New approach to implement cancer patient care: The valutazione percorso rete oncologica campana (ValPeROC)-experience from an Italian oncology network.

OBJECTIVE: The primary goal of the Campania Oncology Network (ROC) was to reduce cancer delay and care fragmentation through the establishment of cancer-specific multidisciplinary oncologic groups (GOMs) and diagnostic and therapeutic assistance paths (PDTAs). METHODS: Five cancer centres of the ROC, with their own cancer specific GOM, were selected. In our analysis, we have focused on four neoplasms: lung, colon, ovarian and prostate cancers. The median time for pre-GOM and GOM Times was calculated for each tumour site. Univariate and multivariate logistic regressions were performed to individuate risk factors for pre-GOM and GOM Time. RESULTS: Significant differences were observed for prostate cancer compared to other patients either for pre-GOM or GOM Times. Significant risks were found for ovarian and prostate cancers in pre-GOM time and for prostate cancer in GOM-Time. CONCLUSIONS: This experience will produce knowledge and data to guide decision-making and to manage more effectively the challenges of fighting cancer in Campania region. The Valutazione Percorso Rete Oncologica Campana (ValPeROC) study evaluates, for the first time, the ROC activity, through the analysis of key performance indices. Pre-GOM and GOM Time represent the quality of the entire regional health system and are useful to define models, which can evaluate the performance of the ROC over time.

Evaluation of the Molecular Landscape in PD-L1 Positive Metastatic NSCLC: Data from Campania, Italy.

BACKGROUND: Immune-checkpoint inhibitors (ICIs) have increased and improved the treatment options for patients with non-oncogene-addicted advanced stage non-small cell lung cancer (NSCLC). However, the role of ICIs in oncogene-addicted advanced stage NSCLC patients is still debated. In this study, in an attempt to fill in the informational gap on the effect of ICIs on other driver mutations, we set out to provide a molecular landscape of clinically relevant oncogenic drivers in programmed death-ligand 1 (PD-L1) positive NSCLC patients. METHODS: We retrospectively reviewed data on 167 advanced stage NSCLC PD-L1 positive patients (≥1%) who were referred to our clinic for molecular evaluation of five driver oncogenes, namely, EGFR, KRAS, BRAF, ALK and ROS1. RESULTS: Interestingly, n = 93 (55.7%) patients showed at least one genomic alteration within the tested genes. Furthermore, analyzing a subset of patients with PD-L1 tumor proportion score (TPS) ≥ 50% and concomitant gene alterations (n = 8), we found that n = 3 (37.5%) of these patients feature clinical benefit with ICIs administration, despite the presence of a concomitant KRAS gene alteration. CONCLUSIONS: In this study, we provide a molecular landscape of clinically relevant biomarkers in NSCLC PD-L1 positive patients, along with data evidencing the clinical benefit of ICIs in patient NSCLC PD-L1 positive alterations.

Chemotherapy-induced neutropenia and treatment efficacy in advanced non-small-cell lung cancer: a pooled analysis of 6 randomized trials.

BACKGROUND: Chemotherapy-induced neutropenia (CIN) has been demonstrated to be a prognostic factor in several cancer conditions. We previously found a significant prognostic value of CIN on overall survival (OS), in a pooled dataset of patients with advanced non-small-cell lung cancer (NSCLC) receiving first line chemotherapy from 1996 to 2001. However, the prognostic role of CIN in NSCLC is still debated. METHODS: We performed a post hoc analysis pooling data prospectively collected in six randomized phase 3 trials in NSCLC conducted from 2002 to 2016. Patients who never started chemotherapy and those for whom toxicity data were missing were excluded. Neutropenia was categorized on the basis of worst grade during chemotherapy: absent (grade 0), mild (grade 1-2), or severe (grade 3-4). The primary endpoint was OS. Multivariable Cox model was applied for statistical analyses. In the primary analysis, a minimum time (landmark) at 180 days from randomization was applied in order to minimize the time-dependent bias. RESULTS: Overall, 1529 patients, who received chemotherapy, were eligible; 572 of them (who received 6 cycles of treatment) represented the landmark population. Severe CIN was reported in 143 (25.0%) patients and mild CIN in 135 (23.6%). At multivariable OS analysis, CIN was significantly predictive of prognosis although its prognostic value was entirely driven by severe CIN (hazard ratio [HR] of death 0.71; 95%CI: 0.53-0.95) while it was not evident with mild CIN (HR 1.21; 95%CI: 0.92-1.58). Consistent results were observed in the out-of-landmark group (including 957 patients), where both severe and mild CIN were significantly associated with a reduced risk of death. CONCLUSION: The pooled analysis of six large trials of NSCLC treatment shows that CIN occurrence is significantly associated with a longer overall survival, particularly in patients developing severe CIN, confirming our previous findings.

