Cancer-related inflammation as predicting tool for treatment outcome in locally advanced and metastatic non-small cell lung cancer.

BACKGROUND: Lung cancer is the leading cause of cancer deaths and the non-small cell lung cancer (NSCLC) represents 80% of all cases. In most cases when diagnosed, it is in locally advanced or metastatic stage, when platinum based doublet chemotherapy is the established therapeutic option for majority of the patients. Predictive factors to filter the patients who will benefit the most from the chemotherapy are not clearly defined. Objective of this study was to explore predictive value of pre-treatment C-reactive protein (CRP), fibrinogen and their interaction, for the response to the frontline chemotherapy. METHODS: In this retrospective cohort study 170 patients with locally advanced and metastatic NSCLC were included. Relationship between baseline level of CRP and fibrinogen and response to the frontline chemotherapy was assessed. RESULTS: We found that pre-treatment CRP and fibrinogen values were statistically significantly correlated. Chemotherapy and CRP, fibrinogen, and their interaction were independently significantly associated with disease control rate at re-evaluation. There was statistically significant difference in median pre-treatment CRP level between the patients with disease control or progression at re-evaluation, 13.8 vs. 30.0 mg/L respectively, P=0.026. By Johnson-Neyman technique we found that in patients with initial fibrinogen value below 3.5 g/L, CRP level was significantly associated with disease control or progression of the disease. Above this fibrinogen value the association of CRP and disease control was lost. CONCLUSIONS: The findings from this study support the growing evidence of inflammation and cancer relationship, where elevated pre-treatment level of CRP has negative predictive significance on the NSCLC frontline chemotherapy response.

[CANCER PATIENTS FOLLOW-UP ­ CROATIAN SOCIETY FOR MEDICAL ONCOLOGY CLINICAL GUIDELINES Part V: melanoma, sarcomas, central nerve system tumors, lung cancer].

Treatment of oncological patients must be based upon multidisciplinary approach, and takes place in specialized oncological centers. By the end of a specific oncological treatment further follow-up is being managed mostly by the oncologists, but the role of the general practitioners becomes more important every day and therefore should be precisely defined. Nowadays, most of the existing follow-up guidelines are not being based on prospective studies, yet on the expert's opinion of a precise oncological center or specialists. The aim of the Croatian Society of Medical Oncology (CSMO) with these recommendations is to standardize and rationalize the diagnostic procedures' algorithm in follow­up of oncological patients after primary treatment, in patients with melanoma, sarcomas, central nerve system tumors and lung cancer.

Talc pleurodesis improves survival of patients with malignant pleural effusions: case-control study.

AIM: The aim of this study is to investigate whether there was a considerable difference in the survival of patients with malignant pleural effusion (MPE) depending on the pleural effusion treatment option. METHODS: One hundred and seven patients with proven MPE (metastatic lung and breast cancer) were included in the retrospective study. Fifty six patients were treated with talc pleurodesis and a control group of 51 patients with similar characteristics (in age, sex and disease) were treated with serial thoracentesis. The patients of both groups underwent chemotherapy and/or radiotherapy. The overall survival and the survival in subgroups of patients with different tumour types and different performance status (PS) equal 1, 2 and 3 were compared. RESULTS: The patients who underwent talc pleurodesis had a longer average survival interval (MS) than the patients without such a treatment (n = 56; MS = 21,5 and n = 51; MS = 9 weeks, respectively; p < 0.001). The best results were achieved in patients with PS 1 (n = 16; MS = 35.5 and n = 10; MS = 11 weeks in the groups with and without talc pleurodesis, respectively; p < 0,001) and PS 2 (n = 27; MS = 21 and n = 30; MS = 10 weeks in the groups with and without talc pleurodesis, respectively; p < 0.001), whereas talc pleurodesis was not effective in PS 3 patients (n = 13; MS = 10 and n = 11; MS = 7 weeks in the groups with and without talc pleurodesis, respectively; p = 0.08). Patients with the breast cancer showed a longer average survival interval after pleurodesis than those with the lung cancer (n = 12; MS = 37.5 and n = 4; MS = 20 weeks in the group with the breast cancer and with the lung cancer, respectively; p < 0.001), whereas the median survival was not significantly different between those patients without pleurodesis (n = 10; MS = 10 and n = 41; MS = 9 weeks in the group with the breast cancer and lung cancer, respectively; p = 0.11). CONCLUSION: The patients treated with talc pleurodesis had a significantly longer average survival than the patients without such a treatment, especially in the group with the breast cancer and in groups with better performance status. This may indicate that talc pleurodesis, apart from its symptomatic effect on the cessation of pleural effusion, may have a direct antitumour effect as well.

