Michele Orditura

Expression of Vascular Endothelial Growth Factor (VEGF) and Epidermal Growth Factor Receptor (EGFR) is an Independent Prognostic Indicator of Worse Outcome in Gastric Cancer Patients

BackgroundUnlike other human tumors, gastric cancer remains a great therapeutic challenge since no standardized postoperative treatment exists. Knowledge of molecular pathways determining the behavior of individual gastric tumors seems to be crucial for therapeutic decisions, and evaluation of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expression might be critical for prognosis, assessment, and identification of patients that could be treated with tailored therapies.MethodsVEGF and EGFR determination was performed in 88 gastric cancer samples as well as 25 normal gastric mucosa specimens from non-cancer patients using a commercially available immunohistochemistry kit. In all samples, the correlation of VEGF and EGFR expression was investigated with each other, and with other prognostic indicators in all samples, and, finally, with survival rates in 69 patients undergoing potentially curative surgery.ResultsForty-eight per cent (42 cases) of gastric cancers expressed VEGF, and 44% (39 cases) stained for EGFR. In curatively treated patients, VEGF and EGFR expression was demonstrated to correlate with worse survival in both univariate and multivariate analyses. Molecular profiling was shown to more accurately estimate the risk of cancer-related death than TNM stage, and, of most interest, to allow sorting out high-risk patients within the same stage.ConclusionsThese findings provide evidence that contemporary evaluation of VEGF and EGFR expression may be crucial to select gastric cancer patients with poor prognosis who may benefit of tailored treatments.

Treatment of gastric cancer

The authors focused on the current surgical treatment of resectable gastric cancer, and significance of peri- and post-operative chemo or chemoradiation. Gastric cancer is the 4(th) most commonly diagnosed cancer and the second leading cause of cancer death worldwide. Surgery remains the only curative therapy, while perioperative and adjuvant chemotherapy, as well as chemoradiation, can improve outcome of resectable gastric cancer with extended lymph node dissection. More than half of radically resected gastric cancer patients relapse locally or with distant metastases, or receive the diagnosis of gastric cancer when tumor is disseminated; therefore, median survival rarely exceeds 12 mo, and 5-years survival is less than 10%. Cisplatin and fluoropyrimidine-based chemotherapy, with addition of trastuzumab in human epidermal growth factor receptor 2 positive patients, is the widely used treatment in stage IV patients fit for chemotherapy. Recent evidence supports the use of second-line chemotherapy after progression in patients with good performance status.

A phase II study of biweekly oxaliplatin plus infusional 5-fluorouracil and folinic acid (FOLFOX-4) as first-line treatment of advanced gastric cancer patients

The aim of the study was to assess the toxicity and the clinical activity of biweekly oxaliplatin in combination with infusional 5-fluorouracil (5-FU) and folinic acid (FA) administered every 2 weeks (FOLFOX-4 regimen) in patients with advanced gastric cancer (AGC). A total of 61 previously untreated AGC patients were treated with oxaliplatin 85 mg m−2 on day 1, FA 200 mg m−2 as a 2 h infusion followed by bolus 5-FU 400 mg m−2 and a 22 h infusion of 5-FU 600 mg m−2, repeated for 2 consecutive days every 2 weeks. All patients were assessable for toxicity and response to treatment. Four (7%) complete responses and 19 partial responses were observed (overall response rate, 38%). Stable disease was observed in 22 (36%) patients, with progressive disease in the other six (10%) patients. Median time to progression (TTP) and median overall survival (OS) were 7.1 and 11.2 months, respectively. National Cancer Institute Common Toxicity Criteria grade 3 and 4 haematologic toxicities were neutropenia, anaemia and thrombocytopenia in 36, 10 and 5% of the patients, respectively. Grade 3 peripheral neuropathy was recorded in three (5%) patients. FOLFOX-4 is an active and well-tolerated chemotherapy. Response rate (RR), TTP and OS were comparable with those of other oxaliplatin-based regimens, suggesting a role for this combination in gastric cancer.

Epidermal Growth Factor Receptor (EGFR) Expression is Associated With a Worse Prognosis in Gastric Cancer Patients Undergoing Curative Surgery

