Non-small cell lung cancer therapy in the elderly.

To date, lung cancer is still the leading cause of cancer-related mortality worldwide, with the majority of lung cancers arising in the elderly. As a consequence, we can expect an increase in the number of older lung cancer patients considered suitable for chemotherapy in the near future. Elderly patients often have comorbid conditions and progressive physiologic reduction of organ function, which can make the selection of proper treatment daunting. Some patients will be able to tolerate chemotherapy as well as their younger counterparts, whereas others will experience severe toxicity and require treatment modifications. Thus, a major issue is effectively selecting patients suitable for standard or attenuated therapy. A comprehensive geriatric assessment performed at baseline is a useful tool that can help select the best treatment regimen to be administered to elderly patients. Until now, few trials have specifically focused on elderly patients affected by non-small cell lung cancer (NSCLC), particularly those with advanced disease; prospective elderly-specific studies in early stages are still lacking. High priority should be given to evaluating the role of new targeted therapies. Unfortunately, to date, clinical trials that include functional status and comorbidity as part of the geriatric assessment are rare. Future trials, specifically in the elderly population, should include these kinds of evaluations. The most recent therapies for the treatment of elderly patients with NSCLC will be discussed here.

Isoflavone Extracts Enhance the Effect of Epidermal Growth Factor Receptor Inhibitors in NSCLC Cell Lines.

AIM: We investigated the effects of the pharmacological inhibition in vitro of epidermal growth factor receptor (EGFR) in combination with isoflavones. MATERIALS AND METHODS: Four anticancer drugs (erlotinib, gefitinib, afatinib and AZD9291) were combined with soy and red clover isoflavone extracts and used in cellular proliferation assays. The antitumor activity of inhibitors alone and in combination with isoflavone extracts was compared on three non-small cell lung cancer (NSCLC) cell lines with affiant EGFR genotype: A549 (EGFR wt); H1795 (EGFR T790M); HCC827 (EGFR del E746-A750). RESULTS: Combined treatment with extracts significantly enhanced the antiproliferative activity of all inhibitors against these cell lines. Bioactive compounds of extracts may synergize the antitumor efficacy of the inhibitors. CONCLUSION: To date, as far as we are aware, this is the first report of the combined effect of isoflavone extracts and EGFR inhibitors on human NCSLC cell growth. Sequential treatment with these drugs combined with isoflavones may represent the basis for a new therapeutic approach.

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.

Combination of radiotherapy and targeted therapies in the treatment of locally advanced non-small cell lung cancer.

Lung cancer is the most common cancer in the world. One third of patients with non-small cell lung cancer (NSCLC) are diagnosed with locally or regionally advanced unresectable disease at presentation. Currently, in this stage of disease, a combination of chemotherapy and radiotherapy is the standard treatment approach for patients with good performance status, and concomitant chemo-radiotherapy has demonstrated to be the best therapeutic approach. However, despite improvements in treatment, local tumor control remains suboptimal and distant metastases remain the major site of failure. The diversity of molecular abnormalities in NSCLC may partly contribute to its resistance to therapy. It is therefore widely accepted that one approach to improve the efficacy of cancer therapy is the development of rational combinations of anticancer agents that may exhibit synergistic interactions. The introduction of several biologic agents represents an important advance in the management of NSCLC and some of them have shown to have a synergistic effect when given in combination with radiotherapy and chemotherapy in preclinical and in clinical models. In the present review we discuss the rationale and the feasibility of these combinations and the first results available from clinical trials.

Non-small-cell lung carcinoma vaccines in clinical trials.

Non-small-cell lung cancer (NSCLC) is not considered to be immunogenic, but it may provide an accessible target for the properly primed immune system. Identifying lung tumor antigens and presenting them in the optimal context may enable the immune system to generate anti-lung tumor effector cells, which are usually absent. Despite encouraging preclinical and Phase I-II data, no specific active cancer vaccine has been approved for NSCLC therapy to date. Patient selection and measurable immune response methodology assessment could explain these negative results. Vaccine therapy has recently been re-emerging as a potential approach. This article discusses the Phase I, II and III trials investigating the most promising vaccines in the treatment of patients affected by any stage of NSCLC, thus providing a perspective on the future of this approach in this setting.

The role of maintenance treatment in advanced non-small-cell lung cancer: reality or early second line?

First-line platinum-based chemotherapy has reached a plateau of effectiveness for the treatment of patients with advanced non-small-cell lung cancer (NSCLC). In patients who reported a stable disease, no more than 4 cycles of chemotherapy are recommended while a maximum of 6 cycles is recommended in patients who are responding to therapy. A potential strategy with the aim of improving outcomes for NSCLC patients is to administer more therapy. This term includes different approaches: duration of therapy, sequential therapy, consolidation therapy, and maintenance therapy. Here, we attempt to define the different approaches that fall under the rubric of maintenance strategy, and discuss the results available to date.

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.

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.

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.