Pixantrone plus rituximab versus gemcitabine plus rituximab in patients with relapsed aggressive B-cell non-Hodgkin lymphoma not eligible for stem cell transplantation: a phase 3, randomized, multicentre trial (PIX306).

PIX306 was a phase 3, randomised, single-blind, multicentre trial conducted in adult patients with diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) grade 3 who relapsed after ≥1 rituximab-containing regimen and were not eligible for a stem cell transplant. Patients were randomised 1:1 to pixantrone 50 mg/m2 or gemcitabine 1000 mg/m2 on days 1, 8 and 15 of a 28-day cycle, combined with rituximab 375 mg/m2 on day 1, for up to six cycles. Patients were followed for up to 96 weeks. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), complete response (CR) rate, overall response rate (ORR) and safety. Overall, 312 patients were randomised (median age 73·0 years). The study did not meet its primary endpoint. Median PFS [95% confidence interval (CI)] was 7·3 months (5·2-8·4) with pixantrone + rituximab (PIX + R) and 6·3 months (4·4-8·1) with gemcitabine + rituximab [GEM + R; hazard ratio (HR): 0·85; 95% CI 0·64-1·14; P = 0·28]. Median OS was 13·3 (10·1-19·8) months with PIX + R and 19·6 (12·4-31·9) months with GEM + R (HR: 1·13; 95% CI 0·83-1·53). ORR was 61·9% and 43·9% respectively and CR rate 35·5% and 21·7%. The incidence of adverse events, including cardiac events, was not statistically significant different between PIX + R and GEM + R.

Health-related quality of life in small-cell lung cancer: a systematic review on reporting of methods and clinical issues in randomised controlled trials.

Small-cell lung cancer represents about 15% of all lung cancers; increasingly, randomised controlled trials of this disease measure the health-related quality of life of patients. In this Systematic Review we assess the adequacy of reporting of health-related quality-of-life methods in randomised controlled trials of small-cell lung cancer, and the potential effect of this reporting on clinical decision making. Although overall reporting of health-related quality of life was acceptable, improvements are needed to optimise the use of health-related quality of life in randomised controlled trials.

Attitudes and referral patterns of lung cancer specialists in Europe to Specialized Palliative Care (SPC) and the practice of Early Palliative Care (EPC).

PURPOSE: To examine availability of Palliative Care (PC) services and referral patterns of European Lung cancer specialists to PC. METHODS: All members of the EORTC Lung Cancer Group (LCG) were asked via email to participate in an on-line survey. RESULTS: 50 out of 170 (29.4%) replied: 24 medical oncologists, 14 radiation/clinical oncologists, 11 pulmonologists and 1 thoracic surgeon. All but two of respondents (96%) had access to at least one component of PC services. In terms of referral of patients to PC almost 75% of respondents would refer most of their patients when there were no treatment options or at the end of life, while only 22% would refer patients at earlier stages of disease. Barriers for referral to PC were negative attitudes of patients to PC (26%), lack of availability of PC services (20%), lack of expertise of PC physicians(18%), the belief that referral to PC signifies abandoning patients (8%), and that PC specialists discourage active oncological therapy (8%). Whilst most of the respondents expressed positive attitudes, 12-22% had overtly negative attitudes towards PC. Seventy-eight (78%) of respondents expressed an interest to participate in a trial of early PC (EPC). CONCLUSION: Despite good availability of SPC services at institutions of members of the EORTC LCG, and most respondents expressing positive attitudes towards PC, their practice involved referral of patients to PC late in the disease trajectory, hence Lung Cancer specialists in Europe have not adopted the practice of EPC concurrent with active oncological care.

Nutritional status, acute phase response and depression in metastatic lung cancer patients: correlations and association prognosis.