Waist circumference does not correlate with functional lung capacity in moderate and severe chronic obstructive pulmonary disease.

Waist circumference is a good predictor of the risk of heart diseases, but data on the relationship between waist circumference and pulmonary diseases are sparse. The aim of this study was to investigate its influence on pulmonary function regarding exercise capacity in moderate and severe chronic obstructive pulmonary disease (COPD), according to Global Initiative for Lung Diseases (GOLD) stages. During 2009, a total of 70 COPD patients aged 33 to 80 years were stratified into GOLD 2 and GOLD 3 stages. Diagnostic separation between COPD severity groups was made upon percentage of predicted forced expiratory volume in 1 second. Anthropometric measures, lung function testing and prognostic scoring systems were assessed. Logistic regression analysis was used to make comparisons while taking into account the possible confounding factors. Waist circumference did not show substantial variations between GOLD 2 and GOLD 3 stages (p > 0.5). There was a weak positive correlation between waist circumference and percent of predicted 6-minute walking distance (r = 0.237; p = 0.001). Another parameter, suprailiac skinfold, was significantly different between GOLD 2 and GOLD 3 stages (19.41 vs. 15.32 mm; p = 0.047). Although waist circumference is a meaningful marker of abdominal obesity, which influences pulmonary function, we failed to prove its importance in correlation with functional lung capacity in a selected COPD population. However, suprailiac skinfold deserves greater attention and further evaluation.

Quality of life in patients with advanced non-small-cell lung cancer given maintenance treatment with pemetrexed versus placebo (H3E-MC-JMEN): results from a randomised, double-blind, phase 3 study.

BACKGROUND: Pemetrexed maintenance therapy significantly improved overall survival and progression-free survival compared with placebo, and had a good safety profile in a phase 3 placebo-controlled study in patients with advanced non-small-cell lung cancer (NSCLC). Results for quality of life, symptom palliation, and tolerability are presented here. METHODS: After four cycles of platinum-based induction therapy, 663 patients with stage IIIB or stage IV NSCLC and Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (in a 2:1 ratio) from March 15, 2005, to July 20, 2007, using the Pocock and Simon minimisation method to receive pemetrexed (500 mg/m(2) every 21 days; n=441) or placebo (n=222) plus best supportive care until disease progression. The primary efficacy data have been reported previously. Patients completed the Lung Cancer Symptom Scale (LCSS) at baseline, after each cycle, and post-discontinuation. Worsening of symptoms was defined as an increase of 15 mm or more from baseline on a 100 mm scale for each LCSS item. The primary outcome for these quality-of-life analyses was time to worsening of symptoms, analysed for all randomised patients. This study is registered with ClinicalTrials.gov, number NCT00102804. FINDINGS: Baseline characteristics, including LCSS scores, were well balanced between groups. Baseline LCSS scores were low, indicating low symptom burden for patients without disease progression after completion of first-line treatment. Longer time to worsening was recorded for pain (hazard ratio [HR] 0·76, 95% CI 0·59-0·99; p=0·041) and haemoptysis (HR 0·58, 95% CI 0·34-0·97; p=0·038) with pemetrexed than with placebo; no other significant differences in analyses of time to worsening were noted. Additional longitudinal analyses showed a greater increase in loss of appetite in the pemetrexed group than in the placebo group (4·3 mm vs 0·2 mm; p=0·028). Rates of resource use were statistically higher for pemetrexed than for placebo: admissions to hospital for drug-related adverse events (19 [4%] vs none; p=0·001), transfusions (42 [10%] vs seven [3%]; p=0·003), and erythropoiesis-stimulating agents (26 [6%] vs four [2%]; p=0·017). INTERPRETATION: Quality of life during maintenance therapy with pemetrexed is similar to placebo, except for a small increase in loss of appetite, and significantly delayed worsening of pain and haemoptysis. In view of the improvements in overall and progression-free survival noted with pemetrexed maintenance therapy, such treatment is an option for patients with advanced non-squamous NSCLC who have not progressed after platinum-based induction therapy. FUNDING: Eli Lilly.

Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study.