BackgroundIn gastric cancer, the recurrence rate is high even after curative surgery. A relevant issue is the identification of independent prognostic factors to select high-risk patients; such features can be used as predictive factors for tailored therapies. In this study we have investigated the role of epidermal growth factor receptor (EGFR) expression as a prognostic marker for predicting cancer behavior and clinical outcome in gastric cancer patients undergoing potentially curative surgery.MethodsEpidermal growth factor receptor determination using a commercially available immunohistochemistry (IHC) kit was performed in tissues from 82 gastric cancer patients receiving primary surgical treatment and in 25 normal gastric mucosa specimens from noncancer patients. The EGFR positivity was correlated with disease recurrence and survival in univariate and multivariate analyses.ResultsForty-four percent (36 cases) of gastric cancers were EGFR positive. In 66 curatively treated patients, EGFR expression correlated with disease recurrence and poorer survival in both univariate and multivariate analyses. In a multivariate model for predicting recurrence and survival, advanced tumor extension (T3 or T4), nodal metastases, and EGFR expression were the only independent covariates. In particular, EGFR expression was shown to be a significant predictor of poor prognosis among gastric cancer patients having the same stage according to the current TNM staging system.ConclusionsThese findings suggest that EGFR expression may be useful in identifying high-risk gastric cancer patients undergoing potentially curative surgery. Multimodal treatments should be considered in the adjuvant treatment of these patients.

DETERMINATION OF MOLECULAR MARKER EXPRESSION CAN PREDICT CLINICAL OUTCOME IN COLON CARCINOMAS

Purpose: Conventional staging procedures are often unable to precisely predict prognosis in colorectal cancer (CRC). In this study, we set out to investigate the possible role of molecular/structural indicators involved in cell cycle regulation (p27 and p53), apoptosis (p53 and p27), and tumor neoangiogenesis [p53, vascular endothelial growth factor (VEGF), and microvessel count] in predicting tumor behavior and clinical outcome in CRC patients Experimental Design: Analysis of the above indicators was performed by immunohistochemistry on 104 CRC patient samples and 25 normal colon mucosa specimens. Results: Intense p27 nuclear staining was found in normal colon mucosa, with p53 nuclear staining and VEGF cytoplasmic accumulation <10%, and low microvessel count. In contrast, in CRC samples, p27 was down-regulated in 53.8%, p53 protein was overexpressed in 52%, and VEGF stained positive in 67.3% of the cases, respectively. Multiple regression analysis showed that molecular markers were strongly correlated. In patients treated with curative surgery, a significant relationship was seen between p27 down-regulation and Dukes’ stage, nodal status, and the presence of distant metastases. VEGF overexpression correlated significantly with Dukes’ stage, tumor (t) and metastasis (m) parameters, and left site. Stepwise regression selected p27, p53, VEGF, and Dukes’ stage as the best combination of variables capable of predicting both disease-specific and disease-free survival. Conclusions: The investigated indicators may be useful for the prediction of outcome and recurrence rate in curatively treated CRC patients. In conjunction with clinical and pathological staging, they may provide a stronger indication of clinical outcome than staging alone and help better select therapeutic options in CRC patients.

Prognostic Significance of Epidermal Growth Factor Receptor Expression in Colon Cancer Patients Undergoing Curative Surgery

BackgroundTo investigate the role of epidermal growth factor receptor (EGFR) expression as a prognostic marker for prediction of cancer behavior and clinical outcomes in colon cancer patients undergoing potentially curative surgery.MethodsEGFR determination using a commercially available immunohistochemistry kit was performed in tissues from 149 colon cancer patients receiving primary surgical treatment and in 25 normal colon mucosa specimens from noncancer patients. EGFR positivity was correlated in univariate and multivariate analyses with disease recurrence and survival. In addition, p27, p53, and vascular endothelial growth factor expression were assessed by immunohistochemistry in 104 patients and correlated with EGFR tumor expression and clinical outcome.ResultsEGFR expression was detected in approximately one third of colon cancer patients (53 of 149; 35.6%). In 126 curatively treated patients, EGFR expression was correlated with disease recurrence and worse survival in both univariate and multivariate analyses. In a multivariate model for predicting recurrence and survival, Dukes’ staging, p27, and EGFR expression were the only independent covariates. In particular, in Dukes’ A and B patients the 5-year survival probability was 96% for EGFR-negative and high p27 expression cases and was 30.7% for EGFR-positive and low p27 expression cases.ConclusionsEGFR expression was an independent prognostic indicator of disease recurrence and poor survival in colon cancer patients undergoing curative surgery. In the context of novel therapeutic options such as molecularly targeted therapies, these findings suggest that anti-EGFR drugs could be evaluated in the adjuvant treatment of EGFR-positive colon cancer patients.