BACKGROUND AND AIM: Cancer cachexia is a metabolic syndrome related with poor outcome. Cytokines play a key role in the pathophysiology of that syndrome. The aim of this study was to investigate the potential correlations between nutritional status, systemic inflammation, and psychological distress in cancer patients. The prognostic significance of the recorded parameters was also assessed. PATIENTS AND METHODS: Patients with metastatic lung cancer were eligible. Mini Nutritional Assessment (MNA) was used for the evaluation of nutritional status, Glasgow Prognostic Score (GPS) for the estimation of systemic inflammation, and Hospital Anxiety and Depression Scale (HADS) for psychological assessment. RESULTS: Totally, 122 patients were enrolled (71.3% with NSCLC and 28.7% with SCLC). The following correlations were observed: MNA and GPS (r = 0.289, p = 0.001), MNA and HADS (depression scale) (r = 0.275, p = 0.002), GPS and HADS (depression scale) (r = 0.256, p = 0.004), and GPS and HADS (anxiety scale) (r =0.194, p =0.033). In univariate analysis, GPS (p = 0.002) and MNA (p = 0.010) emerged as significant predictors of survival. In multivariate analysis, both MNA (p = 0.032) and GPS (p = 0.020) retained their importance. CONCLUSIONS: This study highlights the associations between nutritional status, systemic inflammation, and psychological distress, supporting their common underlying pathophysiological mechanisms and further suggesting the necessity of a holistic anti-cachectic approach.

DNA repair pathways and their implication in cancer treatment.

Many cytotoxic agents used in cancer treatment exert their effects through their ability to directly or indirectly damage DNA and thus resulting in cell death. Major types of DNA damage induced by anticancer treatment include strand breaks (double or single strand), crosslinks (inter-strand, intra-strand, DNA-protein crosslinks), and interference with nucleotide metabolism and DNA synthesis. On the other hand, cancer cells activate various DNA repair pathways and repair DNA damages induced by cytotoxic drugs. The purpose of the current review is to present the major types of DNA damage induced by cytotoxic agents, DNA repair pathways, and their role as predictive agents, as well as evaluate the future perspectives of the novel DNA repair pathways inhibitors in cancer therapeutics.

A randomized phase III study of the docetaxel/carboplatin combination versus docetaxel single-agent as second line treatment for patients with advanced/metastatic non-small cell lung cancer.

BACKGROUND: To compare the activity and toxicity of docetaxel/carboplatin (DC) doublet vs single agent docetaxel (D) as second-line treatment in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Patients pre-treated with front-line platinum-free regimens, were randomized to receive either docetaxel/carboplatin (DC), (docetaxel 50 mg/m2; carboplatin AUC4; both drugs administered on days 1 and 15) or docetaxel single-agent (D), (docetaxel 50 mg/m2 on days 1 and 15). RESULTS: Response rate was similar between the two arms (DC vs D: 10.4% vs 7.7%; p = 0.764). After a median follow-up time of 28.0 months for DC arm and 34.5 months for D arm, progression free survival (PFS) was significantly higher in the DC arm (DC vs D:3.33 months vs 2.60 months; p-value = 0.012), while no significant difference was observed in terms of overall survival (OS) (DC vs D: 10.3 months vs 7.70 months; p-value = 0.550). Chemotherapy was well-tolerated and grade III/IV toxicities were relatively infrequent. No toxic deaths were observed. CONCLUSIONS: This study has not achieved its primary objective of significant OS prolongation with docetaxel/carboplatin combination over single-agent docetaxel in patients who had not received front-line docetaxel; however, the docetaxel/carboplatin combination was associated with a significant clinical benefit in terms of PFS.

Detection of occult HER2 mRNA-positive tumor cells in the peripheral blood of patients with operable breast cancer: evaluation of their prognostic relevance.

To evaluate whether HER2 mRNA could be used as a marker of circulating tumor cells (CTCs) in women with operable breast cancer. A nested RT-PCR assay was developed and used for the detection of HER2 mRNA-positive CTCs. Blood from 216 women with early breast cancer obtained before adjuvant treatment was tested for HER2 mRNA-positive cells to assess their prognostic value. Nested RT-PCR for HER2 mRNA showed high sensitivity whereas no HER2 mRNA-positive cells could be identified in the blood of healthy donors. HER2 mRNA-positive CTCs were detected in 53 (24.5%) of 216 patients and HER2 mRNA detection was associated with reduced disease-free survival (DFS; P < 0.0001) and overall survival (OS; P = 0.004). In multivariate analysis, detection of HER2 mRNA-positive CTCs emerged as independent prognostic factor for DFS (P = 0.0001) and OS (P = 0.003). HER2 mRNA could be a valuable prognostic marker for the detection of CTCs in early breast cancer patients.

