Maria Anna Bareschino

Treatment of advanced non small cell lung cancer

Lung cancer is the major cause of cancer death in the world. Non Small Cell Lung Cancer (NSCLC) accounts approximately 80-85% of all lung cancer diagnosis; the majority of patients will be diagnosed with non operable, advanced-stage disease. Palliative chemotherapy and/or radiotherapy represent the standard of care of this disease. Platinum based doublets with third generation agents are considered the standard of first line advanced NSCLC treatment. However, data arising from the availability of pemetrexed suggest that histology could play a key role in decision making. Advances in understanding of the molecular pathogenesis of lung cancer have led to the identification of several specific targets such as vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) for therapeutic agents. Bevacizumab is the first recombinant humanized monoclonal antibody (mAb) binding VEGF to demonstrate clinical benefit and a rather survival prolongation in combination with chemotherapy in the treatment of non squamous chemo-naive advanced NSCLC patients. Two types of anti-EGFR targeting agents have reached advanced clinical development: mAbs and small molecule inhibitors of the EGFR tyrosine kinase enzymatic activity (TKIs). Among TKIs gefitinib has been tested in several phase II-III studies showing an improvement in survival and responses in first, second and third line treatment in selected patients with specific clinical and molecular characteristics. Furthermore, erlotinib has showed to significantly improve survival in an unselected population of patients following the failure of one or two chemotherapy regimens. This review will discuss the different therapeutic options for first and second line treatment in the clinical practice.

Potential Treatment Options After First-Line Chemotherapy for Advanced NSCLC: Maintenance Treatment or Early Second-Line?

Although substantial progress has been made in the therapeutic options currently available for patients with advanced non-small cell lung cancer (NSCLC), the overall survival profile remains poor for most patients. One of the strategies currently under investigation with the aim of prolonging survival in NSCLC patients is maintenance treatment with either a chemotherapeutic agent or a molecularly targeted agent after first-line chemotherapy. Moreover, this can consist of drugs included in the induction regimen or other noncrossresistant agents. With the currently available data, maintenance treatment with a different noncrossresistant agent (i.e., an early second-line treatment) is perhaps the most promising strategy. The drug chosen for the early second-line treatment should be a well-tolerated agent, considering that patients have just completed a particularly toxic platinum-based chemotherapy. Extending treatment with targeted agents rather than chemotherapy can provide longer progression-free and overall survival times without increasing toxicity. However, at the moment, only progression-free survival has been shown to be consistently superior with maintenance approaches; the evaluation of survival benefits is warranted before defining this strategy as a possible treatment option. Further studies are warranted to establish the role of maintenance chemotherapy in patients with advanced NSCLC.

Advances in chemotherapy in advanced non-small-cell lung cancer.

Importance of the field: Lung cancer is the most common cancer in the world today, in terms of both incidence and mortality. Non-small-cell lung cancer (NSCLC) accounts for about 85% of all lung cancers diagnosis, and the majority of people diagnosed with NSCLC have advanced disease. Areas covered in this review: In this review the main advances achieved in the medical treatment of advanced NSCLC are discussed, regarding both targeted therapies and chemotherapy. Among targeted therapies, recent data on the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab and the epidermal growth factor receptor tyrosyne kinase inhibitors (EGFR-TKIs) gefitinib and erlotinib are described. Among chemotherapeutic agents, the role of pemetrexed is discussed. What the reader will gain: The reader will gain up-to-date information on the main advances, achieved in the last 3 years in the medical treatment of advanced NSCLC. Take home message: Some recent advances have changed the face of the first-line chemotherapy of advanced NSCLC, giving physicians more options to tailor choice in this challenging setting.

The potential role of insulin-like growth factor receptor inhibitors in the treatment of advanced non-small cell lung cancer

Importance of the field: Lung cancer is the leading cause of cancer-related mortality worldwide. NSCLC accounts for > 80% of all lung cancers. The treatment of advanced fit NSCLC patients seems to have reached a plateau. Considerable efforts have been initiated to identify new biological agents. Areas covered in this review: Diagnosis of NSCLC histotype is becoming extremely important to address treatment. While non-squamous histology could start to benefit from the administration of several new drugs only recently, non-adenocarcinoma subtype seems to benefit from the administration of figitumumab (CP-751,871) a fully human anti-IGF 1 receptor (IGF-1R) mAb. In this paper, we reviewed the IGF-1R pathway and its inhibitors. What the reader will gain: Approaches targeting IGF-1R include small-molecule IGF-1R tyrosine kinase inhibitors (TKIs), which are in preclinical and early clinical phases of development, and the mAbs, among which figitumumab is being investigated in Phase III trials of advanced NSCLC. Take home message: Figitumumab reported interesting results in the treatment of advanced non-adenocarcinoma NSCLC patients. Overall, in order to administer the optimal treatment to patients, a more definite histological diagnosis is mandatory.