Evolution in the treatment landscape of non-small cell lung cancer with ALK gene alterations: from the first- to third-generation of ALK inhibitors.

INTRODUCTION: The medical treatment of non-small cell lung cancer (NSCLC) has radically changed over the last 10 years thanks to new molecular-targeted drugs able to act on biological mechanisms involved in tumor development. One such mechanism is the aberrant anaplastic lymphoma kinase (ALK) activation: patients with ALK-driven NSCLC benefit from treatments that selectively inhibit its pathogenetic mechanism. Areas covered: The first-generation ALK inhibitor is crizotinib, initially used in Europe as second-line treatment for ALK-positive metastatic NSCLC patients, then approved as the standard first-line (already approved in the USA as front-line therapy). However, most patients eventually experience disease progression due to the emergence of secondary resistance, partly linked to ALK-dependent mechanisms, hence the development of second- and third-generation ALK inhibitors: ceritinib, alectinib, and brigatinib are approved for ALK-positive NSCLC, lorlatinib is currently being evaluated while others are under development. Expert opinion: Despite the considerable responses to these new inhibitors, however, resistance mechanisms are described. Thus, while the therapeutic scenario of NSCLC has been soon revolutionized introducing next-generation ALK inhibitors in the first-line setting, future research should identify combined therapies or new generation drugs overcoming resistance in pretreated patients.

Emerging drugs targeting PD-1 and PD-L1: reality or hope?

INTRODUCTION: Some tumors evade immune responses by exploiting immune checkpoint pathways and other regulatory mechanisms. Recent advances in the understanding of immune evasion strategies has given rise to development of novel immunotherapies that can restore the patient's own immune system to respond to and eliminate cancer cells. AREAS COVERED: Multiple agents targeting the programmed cell death protein 1 (PD-1) pathway, both anti-PD-1 and anti-programmed death ligand-1 (a key ligand for PD-1) compounds, are currently in active clinical development for lung cancer. Preliminary data of efficacy as monotherapy or in combination with chemotherapy are promising. In this review, we will summarize the immunomodulatory environment in NSCLC, we will focus on immune-checkpoint inhibitors, and the data currently available in lung cancer. EXPERT OPINION: The immune-mediated therapies represent an exciting new therapeutic approach, but evidences are still early in lung cancer, and more data from clinical studies are needed to optimize the clinical impact of these therapies.

The Role of Adjuvant Chemotherapy before Osimertinib in Epidermal Growth Factor Receptor Mutant Resected Non-Small Cell Lung Cancer and Communicating It to Patients.

Patients with radically resected stage II and III NSCLC are exposed to a high risk of disease recurrence. Thus, adjuvant cisplatin-based chemotherapy is routinely offered to this patient population, although it results in an absolute increase in 5-year survival rate of only 4%. This modest improvement in survival rate makes it challenging to communicate to our patients about the decision to be treated with adjuvant chemotherapy or not. Nowadays, the decision to administer adjuvant chemotherapy or not in resected NSCLC is almost never completely shared with patients because its role is very difficult to explain. The risk-benefit ratio becomes clearly unfavourable in elderly and unfit patients. Recently, the phase III ADAURA trial demonstrated a clinically significant disease-free survival and overall survival benefit with adjuvant osimertinib (with or without adjuvant chemotherapy) versus a placebo in EGFR-mutated stage IB-IIIA resected NSCLC. In this patient population, the decision to administer chemotherapy or not is much more challenging given the great benefit offered by osimertinib alone. Thus, it is time now to improve our communication tools to explain the role of adjuvant chemotherapy to our patients, especially in the EGFR-mutated population, in order to undertake real shared decision making in a clinical context in which the opportunity to administer toxic chemotherapy is debatable and subjective.

Emerging mitotic inhibitors for non-small cell carcinoma.

INTRODUCTION: Mitosis is the key event of the cell cycle, and microtubules play an important part in an array of cellular functions besides mitosis, including maintenance of cell shape, cell locomotion, and the movement of intracellular organelles. Various anti-microtubule agents interfere with normal progression of mitosis, such as taxanes and vinca alkaloids. These compounds are widely used in the treatment of advanced non-small cell lung cancer (NSCLC), but their use has been limited by toxicity profile (hematologic and not), acquired resistance, and hypersensitivity reactions. AREAS COVERED: Recently innovative drug carrier such as nanoparticle showed to reduce toxicity and improve drugs' efficacy. Nanoparticle albumin-bound (nab)-paclitaxel has been recently approved for the use in breast and NSCLC with very promising results in pancreatic adenocarcinoma. Furthermore, the identification of novel mitotic drug targets other than microtubules has gained recently much attention, such as aurora kinases, Polo-like kinase1 (PLK1), kinesin spindle protein (KSP), and centromeric protein E (CENPE). EXPERT OPINION: Despite recent advances in treatment, NSCLC continues to be the leading cause of cancer death worldwide. Novel agents that target the spindle microtubule elements of mitosis, as well as those that target the non-microtubule effectors of mitosis, are under investigation.