Patients' perceptions as an indicator of quality of care, in Greek patients with inflammatory bowel disease.

AIM AND METHOD: The chronic nature of inflammatory bowel disease (IBD) and its frequent relapses result to a considerable utilization of healthcare resources. Current approaches for the assessment of quality of care are based on the perception of the healthcare provider, which may be different from that of the healthcare user. The purpose of this study was to assess IBD patients' satisfaction, as an indicator of healthcare quality, with the use of a validated instrument (QUOTE-IBD). Ninety-five patients with IBD completed the GR-QUOTE-IBD questionnaire, for the assessment of patient's perception, regarding the quality of the perceived care. RESULTS: According to this evaluation suboptimal care was observed in the dimensions of accommodation, accessibility and information (mean values: 8.92, 8.94 and 8.95, respectively). In the subgroup analysis significant differences were observed in relation to patient's age groups and educational level. Differences were also noted in relation to the disease duration (longer and shorter than 5 years). CONCLUSIONS: The assessment of the quality of health care, based on patients' perception, revealed quality problems in the dimensions of accommodation, accessibility and information. According to subgroup analysis, disease type, educational status, age and disease duration play an important role in the formation of patients' expectations from the healthcare system.

Central nervous system relapse in patients with breast cancer is associated with advanced stages, with the presence of circulating occult tumor cells and with the HER2/neu status.

INTRODUCTION: To evaluate the incidence of central nervous system (CNS) involvement in patients with breast cancer treated with a taxane-based chemotherapy regimen and to determine predictive factors for CNS relapse. METHODS: The medical files of patients with early breast cancer (n = 253) or advanced stage breast cancer (n = 239) as well of those with other solid tumors (n = 336) treated with or without a taxane-based chemotherapy regimen during a 42-month period were reviewed. HER2/neu overexpression was identified by immunohistochemistry, whereas cytokeratin 19 (CK-19) mRNA-positive circulating tumor cells (CTCs) in the peripheral blood were identified by real-time PCR. RESULTS: The incidence of CNS relapse was similar in patients suffering from breast cancer or other solid tumors (10.4% and 11.4%, respectively; P = 0.517). The incidence of CNS relapse was significantly higher in breast cancer patients with advanced disease (P = 0.041), visceral disease and bone disease (P = 0.036), in those who were treated with a taxane-containing regimen (P = 0.024), in those with HER2/neu-overexpressing tumors (P = 0.022) and, finally, in those with detectable CK-19 mRNA-positive CTCs (P = 0.008). Multivariate analysis revealed that the stage of disease (odds ratio, 0.23; 95% confidence interval, 0.007-0.23; P = 0.0001), the HER2/neu status (odds ratio, 29.4; 95% confidence interval, 7.51-101.21; P = 0.0001) and the presence of CK-19 mRNA-positive CTCs (odds ratio, 8.31; 95% confidence interval, 3.97-12.84; P = 0.001) were independent predictive factors for CNS relapse. CONCLUSION: CNS relapses are common among breast cancer patients treated with a taxane-based chemotherapy regimen, patients with HER2/neu-positive tumor and patients with CK-19 mRNA-positive CTCs.

A multicenter phase II study of sequential vinorelbine and cisplatin followed by docetaxel and gemcitabine in patients with advanced non-small cell lung cancer.

