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Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although significant advances have been made in the treatment of metastatic colorectal cancer (CRC), prognosis remains poor, with a 5-year survival of less than 10%. Monoclonal antibodies that target the epidermal growth factor receptor (EGFR) have shown clinical benefit as single agents and in combination with standard chemotherapy in the refractory setting, with tolerable toxicity. This article will discuss the role of the EGFR pathway in the pathogenesis of CRC, the data supporting the current use of cetuximab and panitumumab in the treatment of CRC, and clinical trials of EGFR tyrosine kinase inhibitors in CRC. Novel strategies of targeting the EGFR pathway to improve efficacy, as well as ongoing research in identifying molecular predictors of response to anti-EGFR agents, will also be reviewed.
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PMID:Targeting the epidermal growth factor receptor in metastatic colorectal cancer. 1800 28

Colorectal cancer (CRC) is a common health problem in Western countries. In advanced disease, either FOLFOX (oxaliplatin/5-fluorouracil [5-FU]/leucovorin [LV]) or FOLFIRI (irinotecan/LV/5-FU) are accepted first-line chemotherapy regimens, but median survival appears to plateau with a chemotherapy-only approach. The use of epidermal growth factor receptor (EGFR)- and vascular endothelial growth factor (VEGF)-targeting monoclonal antibodies has increased the median survival of patients with advanced CRC beyond 20 months. However, the precise role of cetuximab, panitumumab and bevacizumab in combination with different chemotherapeutic regimens is still being determined in first- and second-line settings. The activity and tolerance of the EGFR tyrosine kinase inhibitors (TKIs), gefitinib erlotinib, and EKB-569, alone or in combination with chemotherapy, have been explored in patients with metastatic CRC. Regarding VEGF receptor TKIs, 2 phase III clinical trials determined the role of vatalanib in combination with FOLFOX. Efficacy of the oral multitargeted TKIs sorafenib and sunitinib is under investigation. This article aims to review the role of TKIs in advanced CRC.
Clin Colorectal Cancer 2007 Nov
PMID:Role of tyrosine kinase inhibitors in the treatment of advanced colorectal cancer. 1803 22

(1) Many of the significant advances in cancer management in recent years have centered on the development and introduction of molecularly targeted therapies, such as monoclonal antibodies and tyrosine kinase inhibitors.(2) Despite targeted therapy that has clearly benefited and even cured certain patients (eg, imatinib, trastuzumab), the ultimate goal of curing cancer, and the more immediate goal of replacing non-targeted chemotherapies with less toxic, targeted agents has yet to be achieved for most cancer patients.(3) Based on a systematic review of randomized controlled trials, examples of significant benefits in selected cancers are provided:(a) Non-Hodgkin's lymphoma (NHL) - A large meta-analysis and several individual randomised, controlled trials (RCTs) report that rituximab plus chemotherapy has a major survival advantage over chemotherapy alone in patients with NHL; an overview of six clinical trials supports the survival benefit of rituximab plus chemotherapy.(b) Renal cell carcinoma (RCC) - Temsirolimus or sunitinib has a significant survival benefit relative to interferon-alpha, and sorafenib carries such a benefit in patients resistant to standard therapy.(c) Colorectal cancer (CRC) - An overview of three RCTs in metastatic CRC revealed that bevacizumab plus 5-fluorouracil/leucovorin possesses a significant survival advantage over 5-fluorouracil/leucovorin and irinotecan/5-fluorouracil/leucovorin.(d) Non-small-cell lung cancer (NSCLC) - In refractory NSCLC, erlotinib significantly prolongs survival, particularly in nonsmokers, and gefitinib may have some utility in patients of Asian ethnicity.(e) Head and neck squamous-cell carcinoma (HNSCC) - Cetuximab plus radiotherapy (versus radiotherapy alone) significantly improves locoregional control and survival (hazard ratio [HR] 0.68; p = 0.005) without worsening radiotherapy-related toxicity.
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PMID:Will targeted therapy hold its promise? An evidence-based review. 1804 64