Neutrophil-to-Lymphocyte Ratio Is a Major Prognostic Factor in Non-small Cell Lung Carcinoma Patients Undergoing First Line Immunotherapy With Pembrolizumab.

BACKGROUND/AIM: Lung cancer is one of the most common malignant neoplastic diseases and by far the leading cause of cancer death worldwide. Recently, immune checkpoint inhibitors (ICIs) have received increasing attention for playing a crucial role in non-small cell lung cancer (NSCLC). Biomarkers, such as programmed cell death-ligand 1 (PD-L1) and tumor mutational burden (TMB), seemed to be helpful in selecting patients who are more likely to benefit from ICI treatment: however, their role has not yet been fully clarified. PATIENTS AND METHODS: In this retrospective study, we evaluated the relationship between pre-treatment peripheral blood neutrophil-to-lymphocyte ratio (NLR) and survival in 252 patients suffering from advanced NSCLC who had received pembrolizumab as their first-line immunotherapy. RESULTS: Compared to their NLR low counterparts who had a median overall survival (OS) of 34.8 months, patients with NLRs above 4.8 had a median OS of 7.6 months (HR=3.26, 95%Cl=2.3-4.6, p-value<0.0000001). In multivariate Cox regression analysis, alongside other variables, such as metastatic sites, age, and sex, NLR and PD-L1 predicted progression-free survival and OS; furthermore, a very high NLR - over 10 - seemed to forecast a very dismal prognosis in patients undergoing immunotherapy, with sudden deaths in the days immediately following therapy (median OS=3.8 months). CONCLUSION: NLR acts as a valuable and reliable prognostic factor in non-small cell lung carcinoma patients undergoing first line immunotherapy with pembrolizumab. Additional investigation is necessary to fully elucidate the underlying biological rationale, which can be found in myeloid derived suppressor cells, a heterogeneous population of cells with neutrophil-like immunophenotypic features.

The treatment of advanced non-small cell lung cancer harboring KRAS mutation: a new class of drugs for an old target-a narrative review.

Background and Objective: The genetic nature of cancer provides the rationale to support the need for molecular diagnosis and patient selection for individualised antineoplastic treatments that are the best in both tolerability and efficacy for each cancer patient, including non-small cell lung cancer (NSCLC) patients. Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations represent the prevalent oncogenic driver in NSCLC, being detected in roughly one-third of cases and KRAS G12C is the most frequent mutation found in approximately 13% of patients. Methods: This paper gives an overview of the numerous scientific efforts in recent decades aimed at KRAS inhibition. Key Content and Findings: Sotorasib is the first approved KRAS G12C inhibitor that has been shown to provide a durable clinical benefit in patients with pre-treated NSCLC with KRAS G12C mutation. Together with the development of new targeted drugs, the development of strategies to control resistance mechanisms is one of the major drivers of research that is exploring the use of KRAS inhibitors not only alone, but also in combination with other targeted therapies, chemotherapy and immunotherapy. Conclusions: This review will describe the major therapeutic developments in KRAS mutation-dependent NSCLC and will analyse future perspectives to maximise benefits for this group of patients.

Chemotherapy plus single/double immunotherapy in the treatment of non-oncogene addicted advanced non-small cell lung cancer: where do we stand and where are we going?

INTRODUCTION: Chemo-immunotherapy combinations have revolutionized our treatment algorithm with respect to naïve advanced NSCLC; however, given the great number of developed and approved combinations, the question arises as to which combinations provide the best efficacy and safety. AREAS COVERED: This review assesses and discusses the available data concerning chemo-immunotherapy combinations in the treatment of naïve advanced NSCLC, as well as presenting the most promising data involving combinations currently under investigation. EXPERT OPINION: Pembrolizumab-containing chemo-immunotherapy combinations are associated with the most mature data available and presently represent the standard treatment in clinical practice in naïve advanced NSCLC-affected patients. The nivolumab plus ipilimumab plus short-course chemotherapy combination, more recently approved by regulatory agencies, is an appealing alternative, thanks to the reduced rate of grade 3-5 TRAEs and the limited chemotherapy administration. The new chemo-immunotherapy combinations currently under investigation will help us to better identify both the best immune checkpoints to target and the most effective combinations to administer.