PURPOSE: To evaluate the activity and toxicity of the sequential administration of vinorelbine/cisplatin (VC regimen) followed by the docetaxel/gemcitabine (DG regimen) combination in patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND TREATMENT: Fifty-nine previously untreated patients with advanced/metastatic NSCLC received three cycles of cisplatin 80 mg/m(2) (day 1), and vinorelbine 30 mg/m(2) (days 1 and 8 every 3 weeks; VC regimen), followed by six cycles of docetaxel (65 mg/m(2), day 1) and gemcitabine (1,500 mg/m(2), day 1), (DG regimen) every 2 weeks. RESULTS: One (1.7%) complete and 26 (44.1%) partial responses were achieved for an overall response rate of 45.8% (95% CI 33.05-58.48%); 12 (20.3%) patients had stable disease and 20 (33.9%) progressive disease. The median time to progression was 5.3 months, the median survival time 12.5 months and the 1-year survival rate 51%. The main toxicity was grade III/IV neutropenia occurring in 25.5% of patients; all other hematologic and non-hematologic toxicities were relatively infrequent. CONCLUSIONS: The sequential administration of VC and DG regimens was well tolerated and active against advanced NSCLC and merits to be further evaluated against a single doublet.

Biweekly Carboplatin Plus Gemcitabine as First-Line Treatment of Elderly Patients With Advanced Squamous Non-Small-cell Lung Cancer: A Multicenter Phase I-II Trial by the Hellenic Oncology Research Group.

BACKGROUND: The present study was a phase I/II study to determine the maximum tolerated doses (MTDs) and dose-limiting toxicities of the biweekly carboplatin/gemcitabine combination and evaluate its safety and efficacy in patients aged ≥ 70 years with advanced squamous non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients aged ≥ 70 years with advanced or metastatic squamous NSCLC received escalated doses of carboplatin (area under the curve [AUC] 2-2.5 intravenously) and gemcitabine (800-1100 mg/m2 intravenously) every 2 weeks (phase I). In the phase II, the drugs were administered at their previously defined MTDs (carboplatin, AUC 2.5; gemcitabine, 1100 mg/m2). The primary endpoint was the overall response rate. RESULTS: A total of 69 patients were enrolled (phase I, n = 15). The median age was 76 years (range, 70-84 years); 52 patients had stage IV disease, and 61 and 8 patients had Eastern Cooperative Oncology Group performance status of 0 to 1 and 2, respectively. The MTDs could not be reached at the predefined last dose levels. The dose-limiting toxicities were grade 5 renal toxicity and grade 3 thrombocytopenia. In the phase II study, the overall response rate was 35.8% (95% confidence interval [CI], 23.0%-48.8%). In the intention-to-treat analysis, the median progression-free survival was 6.7 months (95% CI, 4.2-8.8 months), and the median overall survival was 13.3 months (95% CI, 7.1-19.6 months). Grade 3 or 4 neutropenia was observed in 7 patients (12.3%), grade 3 or 4 thrombocytopenia in 4 patients (7.1%), and grade 2 or 3 fatigue in 10 patients (17.5%). One toxic death occurred in the phase I of the study. CONCLUSION: The biweekly regimen of gemcitabine and carboplatin showed satisfactory efficacy and a favorable toxicity profile in elderly patients with advanced or metastatic squamous cell NSCLC.

Multicenter dose-finding study of concurrent capecitabine and radiotherapy as adjuvant treatment for operable rectal cancer.

PURPOSE: 5-Fluorouracil-based chemotherapy with concurrent radiotherapy (RT) is the standard adjuvant treatment in rectal cancer. A Phase I study was conducted to determine the maximal tolerated dose and the dose-limiting toxicities of capecitabine combined with standard RT as adjuvant treatment in patients with rectal cancer. METHODS AND MATERIALS: Patients with Stage II-III rectal cancer after surgery were eligible. RT included a total dose of 50.4 Gy in fractions of 1.8 Gy/d, 5 d/wk, for 5.5 weeks. Capecitabine was administered twice daily in escalating doses during the entire period of RT. Dose-limiting toxicity included Grade 4 neutropenia or thrombocytopenia, febrile neutropenia, Grade 3 or greater nonhematologic toxicity, or treatment delay because of unresolved toxicity for >1 week. RESULTS: Thirty-one patients were enrolled at the following dose levels: 1000 mg/m(2)/d (3 patients), 1150 mg/m(2)/d (4 patients) 1300 mg/m(2)/d (6 patients), 1400 mg/m(2)/d (6 patients), 1500 mg/m(2)/d (3 patients), 1600 mg/m(2)/d (3 patients), and 1700 mg/m(2)/d (6 patients). Dose-limiting toxicities were observed in 2 patients at 1300 mg/m(2)/d (Grade 3 diarrhea), and 2 patients at 1400 mg/m(2)/d (skin toxicity in 1 and abdominal pain with fever in 1, resulting in treatment delay), and 3 patients at 1700 mg/m(2)/d (2 patients had Grade 3 diarrhea and 1 had hand-foot syndrome). Four patients presented with chronic postradiation colitis. CONCLUSIONS: The maximal tolerated dose of capecitabine given concurrently with RT was 1600 mg/m(2)/d in this study. This dose is recommended for additional use in Phase II-III studies.