Interesting activity has been reported by combining chemotherapy with cetuximab. An alternative approach for blocking EGFR function has been the development of small-molecule inhibitors of tyrosine kinase domain such as gefitinib. We designed a multicentre phase II study in advanced colorectal cancer combining gefitinib+FOLFOX in order to determine the activity and to relate EGFR expression and gene amplification and NF-kB activation to therapeutic results. Patients received FOLFOX-4 regimen plus gefitinib as first-line treatment. Tumour samples were analysed for EGFR protein expression by immunohistochemical analysis and for EGFR gene amplification by fluorescence in situ hybridisation (FISH), chromogenic in situ hybridisation (CISH) and NF-kB activation. Forty-three patients were enrolled into this study; 15 patients experienced a partial response (response rate=34.9%), whereas other 12 (27.9%) had a stable disease. Median progression-free survival (PFS) was 7.8 months and median overall survival (OS) was 13.9 months. We did not find any relationship with EGFR overexpression, gene amplification, while NF-kB activation was associated with a resistance to therapy. Gefitinib does not seem to increase the activity of FOLFOX in advanced colorectal cancer even in patients overexpressing EGFR or with EGFR amplification. Furthermore, while NF-kB activation seems to predict resistance to chemotherapy as demonstrated 'in vitro' models, gefitinib does not overcome this mechanism of resistance, as reported for cetuximab.
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PMID:A combination of gefitinib and FOLFOX-4 as first-line treatment in advanced colorectal cancer patients. A GISCAD multicentre phase II study including a biological analysis of EGFR overexpression, amplification and NF-kB activation. 1805 97

There is no effective treatment for recurrent or metastatic medullary thyroid carcinoma (MTC), a tumor arising from thyroid C-cells commonly presenting an inherited or acquired RET mutation. In this study we examined the sensitivity of two human MTC cell lines to novel pyrazolopyrimidine derivates, able to inhibit src-family tyrosine kinase activity. In TT cells [carrying the multiple endocrine neoplasia (MEN)2A Ret mutation Cys 634Trp] and MZ-CRC-1 cells (carrying the MEN2B RET mutation Met891Thr), one of these compounds, namely Si 34, determined a significant growth inhibitory effect (approximately 90% vs control for TT, 80% vs control for MZ-CRC-1) mainly due to enhanced cell mortality after a 6-day incubation. At concentrations that increased cell mortality, neither biochemical or morphological characteristics of apoptosis were detected in TT and MZCRC- 1 cells treated with Si 34. These results, when confirmed in other in vivo preclinical models, suggest that this novel tyrosine kinase inhibitor may be useful for the treatment of MTC.
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PMID:Growth inhibition of medullary thyroid carcinoma cells by pyrazolo-pyrimidine derivates. 1807 81

The epidermal growth factor receptor (EGFR)-mediated pathway is one of the most promising targets for the development of new strategies in anticancer treatments. The so-called "small molecule" tyrosine kinase inhibitor erlotinib has gained marketing authorization in the United States for advanced adenocarcinoma of the lung and for pancreatic cancer, whereas the antibody cetuximab is registered for metastatic colorectal cancer and cancers of the head and neck. Ongoing studies are evaluating the impact of EGFR-targeting therapy in the treatment of locally advanced and metastatic pancreatic cancer.
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PMID:Targeted therapy of the epidermal growth factor receptor in the treatment of pancreatic cancer. 1808 55

The importance of the epidermal growth factor receptor (EGFR) axis in tumorigenesis and tumor progression makes it an attractive target for the development of anticancer therapies. Strategies aimed at inhibiting the EGFR pathway included different classes of compounds, with monoclonal antibodies and tyrosine kinase inhibitors being the most widely-investigated agents in colorectal cancer. Although anti-EGFR therapies are active in some patients, disease will become refractory to therapy in nearly all patients. Identification of specific markers likely to predict which patients will best respond to anti-EGFR therapy is a major challenge. While the occurrence of rash is associated with greater likelihood of response, EGFR staining by immunohistochemistry at baseline is not. Among biological predictors, some studies indicate that activated EGFR, EGFR amplification, absence of KRAS mutations, PTEN expression, and low VEGFR expression are implicated in response to anti-EGFR monoclonal antibodies. Moreover, germinal gene polymorphisms, such as dinucleotide repeats polymorphism or FcgammaR polymorphism, have been shown to be associated with response to anti-EGFR therapy. Since most available data come from retrospective studies, there is a need to validate these results in prospective trials.
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PMID:Potential predictive markers of response to EGFR-targeted therapies in colorectal cancer. 1820 83