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.

The potential role of pharmacogenomic and genomic in the adjuvant treatment of early stage non small cell lung cancer.

Although notable progress has been made in the treatment of non-small-cell lung cancer (NSCLC) in recent years, this disease is still associated with a poor prognosis. Despite early-stage NSCLC is considered a potentially curable disease following complete resection, the majority of patients relapse and eventually die after surgery. Adjuvant chemotherapy prolongs survival, altough the absolute improvement in 5-year overall survival is only approximately 5%. Trying to understand the role of genes which could affect drug activity and response to treatment is a major challenge for establishing an individualised chemotherapy according to the specific genetic profile of each patient. Among genes involved in the DNA repair system, the excision repair cross-complementing 1 (ERCC1) is a useful markers of clinical resistance to platinum-based chemotherapy. In the International Lung Cancer Trial (IALT) adjuvant chemotherapy significantly prolonged survival among patients with ERCC1 negative tumors but not among ERCC1-positive patients. BRCA1 and ribonucleotide reductase M1 (RRM1), two other key enzymes in DNA synthesis and repair, appear to be modulators of drug sensitivity and may provide additional information for customizing adjuvant chemotherapy. Several clinical trials suggest that overexpression of class III β-tubulin is an adverse prognostic factor in cancer since it could be responsible for resistance to anti-tubulin agents. A retrospective analysis of NCIC JBR.10 trial showed that high tubulin III expression is associated with a higher risk of relapse following surgery alone but also with a higher probability of benefit from adjuvant cisplatin plus vinorelbine chemotherapy. Finally, the use of gene expression patterns such as the lung metagene model could provide a potential mechanism to refine the estimation of a patient’s risk of disease recurrence and could affect treatment decision in the management of early stage of NSCLC. In this review we will discuss the potential role of pharmacogenomic approaches to guide the medical treatment of early stage NSCLC.

A Randomized Phase II Study of Pemetrexed or RAD001 as Second-Line Treatment of Advanced Non–Small-Cell Lung Cancer in Elderly Patients: Treatment Rationale and Protocol Dynamics

In the current clinical trial summary, we present a randomized phase II trial of pemetrexed or RAD001 as second-line treatment of elderly patients with advanced non-small-cell lung cancer. The molecular and clinical rationale is reviewed. The primary endpoint is progression-free survival, and secondary endpoints include objective tumor response rates, disease control rates, safety, tolerability, and overall survival. Based on the statistical design, the investigators plan to enroll 92 elderly patients, 46 per arm.

Erlotinib: an EGF receptor tyrosine kinase inhibitor in non-small-cell lung cancer treatment

Approximately 213,380 new cases of non-small-cell lung cancer (NSCLC) were estimated to occur in the USA in 2007, which caused 160,390 NSCLC-related deaths. The majority of patients will be diagnosed with nonoperable, advanced-stage disease. Although combination chemotherapy remains the standard treatment, median survival with these regimens is only 8–10 months. Recent advances in our understanding of lung cancer on a molecular level have led to the introduction of targeted therapies. The EGF receptor (EGFR) was the first receptor to be proposed for cancer therapy and two EGFR-targeted pharmacologic approaches have been successfully developed: monoclonal antibodies (mAbs) and small-molecule inhibitors of the EGFR tyrosine kinase enzymatic activity. Erlotinib is a quinazoline derivative that selectively and reversibly inhibits the tyrosine kinase activity of the EGFR. Here, we review the mechanism(s) of action of erlotinib, as well as the results of Phase I, II and III trials with this drug in NSCLC, which have led to the worldwide approval of erlotinib treatment as monotherapy for therapy-refractory, advanced NSCLC patients.

Pemetrexed in advanced non-small cell lung cancer.

Introduction: For patients with advanced NSCLC, treatment outcomes are still disappointing and the search for new active and safe drugs is warranted. The chemotherapeutic agent pemetrexed has produced, in the last years, an innovation of therapeutic algorithms of this disease, and this review is aimed at describing the role of pemetrexed in the treatment of NSCLC. Areas covered: In the present review, we discuss the mechanism of action of pemetrexed, its safety profile and the main clinical data on pemetrexed in NSCLC treatment. The reader will gain information on pemetrexed efficacy in the first-line, second-line and maintenance treatment of advanced NSCLC. Moreover, the histotype-based approach to NSCLC treatment, which is important for the selection of patients to be treated with pemetrexed, is clarified. Expert opinion: The recent introduction of pemetrexed in the first-line and maintenance treatment of advanced non-squamous NSCLC represents, in our opinion, a significant step forward in the treatment of this disease in the last 3 years. Furthermore, cisplatin plus pemetrexed has a more favorable safety profile as compared with those of pre-existing cisplatin-based regimens.

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.