Assessing health-related quality of life in patients with inflammatory bowel disease, in Crete, Greece.

BACKGROUND: Health Related Quality of Life (HRQoL) is an important outcome measure in Inflammatory Bowel Disease (IBD). The aim of our study was to assess HRQoL in a population of 135 Greek patients with IBD. METHODS: A cohort of 135 patients with IBD, 81 with ulcerative colitis (UC) and 54 with Crohn's disease (CD) were enrolled in our study. Demographic and disease-related data were recorded. HRQoL was assessed by a disease-specific and a generic questionnaire, IBDQ and SF-36, respectively. Disease activity was assessed by Harvey-Bradshaw Index and the Colitis Activity Index for CD and UC patients, respectively. RESULTS: Among all variables recorded in our study, only disease activity had a significant effect on HRQoL. Patients with active disease scored significantly lower on both IBDQ and SF-36 when compared to those in remission. Only two among the four IBDQ dimensions, bowel and systemic, had significant ability in distinguishing best patients in remission from those with active disease. CONCLUSIONS: IBD has a negative impact on HRQoL. Patients with active disease are more impaired than patients in remission. In our population of patients bowel and systemic dimensions had a predominant value in patients' perception of quality of life. Patients in our study using the same instrument scored higher than previously reported.

A dose escalation study of docetaxel and oxaliplatin combination in patients with metastatic breast and non-small cell lung cancer.

OBJECTIVES: To determine the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of docetaxel in combination with oxaliplatin (L-OHP) as first-line treatment of patients with advanced breast (ABC) and non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifty-two patients (26 with NSCLC and 26 with ABC), who had not received prior chemotherapy for metastatic disease, were enrolled. The patients' median age was 64 years, and 42 (71%) had a performance status (WHO) 0-1. Docetaxel was given as a 1-hour infusion after standard premedication on day 1 and L-OHP as a 2 to 6-hour infusion on day 2 every 3 weeks. Doses were escalated at increments of 10 mg/m2. RESULTS: The DLT1 was reached at the doses of docetaxel 75 mg/m2 and L-OHP 80 mg/m2. The addition of rhG-CSF permitted further dose escalation (DLT2: docetaxel 90 mg/m2 and L-OHP 130 mg/m2). The dose-limiting events were grade 4 neutropenia, febrile neutropenia, grades 3 or 4 diarrhea and grade 3 fatigue. Out of 239 delivered cycles, grades 3 or 4 neutropenia occurred in 22 (9%) cycles with 5 (2%) neutropenic febrile episodes. There was one septic death. Grades 3 or 4 fatigue was observed in seven (13%) patients and grades 3-4 diarrhea in five (10%). Out of 42 patients evaluable for response, seven (27%) patients with ABC and five (19%) patients with NSCLC experienced a partial response. CONCLUSION: The combination of docetaxel and oxaliplatin is a feasible and well-tolerated regimen. The recommended doses for future phase II studies are 75 mg/m2 for docetaxel on day 1 and 70 mg/m2 for L-OHP on day 2 without rhG-CSF support and 85 mg/m2 and 130 mg/m2, respectively, with rhG-CSF support.

Completion of radiotherapy is associated with the Vulnerable Elders Survey-13 score in elderly patients with cancer.