BACKGROUND: Several studies have shown the efficacy, tolerability, and ease of administration of pemetrexed-an antifolate antineoplastic agent-in patients with advanced non-small-cell lung cancer. We assessed pemetrexed as maintenance therapy in patients with this disease. METHODS: This randomised double-blind study was undertaken in 83 centres in 20 countries. 663 patients with stage IIIB or IV disease who had not progressed on four cycles of platinum-based chemotherapy were randomly assigned (2:1 ratio) to receive pemetrexed (500 mg/m(2), day 1) plus best supportive care (n=441) or placebo plus best supportive care (n=222) in 21-day cycles until disease progression. Treatment was randomised with the Simon and Pocock minimisation method. Patients and investigators were masked to treatment. All patients received vitamin B(12), folic acid, and dexamethasone. The primary endpoint of progression-free survival and the secondary endpoint of overall survival were analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00102804. FINDINGS: All randomly assigned participants were analysed. Pemetrexed significantly improved progression-free survival (4.3 months [95% CI 4.1-4.7] vs 2.6 months [1.7-2.8]; hazard ratio [HR] 0.50, 95% CI 0.42-0.61, p<0.0001) and overall survival (13.4 months [11.9-15.9] vs 10.6 months [8.7-12.0]; HR 0.79, 0.65-0.95, p=0.012) compared with placebo. Treatment discontinuations due to drug-related toxic effects were higher in the pemetrexed group than in the placebo group (21 [5%] vs three [1%]). Drug-related grade three or higher toxic effects were higher with pemetrexed than with placebo (70 [16%] vs nine [4%]; p<0.0001), specifically fatigue (22 [5%] vs one [1%], p=0.001) and neutropenia (13 [3%] vs 0, p=0.006). No pemetrexed-related deaths occurred. Relatively fewer patients in the pemetrexed group than in the placebo group received systemic post-discontinuation therapy (227 [51%] vs 149 [67%]; p=0.0001). INTERPRETATION: Maintenance therapy with pemetrexed is well tolerated and offers improved progression-free and overall survival compared with placebo in patients with advanced non-small-cell lung cancer. FUNDING: Eli Lilly.

[Thyroid transcription factor-1 in pulmonary cytology]. / TTF-1 u plucnoj citologiji.

UNLABELLED: Currently it is necessary to define in almost each case whether a carcinoma is a small or non-small cell carcinoma, adenocarcinoma, pulmonary or metastatic in origin. Thyroid transcription factor-1 (TTF-1) was positive in more than 80% of primary pulmonary adenocarcinomas and in none from the sites other than the thyroid. Mucinous bronchioloalveolar carcinomas are usually negative. Immunocytochemistry with a panel of cytokeratins (CK) 7 and 20, along with TTF-1, is recommended for identification of the origin of adenocarcinoma in pulmonary cytology. OBJECTIVE: The aim of the study was to assess the value of TTF-1 reactivity in adenocarcinomas determined by immunocytochemistry in different pulmonary cytologic specimens. METHODS AND RESULTS: Cytologic specimens of 83 patients with adenocarcinomas were analyzed. Immunocytochemistry was performed with a panel of antibodies: TTF-1, CK7, CK20 in all cases and CK5/6 if necessary. The study included 17 different bronchoscopic samples (aspirates, brushes, transbronchial FNA), 14 transthoracic FNA, 27 pleural effusions and 25 FNA of peripheral lymph nodes. TTF-1 was positive in 26/83 (31.3%) and negative in 47/83 (68.7%) samples. All TTF-1 positive adenocarcinomas were also CK7 positive, thus being conclusive of pulmonary origin. In TTF-1 negative group, pulmonary origin was proven in 10/57 (17.5%) adenocarcinomas, whereas 18/57 (31.6%) adenocarcinomas were metastatic; in 29/57 (50.9%) adenocarcinomas other diagnostic procedures failed to prove their origin. CK20 positivity with CK7 negativity was conclusive of metastatic gastrointestinal adenocarcinoma. DISCUSSION: Numerous reports support TTF-1 expression in adenocarcinoma as being highly specific for pulmonary origin, if thyroid is excluded. We were able to identify 36/83 (43.4%) adenocarcinomas as pulmonary adenocarcinomas. Among them, only 31.3% were TTF-1 positive. In our study, about 60% of adenocarcinomas with uncertain origin were in the groups of pleural effusions and lymph nodes. In these groups, cytologic diagnosis of adenocarcinoma often provided evidence of the carcinoma expansion, aggressive behavior and poor differentiation, and served as a guideline for patient management. In the studies of mixed pulmonary adenocarcinomas, TTF-1 expression was lower in poorly differentiated segments as well as in the areas with bronchioloalveolar pattern. One explanation for the high percentage of TTF-1 negative adenocarcinomas in our material is morphological selection of adenocarcinomas of presumably non-pulmonary origin before immunocytochemistry. CONCLUSION: TTF-1 in a panel with cytokeratins is specific for differentiation of the origin of adenocarcinomas. TTF-1 negative finding in adenocarcinomas does not exclude pulmonary origin, but only points to other diagnostic procedures for definitive diagnosis.

Effects of inbreeding, endogamy, genetic admixture, and outbreeding on human health: a (1001 Dalmatians) study.

