Cetuximab and Chemotherapy as Initial Treatment for Metastatic Colorectal Cancer

Cutsem, Éric Van; Köhne, Claus Henning; Hitre, Erika; Załuski, J.; Chien, Chung Rong Chang; Makhson, Anatoly; D’Haens, Geert R.; Pintér, Tamás; Lim, Robert; Bodoky, G.; Roh, Jae Kyung; Folprecht, Gunnar; Ruff, Paul; Stroh, Christopher; Tejpar, Sabine; Schlichting, Michael; Nippgen, Johannes; Rougier, Philippe

doi:10.1056/nejmoa0805019

Cited by 3,461 publications

(2,440 citation statements)

References 30 publications

Supporting

Mentioning

2,289

Contrasting

Unclassified

Order By: Relevance

“…Epidermal growth factor receptor (EGFR) contained over 800 SNPs with minor allele frequency41% including biological importance SNPs. 25 The identification of EGFR as an oncogene has led to the development of anticancer therapeutics directed against EGFR (called 'tyrosine kinase inhibitors', TKIs), including gefitinib, erlotinib, afatinib and brigatinib for lung cancer, 26,27 and cetuximab for colon cancer, 28,29 therefore, the impacts of EGFR gene polymorphisms on the cytotoxicity of TKIs, such as gefitinib, erlotinib and cetuximab, have been investigated broadly in patients affected with NSCLC 30,31 and colon cancer. 30 However, no investigation has been reported of the influence of EGFR polymorphisms on Imatinib toxicity in patients with GIST.…”

Section: Discussionmentioning

confidence: 99%

Imatinib-induced ophthalmological side-effects in GIST patients are associated with the variations of EGFR, SLC22A1, SLC22A5 and ABCB1

Qiu

Zhuang

et al. 2017

Pharmacogenomics J

View full text Add to dashboard Cite

Imatinib-induced ophthalmological side-effects, including conjunctiva hemorrhage and periorbital oedema, although very common and still remain relatively little understood. The present study investigated the effects of genetic polymorphisms of drug targets and membrane transporters on these side effects. We found that the minor allele of EGFR rs10258429 and SLC22A1 rs683369 were significant risk determinants of conjunctival hemorrhage with OR of 7.061 (95%CI = 1.791-27.837, P = 0.005 for EGFR rs10258429 CT +TT vs CC), and 4.809 (95%CI = 1.267-18.431, P = 0.021 for SLC22A1 rs683369 GG+CG vs CC). The minor allele of SLC22A5 rs274558 and ABCB1 rs2235040 were protective factors to periorbital oedema with OR of 0.313 (95%CI = 0.149-0.656, P = 0.002 for SLC22A5 rs274558 AA+AG vs GG), and 0.253 (95%CI = 0.079-0.805, P = 0.020 for ABCB1 rs2235040 CT vs CC). These results indicated that variants in EGFR, SLC22A1, SLC22A5 and ABCB1 influenced the incidence of Imatinib-induced ophthalmological toxicities, and polymorphism analyses in associated genes might be beneficial to optimize Imatinib treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

Imatinib-induced ophthalmological side-effects in GIST patients are associated with the variations of EGFR, SLC22A1, SLC22A5 and ABCB1

Qiu

Zhuang

et al. 2017

Pharmacogenomics J

View full text Add to dashboard Cite

show abstract

“…10 Patients with unresectable LM-CRC have a poor prognosis with a median survival of only two years. 11 Therefore, there is a pressing need for more effective therapeutic strategies for LM-CRC.…”

Section: Introductionmentioning

confidence: 99%

Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

et al. 2018

View full text Add to dashboard Cite

Purpose: Liver metastasis develops in >50% of patients with colorectal cancer (CRC), and is a leading cause of CRC-related mortality. We aimed to identify which inhibitory immune checkpoint pathways can be targeted to enhance functionality of intra-tumoral T-cells in mismatch repair-proficient liver metastases of colorectal cancer (LM-CRC). Methodology: Intra-tumoral expression of multiple inhibitory molecules was compared among mismatch repair-proficient LM-CRC, peritoneal metastases of colorectal cancer (PM-CRC) and primary CRC. Expression of inhibitory molecules was also analyzed on leukocytes isolated from paired resected metastatic liver tumors, tumor-free liver tissues, and blood of patients with mismatch repair-proficient LM-CRC. The effects of blocking inhibitory pathways on tumor-infiltrating T-cell responses were studied in ex vivo functional assays. Results: Mismatch repair-proficient LM-CRC showed higher expression of inhibitory receptors on intra-tumoral T-cells and contained higher proportions of CD8+ T-cells, dendritic cells and monocytes than mismatch repair-proficient primary CRC and/or PM-CRC. Inhibitory receptors LAG3, PD-1, TIM3 and CTLA4 were higher expressed on CD8+ T-cells, CD4+ T-helper and/or regulatory T-cells in LM-CRC tumors compared with tumor-free liver and blood. Antibody blockade of LAG3 or PD-L1 increased proliferation and effector cytokine production of intra-tumoral T-cells isolated from LM-CRC in response to both polyclonal and autologous tumor-specific stimulations. Higher LAG3 expression on intra-tumoral CD8+ T-cells associated with longer progression-free survival of LM-CRC patients. Conclusion: Mismatch repair-proficient LM-CRC may be more sensitive to immune checkpoint inhibitors than mismatch repair-proficient primary CRC. Blocking LAG3 enhances tumor-infiltrating T-cell responses of mismatch repair-proficient LM-CRC, and therefore may be a new promising immunotherapeutic target for LM-CRC.