OBJECTIVES: Vulnerability assessment of geriatric patients with cancer may contribute to improved anti-cancer treatment with maximal results and minimal side effects. The aim of the present study was to evaluate whether the Vulnerable Elders Survey-13 (VES-13) score is associated with completion of radiotherapy among elderly patients with cancer. MATERIALS AND METHODS: This was a prospective observational study that included patients greater than age 75 with histologically confirmed cancer disease, referred to the Department of Radiation Oncology to receive radical or palliative radiotherapy, from 2010 to 2012. VES-13 forms were filled in before the initiation of radiotherapy and scores were assigned according to a standardized scoring procedure. RESULTS: Of a total of 230 participants (median age 78.5 years), 41 (17.8%) did not complete radiotherapy. These patients had higher VES-13 scores (median with interquartile range: 5 [2-8.5]) compared to those who completed the treatment (3 [1-7]; P = 0.008). A VES-13 score >3 was associated with 2.14 times higher probability of not completing radiotherapy, whereas in patients with scores >7 this probability was 3.34 times higher. The association between higher VES-13 scores and non-completion of radiotherapy was independent of other factors, such as age, sex, comorbidities, type of radiotherapy, and presence of side effects. CONCLUSION: Patients with higher VES-13 scores had increased probability of not completing radiotherapy in our study, and this effect was independent of other factors that might affect radiotherapy completion.

Evaluating the physiological reserves of older patients with cancer: the value of potential biomarkers of aging?

Aging of an individual entails a progressive decline of functional reserves and loss of homeostasis that eventually lead to mortality. This process is highly individualized and is influenced by multiple genetic, epigenetic and environmental factors. This individualization and the diversity of factors influencing aging result in a significant heterogeneity among people with the same chronological age, representing a major challenge in daily oncology practice. Thus, many factors other than mere chronological age will contribute to treatment tolerance and outcome in the older patients with cancer. Clinical/comprehensive geriatric assessment can provide information on the general health status of individuals, but is far from perfect as a prognostic/predictive tool for individual patients. On the other hand, aging can also be assessed in terms of biological changes in certain tissues like the blood compartment which result from adaptive alterations due to past history of exposures, as well as intrinsic aging processes. There are major signs of 'aging' in lymphocytes (e.g. lymphocyte subset distribution, telomere length, p16INK4A expression), and also in (inflammatory) cytokine expression and gene expression patterns. These result from a combination of the above two processes, overlaying genetic predispositions which contribute significantly to the aging phenotype. These potential "aging biomarkers" might provide additional prognostic/predictive information supplementing clinical evaluation. The purpose of the current paper is to describe the most relevant potential "aging biomarkers" (markers that indicate the biological functional age of patients) which focus on the biological background, the (limited) available clinical data, and technical challenges. Despite their great potential interest, there is a need for much more (validated) clinical data before these biomarkers could be used in a routine clinical setting. This manuscript tries to provide a guideline on how these markers can be integrated in future research aimed at providing such data.

Progression free survival rate at 9 and 18 weeks predict overall survival in patients with malignant pleural mesothelioma: an individual patient pooled analysis of 10 European Organisation for Research and Treatment of Cancer Lung Cancer Group studies and an independent study validation.

BACKGROUND: Response criteria have always been difficult to apply to malignant pleural mesothelioma (MPM), due to its unique pattern of growth. We developed some models to show that progression free survival rate (PFSR) could be a better predictor of overall survival (OS) than the response rate (RR) in MPM patients. The results were validated independently in the European Organisation for Research and Treatment of Cancer (EORTC) 08052, a phase II study in MPM. METHODS: Individual patient data from 10 EORTC-Lung Cancer Group (LCG) studies of first-line chemotherapy in MPM were pooled. Response to therapy was assessed according to World Health Organisation (WHO) criteria in all except the two most recent trials, which used Response Evaluation Criteria in Solid Tumours (RECIST). Landmark analyses (LA) at 9 weeks and 18 weeks after registration/randomisation were performed to assess the association between PFSR and OS. Independent validation of the results was conducted in EORTC 08052 study (82 patients) employing the same LA. RESULTS: All 10 studies (N=523 patients) were included in the LA of PFSR at 9 and 18 weeks (PFSR-9 and PFSR-18). PFSR-9 and PFSR-18 were confirmed as predictors of OS, with hazard ratio (HR) of 0.37 (95% confidence interval (CI), 0.30-0.47) and 0.50 (0.38-0.65) and C-index of 0.62 and 0.58, respectively. In the validation study, 28.4% achieved CR/PR and 77.8% had disease control (CR/PR/SD) as their best overall response. PFSR-9 and PFSR-18 weeks were both strongly correlated with OS (HR of 0.35 [80% CI, 0.25-0.49] and 0.46 (0.32-0.67) and C-index of 0.66 and 0.60, respectively). CONCLUSION: PFSR-18 was strongly correlated and discriminated patients with better OS from the poorer prognosis patients. An earlier end-point, PFSR-9 was also strongly correlated to OS with better discriminating capacity. The results were independently validated.

