Recent developments of targeted therapies in the treatment of non-small cell lung cancer.

Non small cell lung cancer (NSCLC) is a lethal disease with poor prognosis. The main percentage of NSCLC patients are diagnosed to have an advanced disease. Standard treatment, such as chemotherapy and radiotherapy, has apparently reached a plateau of effectiveness in improving survival of advanced NSCLC patients. Hence, considerable efforts have started to be made in order to identify novel targets for new biological agents which may safely and effectively be administered to advanced NSCLC patients. Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) and its receptors play an essential role in tumour proliferation. Approaches targeting EGFR and VEGF include monoclonal antibodies (mAbs) and small molecules inhibiting the corresponding receptor-tyrosine kinase activity. Erlotinib is a small molecule inhibitor of EGFR tyrosine-kinase which has brought significant improvements in median survival, quality of life and related symptoms, in an unselected population of advanced NSCLC patients in the second- or third-line setting. Bevacizumab, an anti-VEGF recombinant humanized mAb, is the first targeted agent which, when combined with chemotherapy, reported superior efficacy versus chemotherapy alone in the treatment of advanced NSCLC. ZD6474, a small molecule targeting VEGF tyrosine-kinase activity, showing early evidence of antitumour activity and the excellent toxicity profile, seems to be a promising agent for the treatment of advanced NSCLC. This review shows the latest and the future developments of erlotinib, bevacizumab and ZD6474 in the treatment of advanced NSCLC patients.

New insights in drug development for the non-small cell lung cancer therapy.

Non-small cell lung cancer (NSCLC) remains a major problem worldwide. Since most patients with NSCLC have advanced disease at diagnosis, to date, chemotherapy, with third-generation platinum-based doublets, represents the standard of care. However, a plateau has been reached with the use of cytotoxic chemotherapy in advanced NSCLC. Advances in the knowledge of tumour biology and mechanisms of oncogenesis have granted the singling out of several molecular targets for NSCLC treatment. To date, erlotinib and gefitinib, epidermal growth factor receptor tyrosine kinase (EGFR-TK) inhibitors have been licensed, erlotinib worldwide and gefitinib in Asian countries, for refractory NSCLC. Currently, bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, is the only clinically available antiangiogenic agent licensed, in combination with carboplatin plus paclitaxel, for first-line therapy of advanced NSCLC patients in the United States. Several new biologic agents are being evaluated in clinical research and some of them, such as ZD6474, sorafenib and sunitinib, due to the reported preliminary results and the oral administration seem to be promising targeted agents for the treatment of NSCLC. Aim of this review is to discuss about the new insights in targeted agents development for the treatment of NSCLC patients.

New targeted therapies and small-cell lung cancer.

Small-cell lung cancer (SCLC) accounts for almost 15% of lung carcinomas. Chemotherapy is the cornerstone of treatment of patients with SCLC. In limited disease, median survival is about 12-20 months, with no more than 6%-12% of patients surviving beyond 5 years. In extensive disease, median survival is 7-12 months, with < 5% of patients living beyond 2 years and a 5-year survival rate of just 2%. Several therapeutic approaches have been used in an attempt to improve the outcome of SCLC. Among these, a better understanding of tumor biology and the subsequent development of novel therapeutic strategies have been identified as a possible approach for increasing the survival rate of patients with SCLC. Several targeted agents have been introduced into clinical trials in SCLC, and a few phase III studies, including matrix metalloproteinase inhibitors, thalidomide, and vaccines, have already produced definitive results. Currently, negative results are more commonly reported than positive ones. However, this first generation of clinical trials represents only the beginning of clinical research in this field. To date, no targeted therapy has been approved for use in the treatment of patients with SCLC. Nevertheless, clinical research in this field is still in progress considering that several new targeted agents, such as antiangiogenic agents and mammalian target of rapamycin inhibitors, offer a promise of improved outcomes. This review will focus on the reported results and the future development of the main novel biologic agents for the treatment of patients with SCLC.

Overexpression of both CXC chemokine receptor 4 and vascular endothelial growth factor proteins predicts early distant relapse in stage II-III colorectal cancer patients.

