Survival after locoregional treatments for hepatocellular carcinoma: a cohort study in real-world patients.

Evidence of relative effectiveness of local treatments for hepatocellular carcinoma (HCC) is scanty. We investigated, in a retrospective cohort study, whether surgical resection, radiofrequency ablation (RFA), percutaneous ethanol injection (PEI), and transarterial embolization with (TACE) or without (TAE) chemotherapy resulted in different survival in clinical practice. All patients first diagnosed with HCC and treated with any locoregional therapy from 1998 to 2002 in twelve Italian hospitals were eligible. Overall survival (OS) was the unique endpoint. Three main comparisons were planned: RFA versus PEI, surgical resection versus RFA/PEI (combined), TACE/TAE versus RFA/PEI (combined). Propensity score method was used to minimize bias related to non random treatment assignment. Overall 425 subjects were analyzed, with 385 (91%) deaths after a median followup of 7.7 years. OS did not significantly differ between RFA and PEI (HR 1.11, 95% CI 0.79-1.57), between surgery and RFA/PEI (HR 0.95, 95% CI 0.64-1.41) and between TACE/TAE and RFA/PEI (HR 0.88, 95% CI 0.66-1.17). 5-year OS probabilities were 0.14 for RFA, 0.18 for PEI, 0.27 for surgery, and 0.15 for TACE/TAE. No locoregional treatment for HCC was found to be more effective than the comparator. Adequately powered randomized clinical trials are still needed to definitely assess relative effectiveness of locoregional HCC treatment.

Angular dependence of the ion-induced secondary electron emission for He+ and Ga+ beams.

In recent years, novel ion sources have been designed and developed that have enabled focused ion beam machines to go beyond their use as nano-fabrication tools. Secondary electrons are usually taken to form images, for their yield is high and strongly dependent on the surface characteristics, in terms of chemical composition and topography. In particular, the secondary electron yield varies characteristically with the angle formed by the beam and the direction normal to the sample surface in the point of impact. Knowledge of this dependence, for different ion/atom pairs, is thus the first step toward a complete understanding of the contrast mechanism in scanning ion microscopy. In this article, experimentally obtained ion-induced secondary electron yields as a function of the incidence angle of the beam on flat surfaces of Al and Cr are reported, for usual conditions in Ga+ and He+ microscopes. The curves have been compared with models and simulations, showing a good agreement for most of the angle range; deviations from the expected behavior are addressed and explanations are suggested. It appears that the maximum value of the ion-induced secondary electron yield is very similar in all the studied cases; the yield range, however, is consistently larger for helium than for gallium, which partially explains the enhanced topographical contrast of helium microscopes over the gallium focused ion beams.

The emerging role of histology in the choice of first-line treatment of advanced non-small cell lung cancer: implication in the clinical decision-making.

Lung cancer is the leading cause of cancer mortality worldwide. Non-small cell lung cancer (NSCLC), accounting for about 85% of all lung cancers, includes squamous carcinoma, adenocarcinoma and undifferentiated large cell carcinoma. The majority of patients have advanced disease at diagnosis, and medical treatment is the cornerstone of management. Several randomized trials comparing third-generation platinum-based doublets concluded that all such combinations are comparable in their clinical efficacy, failing to document a difference based on histology. However, recent evidences, arising from the availability of pemetrexed, have shown that histology represents an important variable in the decision making. The major progresses in the understanding cancer biology and mechanism of oncogenesis have allowed the development of several potential molecular targets for cancer treatment such as vascular growth factor and its receptors and epidermal growth factor receptor. Targeted drugs seem to be safer or more effective in a specific histology subtype. All of these data have led to choose the optimal first-line treatment of advanced NSCLC based on histologic diagnosis. However, this scenario raises a diagnostic issue: a specific diagnosis of NSCLC histologic subtype is mandatory. This review will discuss these new evidences in the first-line treatment of advanced NSCLC and their implication in the current clinical decision-making.

Treatment of advanced non-small-cell lung cancer in the elderly.

Lung cancer in the older individual is an increasingly common problem faced by the oncologist. Elderly patients have more co-morbidities and tend to tolerate toxic medical treatments more poorly than their younger counterparts. Thus, clinical data obtained in a younger population cannot be automatically extrapolated to the great majority of non-selected 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 comes from studies in advanced disease. In elderly advanced NSCLC patients single-agent chemotherapy with third-generation agents (vinorelbine, gemcitabine, taxanes) is to be considered as the standard treatment for unselected patients, based on several phase II and III trials specifically designed for this special population. Retrospective analyses found no differences in survival between elderly and younger patients treated with cisplatin-based chemotherapy, with a small but significant increase in toxicity in the elderly. Cisplatin-based chemotherapy with cisplatin at attenuated doses has demonstrated to be an active and feasible option in phase II trials and deserves prospective phase III comparison against monochemotherapy. Among targeted therapies, the epidermal growth factor receptor tyrosine kinase inhibitors erlotinib and gefitinib are the most promising agents and have relevant phase II prospective data showing activity and good tolerability as first-line treatment in this population. Concerning the anti-vascular endothelial growth factor monoclonal antibody bevacizumab, particular care must be taken for elderly patients because of a possible higher incidence of cardiovascular co-morbidities. However its role in this population remains controversial and specific prospective studies are warranted to clarify this topic. Further specifically designed phase III randomized trials are needed to optimize medical treatment of NSCLC in elderly patients.