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.

The treatment of advanced lung adenocarcinoma with activating EGFR mutations.

INTRODUCTION: Lung adenocarcinomas account for approximately 40-50% of all NSCLC (Non-Small Cell Lung Cancer) cases. In addition, lung adenocarcinomas can harbor several different genetic mutations, EGFR (Epidermal Growth Factor Receptor) being the most frequent one, accounting for approximately 5-15% of all the mutations in western patients and for approximately 40-55% in Asian patients; on the other hand, EGFR mutations are uncommon in squamous histology. Approximately 90% of EGFR mutations are represented by exon 19 in-frame deletion and by the L858R exon 21-point mutation, that confer sensitivity to EGFR TKI (Tyrosine Kinase Inhibitors) treatment. AREAS COVERED: The authors comprehensively review the current state of the art with reference to EGFR+ NSCLC treatment and to discuss the possible future developments. EXPERT OPINION: Osimertinib must be considered the preferred first-line agent in EGFR+ advanced NSCLC patients thanks to its superior performances. With respect to acquired resistance mechanisms to osimertinib, the currently ongoing clinical trials will surely help us to better understand and tackle them. Globally, we strongly believe that a biomarker-driven sequential treatment algorithm is key in order to provide personalized, effective and durable therapies in the increasingly complex landscape of EGFR+ advanced NSCLC.

Cetuximab and other anti-epidermal growth factor receptor monoclonal antibodies in the treatment of non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) accounts for about 85% of all new diagnoses of lung cancer. Unfortunately, few NSCLC patients are suitable for radical treatment for curative intent. Because most patients with NSCLC have advanced disease at diagnosis, chemotherapy represents the standard of care, although, to date, a plateau has been reached with this approach. Improvements in the knowledge of tumor biology and mechanisms of oncogenesis have identified the epidermal growth factor receptor (EGFR), a member of the ErbB family, as a molecular target for NSCLC treatment. EGFR is commonly overexpressed in NSCLC and has been associated with impaired prognosis; therefore, its inhibition may lead, through the suppression of tumor proliferation, to improvement in clinical outcomes. Strategies to block EGFR include tyrosine kinase inhibitors, monoclonal antibodies, ligand-linked toxins, and antisense approaches. This article focuses on the treatment of NSCLC with the anti-EGFR monoclonal antibodies, including cetuximab, for which the largest amount of data in the literature exists. Recently, a phase III randomized trial performed in advanced NSCLC patients yielded a statistically significant survival advantage for patients treated with cetuximab plus chemotherapy versus chemotherapy alone. Other anti-EGFR monoclonal antibodies, such as panitumumab, matuzumab, nimotuzumab, and ch806, are in different stages of development for the treatment of advanced NSCLC.

Vaccines for the treatment of non-small cell lung cancer: a renewed anticancer strategy.

Carcinoma of the lung is the leading cause of cancer death worldwide, with non-small cell lung cancer (NSCLC) constituting about 85% of all new diagnoses. Standard approaches for each NSCLC stage have reached a plateau in effectiveness. A variety of novel approaches are now being investigated to improve the outcome of this disease. Despite decades of research, no specific active cancer vaccine has, to date, been approved for NSCLC therapy; nevertheless, vaccine therapy has recently re-emerged as a potential therapeutic approach. In particular, several new paradigms have stemmed from recent clinical findings both in the use of combination therapy approaches with more sophisticated specific vaccines and in clinical trial design and endpoint analyses. Several vaccine therapies have been investigated in NSCLC, including in the early and advanced disease stages. The best results appear to be in the adjuvant settings and in locally advanced NSCLC. In fact, in these two settings, phase III randomized trials are ongoing evaluating the melanoma-associated antigen A3 vaccine and the liposomal BLP25 vaccine. This paper reviews the main clinical trials involving several different cancer vaccines employed in the treatment of early and advanced stage NSCLC, focusing on those in advanced stages of development.

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.

Vascular disrupting agents: a novel mechanism of action in the battle against non-small cell lung cancer.