show abstract

“…Also, in phase 3 clinical trials, adding cetuximab to first-line chemotherapy or RT improves outcomes in various types of cancers. [9][10][11] Because of encouraging results of clinical trials with cetuximab in different tumors, the need for more effective therapies, particularly in locally advanced anal canal carcinoma (LAACC), 12 and the high expression of EGFR in anal carcinoma, we set out to develop a regimen to evaluate the safety and activity of cetuximab combined with 5-fluorouracil (5-FU)/CP concurrent with radiation for LAACC.…”

Section: Introductionmentioning

confidence: 99%

Phase 1 study of cetuximab in combination with 5‐fluorouracil, cisplatin, and radiotherapy in patients with locally advanced anal canal carcinoma

Olivatto

Vieira

Pereira

et al. 2013

Cancer

View full text Add to dashboard Cite

BACKGROUND: This study sought to determine the feasibility and recommended phase 2 dose (RP2D) of the combination of cetuximab with chemoradiotherapy based on 5-fluorouracil (5-FU) and cisplatin (CP) in locally advanced anal canal carcinoma. METHODS: Cetuximab was administered on days 1,8,15, 29, 36, 43, and 50 (400 mg/m 2 initial dose, then 250 mg/m 2 /week) concurrent with total dose radiation of 55 to 59 Gy, both starting on day 1. Escalating doses of 5-FU (96-hour infusion) and CP (2-hour infusion), both on days 1 and 29, were administered according to the following design: starting dose level (0) 5-FU/CP 5 800/60 mg/m 2 /day and up to dose level (12) 5-FU/CP 5 1000/80 mg/m 2 /day. RESULTS: Dose-limiting toxicity (DLT) events (uncontrolled diarrhea or febrile neutropenia) occurred in 3 of 14 assessable patients receiving escalated dose of 5-FU/CP, with 1 in dose level (0) and 2 in dose level (12). The RP2D was 5-FU/CP 5 800/80 mg/m 2 /day. Because of unexpected non-DLT treatment-related grade 3 (G3) adverse events (AEs) such as thrombosis/embolism, syncope, and infection occurring in 20% of patients, a safety expansion cohort with an additional 9 patients was investigated with the RP2D. The most frequent G3/G4 AEs evaluated in 23 patients were radiation dermatitis (12 patients), diarrhea (10 patients), thrombosis/embolism (6 patients), and infection (5 patients). The study was closed due to these severe AEs, although no G5 AEs occurred. Twenty of 21 patients (95%) achieved pathological complete response at primary tumor. With a median follow-up of 43.4 months, the 3-year locoregional control rate was 64.2%. CONCLUSIONS: Cetuximab could not be integrated with chemoradiotherapy-cisplatin-based therapy due to the high toxicity rate. However, efficacy is encouraging and further investigation of an epidermal growth factor receptor-targeted agent (other than cetuximab) concurrent with chemoradiation should be pursued. Cancer 2013;119:2973-80.

show abstract

Cetuximab and Chemotherapy as Initial Treatment for Metastatic Colorectal Cancer

Abstract: First-line treatment with cetuximab plus FOLFIRI, as compared with FOLFIRI alone, reduced the risk of progression of metastatic colorectal cancer. The benefit of cetuximab was limited to patients with KRAS wild-type tumors. (ClinicalTrials.gov number, NCT00154102.)

Cited by 3,461 publications

References 30 publications

Imatinib-induced ophthalmological side-effects in GIST patients are associated with the variations of EGFR, SLC22A1, SLC22A5 and ABCB1

Imatinib-induced ophthalmological side-effects in GIST patients are associated with the variations of EGFR, SLC22A1, SLC22A5 and ABCB1

Blockade of LAG3 enhances responses of tumor-infiltrating T cells in mismatch repair-proficient liver metastases of colorectal cancer

Phase 1 study of cetuximab in combination with 5‐fluorouracil, cisplatin, and radiotherapy in patients with locally advanced anal canal carcinoma

Contact Info

Product

Resources

About