Fluorouracil, Leucovorin, and Oxaliplatin With and Without Cetuximab in the First-Line Treatment of Metastatic Colorectal Cancer

Bokemeyer, Carsten; Bondarenko, Igor; Makhson, Anatoly; Hartmann, J. T.; Aparicio, Jorge; Braud, Filippo de; Donea, S.; Ludwig, Heinz; Schuch, Gunter; Stroh, Christopher; Loos, Anja H.; Zubel, Angela; Koralewski, P.

doi:10.1200/jco.2008.20.8397

Cited by 1,469 publications

(973 citation statements)

References 23 publications

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“…Both PFS and OS were similar for cetuximab and control groups in patients carrying tumors with KRAS mutations (progression-free interval = 1. 29,30 Retrospective data from the OPUS and CRYSTAL studies indicate that from the addition of cetuximab to first-line FOLFOX (folinic acid, fluorouracil, and oxaliplatin) 30 or FOLFIRI (folinic acid, fluorouracil and irinotecan) 29 chemotherapy does not benefit patients with KRAS mutations. In fact, the OPUS study indicates that addition of EGFR-targeted treatment to chemotherapy may even be detrimental in such patients.…”

Section: Biomarkers Downstream To Egfrmentioning

confidence: 99%

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Prognostic vs predictive molecular biomarkers in colorectal cancer: is KRAS and BRAF wild type status required for anti-EGFR therapy?

Rizzo

Bronte

Fanale

et al. 2010

Cancer Treatment Reviews

102

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s u m m a r yAn important molecular target for metastatic CRC treatment is the epidermal growth factor receptor (EGFR). Many potential biomarkers predictive of response to anti-EGFR monoclonal antibodies (cetuximab and panitumumab) have been retrospectively evaluated, including EGFR activation markers and EGFR ligands activation markers. With regard to the "negative predictive factors" responsible for primary or intrinsic resistance to anti-EGFR antibodies a lot of data are now available. Among these, KRAS mutations have emerged as a major predictor of resistance to panitumumab or cetuximab in the clinical setting and several studies of patients receiving first and subsequent lines of treatment have shown that those with tumors carrying KRAS mutations do not respond to EGFR-targeted monoclonal antibodies or show any survival benefit from such treatments. The role of B-RAF mutations, mutually exclusive with KRAS mutations, in predicting resistance to anti-EGFR mAbs is not yet consolidated. It therefore appears that BRAF mutations may play a strong negative prognostic role and only a slight role in resistance to anti-EGFR Abs.

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Section: Biomarkers Downstream To Egfrmentioning

confidence: 99%

“…In fact, the OPUS study indicates that addition of EGFR-targeted treatment to chemotherapy may even be detrimental in such patients. 30 In some cases the addition of cetuximab or panitumumab to standard chemotherapy may be not useful even in KRAS wt patients.…”

Section: Biomarkers Downstream To Egfrmentioning

confidence: 99%

Prognostic vs predictive molecular biomarkers in colorectal cancer: is KRAS and BRAF wild type status required for anti-EGFR therapy?

Rizzo

Bronte

Fanale

et al. 2010

Cancer Treatment Reviews

102

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“…The EGFR family consists of at least four members, of which both EGFR and human epidermal growth factor 2 (HER2) are critical targets in cancers including breast and gastric malignancies 10, 11, 12, 13. Cetuximab (CTX), an anti‐EGFR monoclonal antibody, has been widely used particularly for treatment of colorectal and lung cancers 14, 15. However, some patients with colorectal cancer (CRC) are resistant to EGFR inhibitors because of the continuous activation of the RAS/mitogen‐activated protein kinase (MAPK) pathway by a mutation in codon 12 of the wild‐type v‐Ki‐ras2 Kirsten rat sarcoma viral oncogene homolog ( KRAS ) gene 14, 15, 16, 17.…”

mentioning

confidence: 99%

“…Cetuximab (CTX), an anti‐EGFR monoclonal antibody, has been widely used particularly for treatment of colorectal and lung cancers 14, 15. However, some patients with colorectal cancer (CRC) are resistant to EGFR inhibitors because of the continuous activation of the RAS/mitogen‐activated protein kinase (MAPK) pathway by a mutation in codon 12 of the wild‐type v‐Ki‐ras2 Kirsten rat sarcoma viral oncogene homolog ( KRAS ) gene 14, 15, 16, 17. Therefore, the use of CTX is currently restricted to patients with wild‐type KRAS .…”

mentioning

confidence: 99%

Combination therapy with zoledronic acid and cetuximab effectively suppresses growth of colorectal cancer cells regardless of KRAS status