Targeting vasculature, essential in oxygen and nutrient supply, represents a new frontier in the treatment of cancer. Apart from angiogenesis inhibitors that compromise the formation of new blood vessels, a second class of vascular disrupting agents (VDAs) targets endothelial cells and pericytes of the already established tumor vasculature, resulting in tumor ischemia and necrosis. VDAs have been divided into two types: ligand-directed VDAs and small molecules. Ligand-directed VDAs consist of targeting and effector moieties that are linked together. Their clinical efficacy appears limited because of cost and a lack of specificity and toxicity. Small molecules include two classes: the synthetic flavonoids, which work through induction of local cytokine production, and the tubulin-binding agents. The aim of this review is to discuss the hypothesized molecular mechanisms of action of VDAs and their early preclinical and clinical results, emphasizing ASA404, combretastatin A-4 disodium phosphate, ABT-751, and NPI-2358, reported in the treatment of non-small cell lung cancer, which is the leading cause of cancer death worldwide, and also to discuss future developments in this cancer population.

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.

Effect on quality of life of cisplatin added to single-agent chemotherapy as first-line treatment for elderly patients with advanced non-small cell lung cancer: Joint analysis of MILES-3 and MILES-4 randomised phase 3 trials.

OBJECTIVES: To evaluate the effect on quality of life (QOL) of the addition of cisplatin to single-agent chemotherapy in the treatment of elderly patients with advanced non-small cell lung cancer (NSCLC) enrolled in two parallel phase 3 trials, MILES-3 and MILES-4. PATIENTS AND METHODS: Advanced NSCLC pts, >70 years old, performance status (PS) 0-1, were eligible. Patients were randomly assigned to chemotherapy without or with cisplatin. EORTC QLQ C30 and LC13 questionnaires were planned at baseline, end of cycle 1 and end of cycle 2 in both trials and were used for joint QOL analysis. Trial-specific data including questionnaires at non-shared time-points were used for additional analyses. Intention-to-treat strategy was applied. Analyses were adjusted for baseline QOL, stage, performance status, gender, age, size of centre, trial, histotype and non-platinum companion drug. RESULTS: Overall, 458/531 pts (86%) answered baseline questionnaire and missing rates over treatment were slightly higher among patients receiving cisplatin. Mean change in sore mouth after cycle 2 was worse with cisplatin (P = 0.02). The size of differences between arms was in the small-medium range for peripheral neuropathy and alopecia (0.25 and 0.31 after one and 0.28 and 0.36 after two cycles, respectively) and for nausea/vomiting, sore mouth and dysphagia after two cycles (0.26, 0.38 and 0.25, respectively) always in the direction of worsening with cisplatin. Using a 10% change from baseline as clinically relevant threshold to categorize response, there was no significant difference between the arms. Time to deterioration of sore mouth and alopecia, with progression/death as competitive risk, was shorter with cisplatin (HR 1.72 95%CI 1.02-2.89, P = 0.04 and HR 1.84 95%CI 1.09-3.10, P = 0.02, respectively). CONCLUSION: The addition of cisplatin to single agent chemotherapy worsens sore mouth and alopecia and does not improve any QOL items in elderly patients with advanced NSCLC.

The potential role of histone deacetylase inhibitors in the treatment of non-small-cell lung cancer.

Non-small-cell lung cancer (NSCLC) arises from a complex series of genetic and epigenetic changes leading to uncontrolled cell growth and metastases. The exponential growth in the level of research about the histone deacetylase (HDAC) enzymes, responsible for deacetylating core nucleosomal histones and other proteins, has been driven by the ability of HDAC inhibitors to modulate transcriptional activity. As a result, this therapeutic class is able to block angiogenesis and cell cycling, and promote apoptosis and differentiation. The mechanisms resulting in the antiproliferative biologic effects of these agents are not yet known. Clinical experience indicates these agents generally well tolerated, and active in several haematological and solid tumours. HDAC inhibitors, under clinical evaluation in the treatment of NSCLC patients, are pivanex, CI-994, vorinostat, and LBH589. Here, we discuss about the potential role of HDAC inhibitors focusing on their activity, tolerability, efficacy and future development, in the treatment of NSCLC.

Combined chemo-radiotherapy for locally advanced non-small cell lung cancer: current status and future development.

Currently, combinations of chemotherapy and radiotherapy are the standard treatment approach for locally advanced NSCLC patients. Concomitant chemo-radiotherapy, although associated with increased acute toxicity, has demonstrated to be the better strategy over sequential chemoradiotherapy, and it is to be considered a standard approach in patients with good performance status (0-1). However, the approach to locally advanced NSCLC and to chemo-radiotherapy regimens remains heterogeneous among oncologists, and clinical outcomes are yet disappointing. Thus, the search of new strategies is mandatory. The main fields of research aiming at improving the survival of locally advanced NSCLC patients are: the addition of further combination chemotherapy as induction or consolidation to concurrent chemo-radiotherapy, and the integration of molecularly targeted therapies into conventional chemo-radiotherapy regimens.