AIM: (1001 Dalmatians) research program collects biomedical information from multiple small isolated populations ((metapopulation)) on Adriatic islands, Croatia, and investigates health effects of human population isolation, inbreeding, admixture, and outbreeding. METHODS: We collected random samples of 100 individuals from 9 island settlements and an additional sample of 101 immigrants to the islands, pooled from all study populations. According to their personal genetic histories, the examinees were categorized as inbred, autochthonous, admixed, and outbred. A total of 76 inbred individuals from a total sample of 1001 examinees were matched to 76 autochthonous, 76 admixed, and 76 outbred controls by gender, age (+/-5 years), village of residence, education, and socio-economic status. We investigated the effects of presumed individual genome-wide heterozygosity predicted from personal genetic histories on the following 10 traits: systolic and diastolic blood pressure, body mass index, high and low density lipoproteins and total cholesterol, triglycerides, uric acid, creatinine, and blood glucose. RESULTS: Personal genetic history significantly affected systolic blood pressure (Spearman rho=0.157, P=0.006), while the effect on cholesterol (rho=0.105, P=0.069), and high density lipoprotein cholesterol (rho=0.104, P=0.071) was suggestive. Admixed individuals and immigrants consistently showed values associated with lower health risk. When inbred and autochthonous samples were merged and compared with the admixed and outbred samples to increase the power of the study, the effects on the three traits above and also on body mass index and diastolic blood pressure became statistically significant. The medians for all 10 medically relevant traits in inbred and autochthonous group, with lower values of presumed individual genome-wide heterozygosity, were less favorable in terms of health. CONCLUSION: The combined effects of founder effect, genetic drift, and inbreeding can increase the frequency of detrimental rare variants in human metapopulations, leading to overall worsening of population health, whereas admixture and outbreeding appear to have the opposite effect.

Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: a phase III trial.

PURPOSE: The primary objective of this randomized phase III study was to show significant difference in median time to progression (TTP) in patients with advanced NSCLC treated with single-agent gemcitabine maintenance therapy versus best supportive care following gemcitabine plus cisplatin initial first-line therapy. PATIENTS AND METHODS: Chemonaive patients with stage IIIB/IV NSCLC received gemcitabine 1,250 mg/m(2) (days 1 and 8) plus cisplatin 80 mg/m(2) (day 1) every 21 days. Patients achieving objective response or disease stabilization following initial gemcitabine plus cisplatin therapy were randomized (2:1 fashion) to receive maintenance gemcitabine (1,250 mg/m(2) on days 1 and 8 every 21 days) plus best supportive care (GEM arm), or best supportive care only (BSC arm). RESULTS: Between November 1999 and November 2002, we enrolled 352 patients (median age: 57 years; stage IV disease: 74%; Karnofsky performance status (KPS) >80: 41%). Following initial therapy, 206 patients were randomized and treated with gemcitabine (138) or best supportive care (68). TTP throughout the study period was 6.6 and 5 months for GEM and BSC arms, respectively, while values for the maintenance period were 3.6 and 2.0 months (for p < 0.001 for both). Median overall survival (OS) throughout study was 13.0 months for GEM and 11.0 months for BSC arms (p = 0.195). The toxicity profile was mild, with neutropenia being most common grade 3/4 toxicities. CONCLUSION: Maintenance therapy with gemcitabine, following initial therapy with gemcitabine plus cisplatin, was feasible, and produced significantly longer TTP compared to best supportive care alone. Further studies are warranted to establish the place of maintenance chemotherapy in patients with advanced NSCLC.

Gemcitabine in the first and second-line chemotherapy of advanced non-small cell lung cancer.

Aim of this study was to estimate efficacy of gemcitabine in first and the second-line chemotherapy for patients with advanced non-small cell lung cancer (stage III and IV). In first-line chemotherapy, 120 patients were treated with different chemotherapy regimens. Fifty-nine patients were treated with gemcitabine / cisplatin (PG), 41 with cisplatin / etoposide (PE) and 20 with mitomycin / ifosfamide / cisplatin (MIC). Forty patients, unsuccessfully treated with PE and MIC in first-line therapy were treated with PG (24 pts) and with best supportive care (BSC) (16 pts). In first-line therapy PG was superior to PE and MIC protocol (mean survival (MS) 10 vs. 7 vs. 8.5 months). Response rate (RR) for PG in first-line therapy was 46% and 21% in second-line. We showed also significantly better survival in patients treated with PG in second-line chemotherapy comparing to best supportive care (MS 9 vs. 5.5 months). Toxic side effects for combination PG was acceptable. This study confirmed that PG combination is safe and effective as first and second-line chemotherapy for patients with advanced non-small cell lung cancer.