, few trials have studied anti-epidermal growth factor receptor (EGFR) antibodies in the same population. This review presents the results of studies carried out with anti-EGFR agents, with a hope that more trials will be carried out with these drugs in the elderly in the future.

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