Biomedical subjects

Clare Topham

Publications and source records attributed to Clare Topham.

7 recordsLinked to original sources

PubMed2006

Coexpression of the IGF-IR, EGFR and HER-2 is common in colorectal cancer patients.

Signalling via the insulin-like growth factor-I receptor (IGF-IR) has been associated with resistance to anti-epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER-2)-based therapies in the experimental system, but the coexpression and clinical significance of the IGF-IR, EGFR and HER-2 in cancer patients remains unclear. IGF-IR, EGFR, and HER-2 status was assessed retrospectively in tumour specimens from 87 Dukes' C colorectal cancer patients using immunohistochemistry. Sections were scored by the percentage of positive cells (membrane and cytoplasmic) and intensity of staining. The association between receptor coexpression and clinicopathological parameters and overall survival were evaluated using univariate and multivariate (Cox) analysis. Overall, 93, 83 and 89% of the cases expressed IGF-IR, EGFR and HER-2, respectively. While 60% of the cases expressed membranous IGF-IR, the expression of EGFR and HER-2 was predominantly cytoplasmic. Coexpression of the IGF-IR, EGFR and HER-2 was present in tumours from 75% of the patients. No significant association was found between the expression or coexpression of total IGF-IR, EGFR and HER-2 and clinicopathological parameters or overall survival. Our results indicate that coexpression of IGF-IR, EGFR and HER-2 is common in Dukes' C colorectal cancer, warranting further investigation on the co-targeting of such receptors in colorectal cancer patients.

Aged↗

PubMed2005

Once-weekly treatment of anemia in patients with cancer: a comparative review of epoetins.

Anemia is common in cancer patients, but its impact is often poorly appreciated. As well as the negative effect of anemia on the quality of life, there is strong evidence that it is associated with poor treatment outcome and reduced survival. The introduction of recombinant human erythropoietin (epoetin) has provided an effective treatment of anemia, without the risk associated with blood transfusion. A recent randomized study of patients with hematological malignancies showed that once-weekly epoetin beta has comparable efficacy at the same overall weekly dose as three-times-weekly treatment. This once-weekly regimen of epoetin beta (NeoRecormon) has been approved by European Regulatory Authorities for patients with lymphoproliferative malignancies and relative erythropoietin deficiency, who are receiving anti-tumor therapy. Darbepoetin alpha (Aranesp) has also recently been approved for once-weekly treatment of anemia in patients with nonmyeloid malignancies receiving chemotherapy. The improved convenience and reduced administration costs associated with a once-weekly treatment may result in more patients receiving the benefits of epoetin therapy.

Anemia, Hypochromic↗

PubMed2005

Coexpression, prognostic significance and predictive value of EGFR, EGFRvIII and phosphorylated EGFR in colorectal cancer.

In colorectal cancer, epidermal growth factor receptor (EGFR) expression is reported in 8-100% of the cases examined and there has been no clear association between EGFR expression and prognosis, or response to EGFR inhibitors. In this retrospective study, 87 archival specimens from node positive (Dukes' C) colorectal cancer patients were analysed immunohistochemically, for the expression of EGFR, mutant EGFR (EGFRvIII) and phosphorylated EGFR (pEGFR, tyr1068). Each section was scored on the basis of location and intensity of staining, and the immunostaining was considered positive if greater than 10% of the tumour cells were stained by the antibody. The association between these scores and overall survival was estimated using univariate and multivariate (Cox) analysis. Overall, we found that 76% and 100% of cases were EGFR positive using antibodies to the external or internal domain of EGFR respectively, and 34% of the cases were EGFRvIII positive. However, only 8% of the cases expressed pEGFR and pEGFR immunostaining was never present in more than 10% of tumour cells. The expression of EGFR, EGFRvIII, pEGFR, or coexpression of EGFR and EGFRvIII was not associated with overall survival. Cytoplasmic expression of EGFR (p = 0.0141) or EGFRvIII (p = 0.005) was, however, associated with improved survival in patients receiving radiotherapy. Our results suggest that coexpression of cytoplasmic EGFR and EGFRvIII occurs in a significant proportion (34%) of Dukes' C colorectal cancer and the cytoplasmic expression of EGFR or EGFRvIII is a good indicator of response to radiotherapy.

Aged↗

PubMed2004

A randomized trial comparing defined-duration with continuous irinotecan until disease progression in fluoropyrimidine and thymidylate synthase inhibitor-resistant advanced colorectal cancer.

PURPOSE: Irinotecan given until disease progression is an accepted standard treatment for advanced colorectal cancer (CRC) resistant to fluoropyrimidines. It is not known whether a predefined period of irinotecan treatment would result in similar duration of disease control. We performed a multicenter phase III trial to compare the two policies of defined-duration versus continuous irinotecan treatment. PATIENTS AND METHODS: Three hundred thirty-three eligible patients with advanced CRC progressing on or within 24 weeks of completing fluoropyrimidine-based chemotherapy were prospectively registered. After receiving eight cycles of irinotecan given at 350 mg/m2 once every 3 weeks, 55 patients with responding or stable disease were randomly assigned to stop irinotecan (n = 30) or continue until disease progression (n = 25). Registered patients were not randomly assigned predominantly due to disease progression (n = 236) and intolerable toxicity (n = 38). RESULTS: From the time of random assignment, there were no differences in failure-free survival (P = .999) or overall survival (P = .11) between the two arms. No difference was seen in mean global health status quality-of-life score between the two arms at 12 weeks after random assignment. No grade 3 diarrhea and febrile neutropenia was seen in the continue-irinotecan arm after random assignment. CONCLUSION: For most patients, the decision to continue on irinotecan beyond 24 weeks is influenced by disease progression or treatment-related toxicity. However, for 17% of patients in whom this decision is clinically relevant, there seems to be little benefit from continuing irinotecan, though the drug was well tolerated without any deterioration in quality of life.