There are data suggesting that inhibition of epidermal growth factor receptor (EGFR) tyrosine kinase signalling may reverse resistance to fluoropyrimidine treatment. To investigate this further, the INFORM study was an open-label, non-comparative phase II study of gefitinib (Iressa, ZD1839; AstraZeneca, Wilmington, DE, USA) 250 mg daily in combination with 5-fluorouracil (5-FU administered as an intravenous 400 mg m(-2) bolus injection followed by 2800 mg m(-2) infusion over 46 h and folinic acid administered as a 350 mg infusion over 2 h) every 2 weeks for up to 12 cycles in 24 patients with metastatic colorectal cancer refractory to previous fluoropyrimidine treatment. There were no objective responses. The stable disease rate was 37.5% (95% CI: 18.80, 59.41), median progression-free survival measured 116 days and overall survival was 226 days. Quality of life was unchanged compared to baseline values, and the commonest toxicities were diarrhoea, rash and fatigue with 7 out of 24 (29%) patients having a grade 3 or 4 toxicity. Gefitinib does not sensitise patients with fluoropyrimidine refractory metastatic colorectal cancer to 5-FU chemotherapy.
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PMID:A phase II study to determine the ability of gefitinib to reverse fluoropyrimidine resistance in metastatic colorectal cancer (the INFORM study). 1825 19

The human epidermal growth factor receptor (HER1/EGFR/ErbB1) signaling is aberrant and overexpressed in many solid malignancies making it an appealing target for biologic agents. Among the classes of drugs targeting EGFR are monoclonal antibodies and EGFR tyrosine kinase inhibitors, which have been shown effective and generally well tolerated in different clinical settings. The majority of patients treated with EGFR inhibitors (EGFRIs) develop specific dose-dependent skin toxicity. This side effect may lead to physical and psychosocial discomfort which can result in dose reduction or treatment interruption. The relationship between rash and clinical outcome has stimulated interest in this particular toxicity as a possible surrogate marker of efficacy in patients treated with targeted agents against EGFR. This review aims to summarize and update the current knowledge of the clinical presentation, predictive and prognostic value, and the management of EGFRI-related skin toxicity.
Clin Colorectal Cancer 2008 Jan
PMID:Epidermal growth factor receptor inhibitor-related skin toxicity: mechanisms, treatment, and its potential role as a predictive marker. 1827 75

As new multi-target tyrosine kinase inhibitors are emerging in the therapy of various malignancies, our aim was to define the co-expression pattern of receptor-tyrosine-kinase platelet-derived growth factor receptors alpha and beta (PDGFRalpha/beta) in human colorectal cancer. The co-expression pattern of PDGFRalpha/beta was analyzed by RT-PCR in 99 histologically confirmed human colorectal carcinomas and five colorectal cancer cell lines. In addition, immunohistochemical (IHC) staining was applied for confirmation of expression and analysis of receptor tyrosine kinase (RTK) localisation. The colorectal cancer cell lines that were analysed revealed varying expression intensities of PDGFRalpha and PDGFRbeta. The majority of human colorectal cancer specimens revealed a PDGFRalpha (83%) or PDGFRbeta (60%) expression. While PDGFRalpha showed a predominantly cytoplasmic staining in tumor cells as well as in stromal pericytes, PDGFRbeta was restricted to stromal pericytes only. Furthermore, PDGFRalpha expression significantly correlated with lymph node metastasis (P=0.0082) and advanced UICC stages III/IV (P=0.018) in older patients (P=0.043). PDGFRbeta expression only revealed a trend towards lymphatic dissemination (P=0.099). Co-expression of PDGFRalpha/beta occurred in 57% of the colorectal cancer samples, whereas another 29% of the samples depicted mono-expression of PDGFRalpha or PDGFRbeta. Notably, PDGFRalpha/beta expression significantly correlated with lymphatic metastasis (P=0.007) and advanced UICC stages III/IV (P=0.017) in older patients (P=0.03). In summary, our results revealed that PDGFRalpha/beta expression significantly correlates with lymphatic dissemination and therefore encourages application of PDGFRalpha/beta RTK-inhibitors within a combination therapy.
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PMID:PDGFRalpha/beta expression correlates with the metastatic behavior of human colorectal cancer: a possible rationale for a molecular targeting strategy. 1828 4


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