Kato

Futamura

Kanematsu

et al. 2015

Intl Journal of Cancer

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Targeted molecular therapy is an effective anticancer strategy. Anti‐EGFR monoclonal antibodies such as cetuximab (CTX) have been approved for the treatment of various malignancies, including colorectal cancer (CRC) with wild‐type KRAS. However, their efficacy in patients with KRAS mutations has not been established. Therefore, we investigated whether CTX treatment was effective as a single agent or in combination with zoledronic acid (ZOL) in human CRC cell lines with different KRAS status. CRC cell lines SW48 (wild‐type KRAS) and LS174T (mutant KRAS) were treated with ZOL, CTX and a combination of both drugs. Cytotoxicity was measured using the MTT assay. Changes in the levels of intracellular signaling proteins were evaluated using western blot analysis. Finally, we evaluated the efficacy of the combination treatment in an in vivo xenograft model. We observed that ZOL apparently inhibited growth in both cell lines, whereas CTX showed little effect. ZOL also increased the levels of unprenylated RAS. Combined ZOL and CTX treatment was synergistic in both cell lines and was associated with inhibition of the RAS‐MAPK and AKT‐mTOR signaling pathways. Furthermore, the combination treatment was more effective in suppressing the growth of xenografts derived from both SW48 and LS174T cells; this effect was associated with increased apoptosis. These results demonstrate that ZOL inhibits the growth of colon cancer cells regardless of KRAS status, and combination therapy using ZOL and CTX enhances this growth suppression. These findings suggest a novel strategy for the treatment of CRC independent of KRAS mutational status.

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“…1,2 Several clinical trials have demonstrated that EGFR-targeted therapies are not effective in patients whose tumors have a mutation in the oncogene Kirsten ras (KRAS). [3][4][5][6][7][8][9][10][11] Tumors that have a mutation in codon 12 or 13 of the KRAS gene will not respond to treatment with EGFR inhibitors such as cetuximab or panitumumab. Approximately 40% of mCRC tumors have these KRAS gene mutations.…”

Section: Introductionmentioning

confidence: 99%

Cost‐effectiveness of KRAS testing in metastatic colorectal cancer patients in the United States and Germany

Vijayaraghavan

Efrusy²,

Göke

et al. 2012

Intl Journal of Cancer

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The objective of this study was to determine the cost-effectiveness of testing for KRAS mutations before administering EGFR inhibitors such as cetuximab and panitumumab for patients with advanced metastatic colorectal cancer (mCRC) in the United States and Germany. We developed a lifetime Markov model of costs and survival associated with treating mCRC patients to assess the impact of KRAS testing before administering EGFR inhibitor-containing chemotherapy regimens. Overall, combination therapies involving cetuximab plus irinotecan/FOLFIRI had a better life expectancy (25.83 weeks) than cetuximab or panitumumab alone. Use of KRAS testing (assuming KRAS mutant patients receive only irinotecan) was equally effective and saved $12,428 per patient in the United States. When KRAS mutant patients received best supportive care, the life expectancy decreased slightly (24.26 weeks vs. 25.83 weeks) and the costs decreased by $13,501 in the United States and €9,560 in Germany. For patients treated with cetuximab alone, use of KRAS testing to identify mutations lowered costs by $8,040 per patient in the U.S. analysis and €3,856 per patient in the German analysis. For patients treated with panitumumab alone, use of KRAS testing to identify mutations lowered costs by $7,546 per patient in the U.S. analysis and €4,612 per patient in the German analysis. Model results were sensitive to the cost of chemotherapy regimens and the prevalence of KRAS mutations in the population. Under most scenarios, using KRAS testing to select patients for EGFR inhibitor therapy saved $7,500-$12,400 per patient in the United States and €3,900-€9,600 per patient in Germany with equivalent clinical outcomes.

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Fluorouracil, Leucovorin, and Oxaliplatin With and Without Cetuximab in the First-Line Treatment of Metastatic Colorectal Cancer

Abstract: KRAS mutational status was shown to be a highly predictive selection criterion in relation to the treatment decision regarding the addition of cetuximab to FOLFOX-4 for previously untreated patients with metastatic colorectal cancer.

Cited by 1,469 publications

References 23 publications

Prognostic vs predictive molecular biomarkers in colorectal cancer: is KRAS and BRAF wild type status required for anti-EGFR therapy?

Prognostic vs predictive molecular biomarkers in colorectal cancer: is KRAS and BRAF wild type status required for anti-EGFR therapy?

Combination therapy with zoledronic acid and cetuximab effectively suppresses growth of colorectal cancer cells regardless of KRAS status

Cost‐effectiveness of KRAS testing in metastatic colorectal cancer patients in the United States and Germany

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