Advanced lung adenocarcinoma (LAC) is one of the most lethal malignancies worldwide. The aim of this study was to evaluate the global survival in a real-life cohort of patients with LAC harboring ...driver genetic alterations.
A series of 1282 consecutive Sardinian LAC patients who underwent genetic testing from January 2011 through July 2016 was collected. Molecular tests were based on the clinical needs of each single case (EGFR-exon18/19/21, ALK, and, more recently, BRAF-exon15), and the availability of tissue (KRAS, MET, and presence of low-frequency EGFR-T790M mutated alleles at baseline).
The mean follow-up time of the patients was 46 months. EGFR, KRAS, and BRAF mutations were detected in 13.7%, 21.3%, and 3% of tested cases, respectively; ALK rearrangements and MET amplifications were found respectively in 4.7% and 2% of tested cases. As expected, cases with mutations in exons 18-21 of EGFR, sensitizing to anti-EGFR tyrosine kinase inhibitors (TKIs) agents, had a significantly longer survival in comparison to those without (p < 0.0001); conversely, KRAS mutations were associated with a significantly lower survival (p = 0.0058). Among LAC patients with additional tissue section available for next-generation sequencing (NGS)-based analysis, 26/193 (13.5%) patients found positive for even low-rate EGFR-T790M mutated alleles at baseline were associated with a highly significant lower survival in comparison to those without (8.7 vs. 47.4 months, p < 0.0001).
In addition to its predictive value for addressing targeted therapy approaches, the assessment of as more inclusive mutation analysis at baseline may provide clues about factors significantly impacting on global survival in advanced LAC patients.
Abstract
Background: Osteopontin (OPN) is a secreted, integrin-binding phosphoprotein that has been correlated with tumor grade and stage and disease progression in several tumor types. Moreover, ...high OPN levels have been clinically correlated with metastatic bone disease and bone resorption in cancer patients. The “secreted protein, acidic and rich in cystein” (SPARC) is closely related to progression, invasion, angiogenesis and metastatic process of several malignant tumors.
Aim of the study: The aim of the study was to verify in a population of advanced cancer patients with tumors at different sites whether there is a correlation between circulating levels of OPN and SPARC and clinical parameters (such as bone metastases, pain and quality of life), circulating bone remodeling (skeletal) parameters (alkaline phosphatase, C- and N-terminal fragments of type I collagen, osteocalcin, Vitamin D), inflammatory (IL-8 and TNF-alpha) and metabolic parameters (BMI, serum cholesterol and triglycerides). The correlation between OPN and SPARC and survival was also assessed.
Patients and Methods: From April 2010 to August 2010, we enrolled 33 metastatic cancer patients with tumors at different sites (M/F: 16/17, mean age 66 years): 17 patients with bone metastases, 16 with metastases not involving bone. OPN and SPARC were measured using an antigen-capture enzyme-linked immunosorbent assay technique. BMI, pain by analogical visual scale and quality of life by EORTC QLQ C30 were assessed. Comparison between groups (controls vs cancer patients and cancer patients with vs without bone metastases) was performed by two-sided Student's t test. Correlation between OPN/SPARC and the other variables was performed by Spearman's correlation analysis.
Results: OPN and SPARC in cancer patients were significantly higher compared to controls but did not differ between patients with or without bone metastases. OPN showed a positive significant correlation with C and N terminal fragments of type I collagen (r=0.390 and r=0.410, p=0.024 for both), IL-8 (r=0.390, p=0.034) and a negative significant correlation with quality of life (r=−0.400, p=0.025) and BMI (r=−0.300, p=0.046). SPARC showed a positive significant correlation with BMI (r=0,360, p=0.049). Moreover, patients with ≤3 month survival showed significantly higher levels of OPN in comparison to patients with > 3 month survival (613.7+/-229.2 ng/ml versus 195.8 +/- 165 ng/ml, p<0.001).
Conclusions: The results of the present study show that high OPN levels are associated with poor survival in advanced cancer patients. Further studies are warranted to assess the role of OPN and SPARC to both monitor the effects of antineoplastic regimens and to assess them as potential targets of new treatment strategies.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5223. doi:10.1158/1538-7445.AM2011-5223
Abstract Objectives To establish a correlation between a specific MGA category, an appropriate preventively established treatment and clinical outcome in a population of elderly cancer patients. The ...ultimate goal was to verify whether the appropriate treatment given to elderly cancer patients according to their MGA category could translate into a better clinical outcome assessed as clinical response and toxicity, i.e whether this process might achieve a clinically meaningful impact. Patients and methods We carried out a phase II open, prospective non-randomized study in 75 elderly cancer patients (lung, head and neck, colorectal, gynecologic and breast) hospitalized at the Department of Medical Oncology, University of Cagliari, Italy. All patients underwent MGA evaluation and were assigned to three different categories: fit, intermediate and frail. Thereafter, an appropriate preventively established treatment was administered and the clinical outcome was assessed. The clinical outcome after 3 month treatment was defined on the basis of objective clinical response and toxicity. The difference of clinical outcome in the MGA categories was assessed by ANOVA test. Moreover, the correlation between MGA category and the clinical outcome (clinical response and toxicity) was assessed by Spearman's correlation test. Results A better clinical response was observed in fit patients as compared both to intermediate and frail patients. Treatment toxicity was comparable in the different MGA categories. The correlation analysis between MGA category, clinical response to treatment and toxicity showed that there was a significant direct correlation with clinical response and no correlation with toxicity. Overall, the regression analysis showed that MGA was predictive of clinical outcome, in the sense that it is truly predictive for clinical response and no predictive for toxicity. Conclusion Our study demonstrates that the MGA, although time-consuming, is a useful and cost-benefit effective tool to appropriately select elderly cancer patients to be treated effectively in terms of a survival advantage and those who would benefit mainly in terms of improvement of quality of life. Moreover, the treatment preventively established for each MGA category was shown to be adequate and accomplished the most appropriate performances in terms of effectiveness and toxicity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract
Chronic inflammation is one of the main features of cancer cachexia. Experimental and clinical studies showed that cyclooxygenase (COX)-2 inhibitors, such as celecoxib, may be beneficial in ...counteracting major symptoms of this devastating syndrome.