Adult↗

PubMed2004

Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer.

BACKGROUND: The standard adjuvant treatment of colon cancer is fluorouracil plus leucovorin (FL). Oxaliplatin improves the efficacy of this combination in patients with metastatic colorectal cancer. We evaluated the efficacy of treatment with FL plus oxaliplatin in the postoperative adjuvant setting. METHODS: We randomly assigned 2246 patients who had undergone curative resection for stage II or III colon cancer to receive FL alone or with oxaliplatin for six months. The primary end point was disease-free survival. RESULTS: A total of 1123 patients were randomly assigned to each group. After a median follow-up of 37.9 months, 237 patients in the group given FL plus oxaliplatin had had a cancer-related event, as compared with 293 patients in the FL group (21.1 percent vs. 26.1 percent; hazard ratio for recurrence, 0.77; P=0.002). The rate of disease-free survival at three years was 78.2 percent (95 percent confidence interval, 75.6 to 80.7) in the group given FL plus oxaliplatin and 72.9 percent (95 percent confidence interval, 70.2 to 75.7) in the FL group (P=0.002 by the stratified log-rank test). In the group given FL plus oxaliplatin, the incidence of febrile neutropenia was 1.8 percent, the incidence of gastrointestinal adverse effects was low, and the incidence of grade 3 sensory neuropathy was 12.4 percent during treatment, decreasing to 1.1 percent at one year of follow-up. Six patients in each group died during treatment (death rate, 0.5 percent). CONCLUSIONS: Adding oxaliplatin to a regimen of fluorouracil and leucovorin improves the adjuvant treatment of colon cancer.

Adult↗

PubMed2004

The expression and prognostic significance of HER-2 in colorectal cancer and its relationship with clinicopathological parameters.

The prognostic role of HER-2 has been established in breast cancer but remains controversial in colorectal cancer. In this study, 170 archival specimens of Dukes' B and C colorectal cancer were analysed immunohisto-chemically, using an anti-HER-2 monoclonal antibody HM64.13. Immunostaining was classified as cytoplasmic or membranous, and the intensity of the immunostaining was graded negative, weak or strong. The association between these scores and survival was estimated using Cox survival analyses. Overall, 87% of cases showed cytoplasmic HER-2 staining, with 54% exhibiting strong intensity cytoplasmic immunostaining. Membranous HER-2 was seen in 41% of cases, with most of these being of strong intensity. No correlation with clinical outcome was seen with membranous HER-2. Positive cytoplasmic immunostaining was found to be associated with a significantly better overall survival (HR 0.46, CI95 0.24-0.87) in the Dukes C cancers, but no survival benefit was seen in the Dukes' B cancers. Tumour grade, depth of tumour invasion and positive apical node were also found to be independent prognostic factors in Dukes' C cancers. We conclude that HER-2 over-expression occurs in a significant number of colorectal cancers. Since cytoplasmic HER-2 is incapable of transmitting the strong mitogenic signal via heterodimerization with other members of the Epidermal Growth Factor Receptor (EGFR) family, this may partly explain the correlation between cytoplasmic HER-2 over-expression and a better prognosis in the Dukes' C colorectal cancers. In addition, high levels of membraneous HER-2 in colorectal cancer could make HER-2 a good target for monoclonal antibody-based immunotherapy.

Antibodies, Monoclonal↗

PubMed2002

Oncosurgery: a new reality in metastatic colorectal carcinoma.

Surgery is the only curative option for the treatment of liver metastases from colorectal cancer. However, fewer than 25% of hepatic metastases are suitable for resection and as many as 70% of these will recur. A variety of factors have been identified as significant predictors of long-term survival following hepatic resection, and improved surgical techniques such as cryosurgery, radiofrequency ablation, portal vein embolization, and two-stage hepatectomy have been developed to overcome some of the negative factors that contribute to poor prognosis. Whereas adjunctive 5-fluorouracil-based chemotherapy has had little impact on outcome, the new platinum derivative oxaliplatin added to 5-fluorouracil plus leucovorin has improved time-dependent parameters of efficacy and successfully downstaged the disease in some patients with unresectable metastases. In a recent study in 389 such patients, 151 of which had liver-only metastases, 51% treated with oxaliplatin became resectable with some patients achieving a complete histologic response. In another series of 95 initially unresectable patients who became resectable after treatment with oxaliplatin-based therapy, 41% were still alive after 4.2 years, with 64% of these being recurrence-free. Postoperative chemotherapeutic regimes have also been developed to eliminate residual disease after surgery; however, the advantage of preoperative chemotherapy is the potential to achieve a conversion from unresectability to resectability of hepatic metastases from primary colorectal cancer.

Colorectal Neoplasms↗