Targeting tumor neovasculature in non-small-cell lung cancer.

Recent insight into the molecular biology of cancer and mechanisms of tumorigenesis, has allowed for the identification of several potential molecular targets and the development of novel "targeted therapies". One of the most active research fields in NSCLC is the discovery of therapies that target angiogenesis. The vascular endothelial growth factor (VEGF) pathway represents a crucial component of the tumor angiogenesis process. Two different strategies have been developed in clinical practice in order to restrict tumor vasculature development; either the use of monoclonal antibodies against VEGF or small molecule tyrosine kinase inhibitors to target the tyrosine kinase domain of VEGF receptor. Among these agents that have been tested bevacizumab, a monoclonal antibody against VEGF, has been approved for the treatment of metastatic NSCLC in combination with chemotherapy, while several other agents are under phase III investigation. Moreover, several issues such as predictive biomarkers of response to antiangiogenic therapy and mechanisms of resistance to these agents remain to be elucidated. The purpose of this paper is to present the current status of antiangiogenic therapies in the treatment of NSCLC and to discuss these issues.

Lung cancer in never smokers: disease characteristics and risk factors.

It is estimated that approximately 25% of all lung cancer cases are observed in never-smokers and its incidence is expected to increase due to smoking prevention programs. Risk factors for the development of lung cancer described include second-hand smoking, radon exposure, occupational exposure to carcinogens and to cooking oil fumes and indoor coal burning. Other factors reported are infections (HPV and Mycobacterium tuberculosis), hormonal and diatery factors and diabetes mellitus. Having an affected relative also increases the risk for lung cancer while recent studies have identified several single nucleotide polymorphisms associated with increased risk for lung cancer development in never smokers. Distinct clinical, pathology and molecular characteristics are observed in lung cancer in never smokers; more frequently is observed in females and adenocarcinoma is the predominant histology while it has a different pattern of molecular alterations. The purpose of this review is to summarize our current knowledge of this disease.

End points and trial design in geriatric oncology research: a joint European organisation for research and treatment of cancer--Alliance for Clinical Trials in Oncology--International Society Of Geriatric Oncology position article.

Selecting the most appropriate end points for clinical trials is important to assess the value of new treatment strategies. Well-established end points for clinical research exist in oncology but may not be as relevant to the older cancer population because of competing risks of death and potentially increased impact of therapy on global functioning and quality of life. This article discusses specific clinical end points and their advantages and disadvantages for older individuals. Randomized or single-arm phase II trials can provide insight into the range of efficacy and toxicity in older populations but ideally need to be confirmed in phase III trials, which are unfortunately often hindered by the severe heterogeneity of the older cancer population, difficulties with selection bias depending on inclusion criteria, physician perception, and barriers in willingness to participate. All clinical trials in oncology should be without an upper age limit to allow entry of eligible older adults. In settings where so-called standard therapy is not feasible, specific trials for older patients with cancer might be required, integrating meaningful measures of outcome. Not all questions can be answered in randomized clinical trials, and large observational cohort studies or registries within the community setting should be established (preferably in parallel to randomized trials) so that treatment patterns across different settings can be compared with impact on outcome. Obligatory integration of a comparable form of geriatric assessment is recommended in future studies, and regulatory organizations such as the European Medicines Agency and US Food and Drug Administration should require adequate collection of data on efficacy and toxicity of new drugs in fit and frail elderly subpopulations.