PURPOSE: CXC chemokine receptor 4 (CXCR4) and vascular endothelial growth factor (VEGF) are implicated in the metastatic process of malignant tumors. However, no data are currently available on the biological relationship between these molecules in colorectal cancer. We studied whether CXCR4 and VEGF expression could predict relapse and evaluated in vitro the contribution of CXCR4 in promoting clonogenic growth, VEGF secretion, and intercellular adhesion molecule-1 (ICAM-1) expression of colorectal cancer cells. EXPERIMENTAL DESIGN: CXCR4 and VEGF were studied in colorectal cancer tissues and in Lovo, HT29, and SW620 colorectal cancer cell lines by immunohistochemistry. Correlations with baseline characteristics of patients and tumors were analyzed by chi2 test. VEGF secretion induced by CXCL12 was measured by ELISA. The effect of CXCL12 on ICAM-1 expression was evaluated by flow cytometry. Clonogenic growth induced by CXCL12 was determined by clonogenic assays. Functional effects induced by CXCL12 were prevented by the administration in vitro of AMD3100, a bicyclam noncompetitive antagonist of CXCR4. RESULTS: Seventy-two patients, seen between January 2003 and January 2004, were studied. CXCR4 was absent in 16 tumors (22.2%); it was expressed in < or = 50% of cells in 25 (34.7%) tumors and in >50% of cells in 31 (43.0%) tumors. VEGF was absent in 17 (23.6%) tumors; it was expressed in < or = 50% of cells in 16 (22.2%) tumors and in >50% of cells in 39 (54.2%) tumors. There was a significant association between CXCR4 expression and lymph nodal status (P = 0.0393). There were significant associations between VEGF and tumor invasion (P = 0.0386) and lymph nodal involvement (P = 0.0044). American Joint Committee on Cancer stage (P = 0.0016), VEGF expression (P = 0.0450), CXCR4 expression (P = 0.0428), and VEGF/CXCR4 expression (P = 0.0004) had a significant prognostic value for disease-free survival with univariate analysis. The predictive ability of the American Joint Committee on Cancer stage and of the concomitant and high expression of VEGF and CXCR4 was confirmed by multivariate analysis. Prognosis is particularly unfavorable for patients whose primary tumors express CXCR4 and VEGF in >50% of cells (median disease-free survival in relapsed patients, 5.8 months; hazard ratio of relapse, 8.23; 95% confidence interval, 7.24-14.29). In clonogenic assays, CXCL12 (20 ng/mL/d) significantly increased the number of clones in SW620, HT29, and Lovo cells at 7 and 14 days. Again, CXCL12 was able to stimulate VEGF secretion in SW620, HT29, and Lovo cells as well as up-regulated ICAM-1. These effects were prevented by the administration of AMD3100 (1 micromol/L). CONCLUSIONS: We have shown that concomitant and high expression of CXCR4 and VEGF is a strong and independent predictor of early distant relapse in colorectal cancer. CXCR4 triggers a plethora of phenomena, including stimulation of clonogenic growth, induction of VEGF release, and ICAM-1 up-regulation. These data support the inhibition of CXCR4 to prevent the development of colorectal cancer metastasis.

Cyclooxygenase-2 expression is associated with increased size in human sporadic colorectal adenomas.

BACKGROUND: Cyclooxygenase-2 (COX-2) has been implicated in colorectal carcinogenesis but its role is not completely defined. MATERIALS AND METHODS: The expression of COX-2 was evaluated in 68 paraffin-embedded sporadic colorectal adenomas by immunohistochemistry. Associations between COX-2 expression and the clinicopathological characteristics of the adenomas were studied by contingency tables and the Chi-square test. RESULTS: Cytoplasmic staining for COX-2 protein was present in epithelial cells of 62 out of the 68 adenomas. COX-2 expression was not associated with age or gender. Furthermore, no significant correlations were found between the expression of the protein and histology (tubular vs tubulovillous), localization (proximal vs distal) or morphology (sessil vs pedunculated) of the adenomas. Both stromal and epithelial COX-2 expressions were higher in larger (>4 mm) compared with smaller (< or =4 mm) adenomas (p =0. 037 and p=0. 024). CONCLUSION: These data support the hypothesis that the expression of COX-2 may occur as a general phenomenon in colorectal adenomas. A size-dependent increase of COX-2 expression might be involved in colorectal carcinogenesis.

Activity of chemotherapy in mucinous epithelial ovarian cancer: a retrospective study.