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.

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.

The potential role of bevacizumab in early stages and locally advanced non-small cell lung cancer.

Improving outcomes for early-stage non-small cell lung cancer (NSCLC) is a major research area considering that a significant percentage of such patients develop recurrent disease within 5 years of complete lung resection. Adjuvant chemotherapy prolongs survival, with an absolute improvement in 5-year overall survival of about 5% with drawbacks such as treatment toxicity. Approximately, one third of patients with newly diagnosed NSCLC have locally advanced disease not amenable for surgical resection - in this setting of patients concurrent chemoradiation is the standard of therapy. However, the treatment of locally advanced NSCLC is still controversial and clinical outcomes are disappointing, and so new approaches are required to improve the clinical benefit in this setting of patients. Vascular endothelial growth factor (VEGF) is a key angiogenic factor implicated in tumor blood vessels formation and permeability, and tumor VEGF overexpression in patients with early stage lung cancer has been associated with worse relapse free and overall survival. Several agents have been developed that inhibit VEGF or its receptor signalling system. Bevacizumab is the first recombinant humanized monoclonal antibody binding VEGF to demonstrate clinical benefit or rather a survival prolongation in combination with chemotherapy in the treatment of non-squamous advanced NSCLC patients. These positive results led to a large number of clinical trials to evaluate bevacizumab in combination with other targeted agents in advanced disease, and to define the role of this agent in early stage NSCLC such as the impact of bevacizumab integration in chemoradiotherapy strategy for locally advanced disease.

Safety profile of gefitinib in advanced non-small cell lung cancer elderly patients with chronic renal failure: two clinical cases.

OBJECTIVES: Comorbidities often contraindicate any chemotherapy in non-small cell lung cancer (NSCLC) patients, even single-agent one. This is the case of chronic renal failure. METHODS: Two elderly patients (age >70 years) affected by advanced non-small cell lung cancer and chronic renal failure were treated, as front-line treatment, with gefitinib (ZD1839--'Iressa') administered orally at the dose of 250 mg daily. RESULTS: In both patients renal function was not impaired by the treatment with gefitinib and no severe toxicity was recorded. One patient reported a stable disease, lasted 141 days, with symptoms relief. In the other patient a mixed response was reported with one large pulmonary site responding to gefitinib, but with appearance of new small lung metastases. He is still alive at 359 days. CONCLUSIONS: Gefitinib resulted safety when administered to advanced NSCLC elderly patients affected by chronic renal failure. Gefitinib should be further evaluated as front-line treatment in a larger sample of such patients, in order to establish a therapeutic option for a sort of patients unsuitable for any chemotherapy.

The role of targeted therapy in non-small cell lung cancer.

The therapy of non-small cell lung cancer (NSCLC) has reached a plateau in improving patient survival, with overall disappointing results. Thus, clinical research for new treatment strategies is warranted. Advances in the singling out molecular targets for NSCLC treatment has granted the development of several new biological agents. In the present paper we describe the main clinical data currently available on targeted agents in the treatment of NSCLC, focusing on epidermal growth factor receptor family inhibitors, angiogenesis inhibitors, signal transduction inhibitors, eicosanoid pathway inhibitors, vaccines and gene therapy. Several targeted agents have been introduced into clinical trials in NSCLC, mainly in advanced disease, with the first phase III study results being recently made available. To date, few of these new agents can offer hope of a substantial impact on the natural history of NSCLC, and negative results are more commonly reported than positive ones. Nevertheless, clinically-meaningful advances have already been achieved in chemotherapy refractory advanced NSCLC patients, with gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, representing a further chance of tumor control and symptom palliation. Moreover, important lessons can be learned from this first generation of clinical trials.

Single agent vinorelbine as first-line chemotherapy in elderly patients with advanced breast cancer.

BACKGROUND: Breast cancer arises in about 48% of patients (pts) older than 65 years. Chemotherapy is administered to elderly pts with advanced breast cancer (ABC) resistant to hormonal treatment or with visceral metastases. Vinorelbine (VNR), a semisynthetic vinca alkaloid, is active and well-tolerated in ABC reporting, as a single agent, an objective response (OR) rate of 41%-60%. The ELVIS (Elderly Lung cancer Vinorelbine Italian Study) trial demonstrated the tolerability and efficacy of VNR in elderly pts with advanced non-small cell lung cancer (JNCI 91: 66-72, 1999). MATERIALS AND METHODS: From January 1999 to December 2000, we analysed, retrospectively, our data about single-agent VNR as a first-line chemotherapy in elderly pts (> or = 70 years) with ABC. Twenty-four pts were analysed. VNR was administered at the dose of 30 mg/m2, i.v., days 1 and 8, every 3 weeks for a maximum of 6 cycles. RESULTS: The main toxicity was (% of pts): grade (G) 3-4 neutropenia 25%; G 2 thrombocytopenia 4.1%; G 2 asthenia 25%; G 2-3 constipation 16.6%; and G 1 neurotoxicity 25%. No cycles of chemotherapy were omitted or postponed. Granulocyte colony-stimulating factor was administered in 12.5% of a total of 112 cycles. Nine (37.5%) objective responses (2 complete and 7 partial responses) were observed. The median duration of response and survival were 7 and 11 months, respectively. CONCLUSION: These results suggest that single agent VNR is active and well-tolerated in elderly pts with ABC. Further prospective trials are warranted.