First-Line Chemotherapy vs Bowel Tumor Resection Plus Chemotherapy for Patients With Unresectable Synchronous Colorectal Hepatic Metastases

HYPOTHESIS Bowel resection followed by chemotherapy is a better management strategy than immediate chemotherapy in asymptomatic patients with colorectal cancer and unresectable liver-only metastases at presentation. DESIGN Retrospective study. SETTING University hospital. PATIENTS Sixty-five consecutive symptom-free colorectal cancer patients with unresectable synchronous metastases confined to the liver undergoing bowel tumor resection plus systemic chemotherapy (42 patients [resection group]) or chemotherapy first (23 patients [chemotherapy group]). MAIN OUTCOME MEASURES Long-term survival and identification of prognostic indicators of outcome. RESULTS In the resection group, the mean and median overall survival times were shown to be significantly better than those in the chemotherapy group (P = .03). Performance status, basal serum levels of lactic dehydrogenase and alkaline phosphatase, percentage of liver involvement, potentially curative resection of the bowel tumor, and type of treatment (resection vs chemotherapy) were demonstrated to be the only variables significantly correlated with long-term survival. On multivariate analysis, performance status, extent of liver involvement, and type of treatment were shown to be the only covariates independently associated with survival rate. The rate of liver metastasis downstaging with subsequent curative hepatic resection was clearly associated with good performance status, limited liver involvement, and resection of the bowel tumor. CONCLUSIONS Achieving complete cure in asymptomatic colorectal cancer patients with unresectable synchronous liver-only metastases appears to be mostly the result of shrinkage and resection of hepatic metastases. In patients with good performance status and limited liver involvement, bowel tumor resection appears to be the best treatment option for this purpose.

Phase II study of gefitinib in combination with docetaxel as first-line therapy in metastatic breast cancer.

We have evaluated the activity and safety of gefitinib, a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in combination with docetaxel as first-line treatment of women with metastatic breast cancer (MBC). In total, 41 patients with MBC were enrolled in a first-line combination therapy study with oral gefitinib (250 mg day−1) and intravenous docetaxel (75 mg m−2, the first 14 patients; or 100 mg m−2, the following 27 patients, on day 1 of a 3-week cycle). Out of 41 patients, 38 received at least one cycle of therapy. There were no differences in activity or tolerability between the two docetaxel doses. G3/4 toxicities were neutropenia (49%), diarrhoea (10%), acne-like rash (5%), and anaemia (2%). Complete plus partial responses (CR+PR) were observed in 22 out of 41 patients with a 54% response rate (95% confidence interval (CI) 45–75%). The 22 patients that achieved a response following six cycles of docetaxel plus gefitinib continued gefitinib monotherapy (median duration, 24 weeks; range, 2–108+ weeks). Two patients with PR following combination therapy achieved a CR during gefitinib monotherapy. Complete plus partial responses correlated with oestrogen receptor (ER) status, since they occurred in 19 out of 27 (70%) patients with ER-positive tumours as compared to three out of 14 (21%) patients with ER-negative tumours (P=0.01).

The role of EGFR inhibitors in nonsmall cell lung cancer.

Purpose of review The epidermal growth factor receptor is a cell membrane receptor that plays a key role in cancer development and progression. Ligand-activated epidermal growth factor receptor-dependent signaling is involved in cell proliferation, apoptosis, angiogenesis, invasion, and metastasis. Targeting the epidermal growth factor receptor represents a promising molecular approach in cancer treatment. Several antiepidermal growth factor receptor agents are in clinical development. This review focuses on the available clinical data on epidermal growth factor receptor-targeting drugs in the treatment of nonsmall cell lung cancer. Recent findings Three drugs are currently in phase 2 and phase 3 development as single agents or in combination with other anticancer therapies in nonsmall cell lung cancer patients: cetuximab (Erbitux), a chimeric human–mouse monoclonal IgG1 antibody that blocks ligand binding and functional epidermal growth factor receptor activation; and erlotinib (Tarceva) and gefitinib (Iressa), two orally bioavailable, small-molecule epidermal growth factor receptor inhibitors of tyrosine kinase enzymatic activity that prevent epidermal growth factor receptor autophosphorylation and activation. Single-agent gefitinib treatment has determined a 10 to 20% response rate and a 30 to 50% symptom improvement in previously treated, chemotherapy-refractory advanced nonsmall cell lung cancer patients. Gefitinib has been the first epidermal growth factor receptor-targeting agent to be registered as an anticancer drug in several countries, including Japan, Australia, and the United States, for the third-line treatment of chemoresistant nonsmall cell lung cancer patients. Summary Antiepidermal growth factor receptor has shown promising antitumor activity in nonsmall cell lung cancer patients with a mild toxicity profile. However, a series of important clinical issues such as selection of potentially responsive patients and optimal combination with conventional anticancer treatments needs to be addressed to use these drugs better in lung cancer.

Serum interleukin-10 levels in patients with advanced gastrointestinal malignancies

Interleukin‐10 (IL‐10) is a cytokine with immunosuppressive properties. In this study, the authors investigated the prognostic significance of IL‐10 levels in the sera of 58 patients with advanced gastric or colorectal carcinoma.