OBJECTIVE: Mucinous ovarian carcinoma has a poorer prognosis compared with other histological subtypes. The aim of this study was to evaluate, retrospectively, the activity of first-line and second-line chemotherapy in patients with mucinous ovarian cancer in a mono-institutional series. PATIENTS AND METHODS: In the period under survey (1996-2003), 225 new patients with ovarian cancer were treated. Twenty-one out of these patients (9.3%) received a diagnosis of mucinous ovarian cancer. The median age, performance status, stage at diagnosis and residual disease after surgery were similar in the mucinous compared to the other histological groups (P=NS). RESULTS: In mucinous ovarian cancer the grading of the tumors was 2 in 76% of the cases, while grade 3 was more frequent in the other subtypes (p<0.002). Eighty-five % of the patients had received carboplatin/paclitaxel, while the remaining cases had been treated with a cisplatin-based chemotherapy not containing paclitaxel. Two patients with early stage were treated with adjuvant chemotherapy and were not evaluable for response while 19 patients had measurable disease (12 pts) or were assessed at second-look (7 pts). Forty-seven % of the 19 patients experienced disease progression during first-line, while 31.5% and 10.5% complete and partial responses were recorded, respectively. Fifteen out of the 21 patients had progressed at the time of the analyses. Sixty % of the progressed patients were platinum-refractory, 3 cases were platinum-sensitive and 3 platinum-resistant. The 3 platinum-sensitive patients were treated with single agent carboplatin without any response. No response was recorded with topotecan or liposomal doxorubicin when given as second- or third-line treatment in platinum-refractory/resistant patients. CONCLUSION: Mucinous ovarian cancer has a poor response to chemotherapy both in the first-line and in the recurrence settings. Studies with alternative chemotherapy combinations are mandatory in this histological subgroup.

Factors driving the choice of the best second-line treatment of advanced NSCLC.

Platinum-based chemotherapy, with or without the antiangiogenetic drug bevacizumab, is the standard first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC). The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) gefitinib has been recently approved as treatment of patients with EGFR mutated tumors (including first-line). Three agents are approved for treating non-selected patients who progress after one prior regimen: docetaxel, pemetrexed, and the EGFR-TKI erlotinib. Gefitinib can be used as second-line treatment in patients with EGFR mutated tumors. Although these agents have yelded similar outcomes in terms of antitumor activity and efficacy in unselected NSCLC patients, they have different toxicity profiles, and recently some strong factors that can help in the choice among them have been detected. In particular, the hystotype, the EGFR gene mutational status, the response to previous first-line chemotherapy and the correlation of the safety profile of the agents with Performance Status and comorbidities of the patients, are the most important factors that drive the choice of the second-line treatment. Obviously, the drugs administered in the first-line treatment strongly influence the choice of the second-line treatment because some of the currently available drugs can be used in both settings. Thus, more than in the past, first and second-line treatment of advanced NSCLC are linked, and the choice of second-line treatment is part of a strategy decided when beginning the first-line treatment.

Erlotinib in the treatment of non-small cell lung cancer: current status and future developments.

Erlotinib is an orally small molecule inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR). Currently, erlotinib, at a standard oral daily dose of 150 mg, is licensed for the treatment of unselected recurrent non-small cell lung cancer (NSCLC) patients, however, it is being investigated in all stages of NSCLC. Erlotinib is well tolerated, with common toxicities including rash and diarrhoea. The optimization of the therapeutic impact of erlotinib in NSCLC will be more defined when reliable predictive factors are identified. An important step has been made in the molecular characterization of potentially sensitive NSCLC patients. In fact, we have learned that activation, somatic EGFR gene mutations within the tyrosine kinase domain, are associated with a high possibility of a long lasting therapeutic response to erlotinib. The present review discusses the role of erlotinib in the treatment of NSCLC.

Vascular endothelial growth factor receptor as target for advanced non-small cell lung cancer therapy.

Lung cancer remains the leading cause of malignancy-related mortality world-wide, in both men and women, with over a million cases diagnosed yearly. Non-small cell lung cancer (NSCLC) accounts for more than 80% of all lung cancers, and most patients are diagnosed with advanced disease. Although substantial progress has been made in the therapeutic options currently available for patients with advanced NSCLC, chemotherapy has apparently reached a plateau of effectiveness in improving survival in this subgroup of patients. Considerable efforts have been initiated to identify novel targets for new biological agents which may safely and effectively be administered to NSCLC patients. New blood vessel formation, known as angiogenesis, is a fundamental event in the process of tumor growth and metastatic dissemination. The vascular endothelial growth factor receptor (VEGFR) plays an essential role in tumor angiogenesis and proliferation, and has been a major focus of basic research and drug development in the field of Oncology. Approaches targeting VEGFR include mainly small molecule inhibitors of VEGFR tyrosine kinase activity. Among these, vandetanib, due to early findings of its antitumor activity and a good toxicity profile, has been largely investigated in advanced NSCLC. Other antiangiogenic drugs, such as sorafenib, and sunitinib are being tested in ongoing clinical trials which will further define their role in the management of NSCLC. Here we review the current results and give an overview of some of the future developments of the main anti-VEGFR drugs in the treatment of NSCLC patients.

Treating advanced non-small cell lung cancer in the elderly.

More than 40% of cases of all lung cancers are diagnosed in patients over the age of 70 years. Elderly patients have more comorbidities and tend to be less tolerant to toxic medical treatments than their younger counterparts. Thus, clinical data obtained in a younger population cannot be automatically extrapolated to the great majority of nonselected elderly patients with non-small cell lung cancer (NSCLC). The bulk of prospective clinical data regarding chemotherapy and molecularly targeted therapy for elderly NSCLC patients come from studies in advanced disease. In elderly advanced NSCLC patients, single-agent chemotherapy with third-generation agents (vinorelbine, gemcitabine, taxanes) is to be considered the routine standard of care for unselected patients, based on phase II and III trials specifically designed for this special population. Cisplatin-based chemotherapy with cisplatin at attenuated doses has been demonstrated to be an active and feasible option in phase II trials. Among targeted therapies, the epidermal growth factor receptor tyrosine kinase inhibitors, erlotinib and gefitinib, have relevant phase II prospective data showing activity and good tolerability as first-line treatment in this population. Concerning the antivascular endothelial growth factor monoclonal antibody, bevacizumab, combined with chemotherapy, particular care must be taken for elderly patients because of the higher incidence of cardiovascular comorbidities. The lack of data on octogenarians suggest that clinicians should exercise caution when applying the existing data on chemotherapy and targeted therapies for patients aged 70-79 years to those aged >80 years. Further specifically designed clinical trials are needed to optimize medical treatment of NSCLC in elderly patients.

New avenues for second-line treatment of metastatic non-small-cell lung cancer.

Platinum-based doublets are the standard first-line therapy for patients with advanced non-small-cell lung cancer, with approximately a third of patients obtaining an objective response with first-line chemotherapy and another 20-30% achieving temporary disease stabilization. However, all patients inevitably experience disease progression. Three agents are approved for treating patients who progress after one prior regimen: docetaxel, pemetrexed and erlotinib. Erlotinib is the only agent approved for use in the third-line setting. Although these agents have yielded similar outcomes in terms of anti-tumor activity and efficacy, they have different toxicity profiles, and some factors that can help in the choice among them have begun to emerge, such as smoking history and histotype. Several new molecularly targeted agents have shown activity in Phase II trials and may be integrated into second-line therapy as single agents or in combination with current agents in the future. In particular, the most encouraging data in this clinical setting have been reported with the antiangiogenetic drugs bevacizumab (already approved for use in the first-line setting), vandetanib and sunitinib. Phase III trials with these agents are ongoing.

The role of cetuximab and other epidermal growth factor receptor monoclonal antibodies in the treatment of advanced non-small cell lung cancer.

Lung cancer continues to be the leading cause of cancer-related deaths in the western civilization and developing countries. Non-small cell lung cancer (NSCLC) accounts for > 85% of all cases of lung cancer. Since most patients with NSCLC have advanced disease at diagnosis, to date chemotherapy with third-generation platinum-based doublets represents the standard of care. However, a plateau has been reached with the use of cytotoxic chemotherapy in advanced NSCLC. Advances in the knowledge of tumour biology and mechanisms of oncogenesis have granted the singling out of several molecular targets for NSCLC treatment. In particular, the epidermal growth factor receptor (EGFR), a member of the ErbB family and commonly overexpressed in NSCLC, is one of the most studied targets. Overexpression of EGFR has been associated with a poorer prognosis in patients with cancer, therefore its inhibition may lead to the suppression of tumor proliferation improving clinical outcome. Strategies to block EGFR include development of monoclonal antibodies to EGFR, tyrosine kinase inhibitors, ligand-linked toxins, and antisense approaches. This article will focus on cetuximab and other monoclonal antibodies and their applications in the treatment of advanced NSCLC.