We carried out a prospective non randomised phase II clinical trial to test the safety and effectiveness of an intervention with the COX-2 inhibitor celecoxib (300 mg/day for 4 months) on key variables of cachexia (lean body mass, resting energy expenditure, serum levels of proinflammatory cytokines, and fatigue) in patients with advanced cancer at different sites.
Patient eligibility criteria were: age range of 18-80 years, histologically confirmed tumor of any site at an advanced stage, loss of ≥5% of body weight in the previous 3 months and a life expectancy of ≥4 months. Patients could be receiving concomitant antineoplastic chemotherapy or hormone therapy with palliative intent or supportive care. Exclusion criteria were: women of child-bearing age, positive history of heart disease, history of previous myocardial infarction, unstable angina, coronary revascularization, uncontrolled arrhythmia, congestive heart failure and cerebrovascular accident, previous gastrointestinal inflammatory disease and history of gastrointestinal ulceration, mechanical obstruction to feeding, and medical treatments inducing significant changes of patient metabolism or body weight.
A sample of 24 patients was enrolled from January to December 2008 and all were deemed assessable. The men/women ratio was well balanced (13/11). The mean age was 60.6 years. The most frequent tumor sites were head and neck, lung, and colorectal. Patients were >90% stage IV and the Glasgow Prognostic Score (GPS), an inflammation-based score predictive of patient survival, was high (two) in 50% of them.
Among primary efficacy endpoints, LBM assessed both by BIA (mean increase, +0.6±2.4 kg) and DEXA (mean increase, +0.6±2.7 kg) increased significantly (p<0.0001). The proinflammatory cytokine TNF-α decreased significantly (mean decrease, —6.9±11 pg/ml; p=0.007). Among patients with weight loss associated with high TNF-α levels (16), ten showed an increase of LBM accompanied by a decrease of TNF-α levels, while two showed an increase of LBM without a concomitant decrease of TNF-α.
Among secondary efficacy endpoints, an improvement of grip strength, quality of life, performance status, and Glasgow prognostic score was shown. There were no grade 3/4 toxicities.
Patient compliance was very good; no patient had to reduce the celecoxib dosage nor interrupt treatment.
Our results show that the COX-2 selective inhibitor celecoxib is an effective single agent for the treatment of cancer cachexia. Therefore, phase III clinical trials are warranted to test the efficacy and safety of celecoxib.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3724.
In the present open non-randomized phase II study we looked for effectiveness, safety, tolerability and costs of locally applied GM-CSF in preventing or treating mucositis in patients receiving ...chemotherapy or chemoradiotherapy for head and neck cancer. In addition to clinical mucositis scoring system, the effects of treatment with GM-CSF were evaluated by its impact on patient quality of life and by laboratory immunological assays such as serum proinflammatory cytokines, IL-2 and leptin. The trial was designed to assess the effectiveness of local GM-CSF treatment in two different settings: i) prophylaxis of mucositis; ii) treatment of mucositis. Prophylaxis was chosen for chemoradiotherapy treatments of high mucosatoxic potential, while curative treatment was reserved for chemotherapy or chemoradiotherapy treatments of lesser potential of inducing mucositis. From January 1998 to December 2001, 68 patients entered the study. The great majority of patients of both groups had head and neck cancer, were stage IV, PS ECOG 0-1, were habitual smokers and were treated with chemotherapy and concomitant (or sequential) chemoradiotherapy. Forty-six patients were included in the 'prophylactic' setting and 22 patients in the 'curative' setting. The main findings of our study are: only 50% of patients included in the 'prophylactic' setting developed mucositis; the duration of oral mucositis from appearance until complete remission was significantly shorter in the 'prophylactic' than in the 'curative' setting; the mean grade of oral mucositis at baseline, on day 3 of therapy and on day 6 of therapy was significantly lower in the 'prophylactic' than in the 'curative' setting; 24 (55.82%) patients in the 'prophylactic' setting had grade 3/4 oral mucositis at baseline compared to 25 (80.60%) patients in the 'curative' setting (p=0.048). Thirteen (30.23%) patients in the 'prophylactic' setting had grade 3/4 oral mucositis on day 3 of therapy compared to 19 (61.29%) patients in the 'curative' setting (p=0.015); 'prophylactic' setting was able to shorten grade 3/4 oral mucositis to grade 0/1 more effectively than the 'curative' one on day 6 of therapy (p=0.05). The present clinical trial is to date by far the largest study assessing the effectiveness of topical GM-CSF and it is the first study comparing the efficacy of topical GM-CSF in the 'prophylactic' setting, i.e., with the aim to prevent the chemoradiotherapy-induced oral mucositis, with that in the 'curative' treatment, i.e., the therapy for established oral mucositis. The topical application of GM-CSF was demonstrated to be effective for oral mucositis induced by chemotherapy and chemoradiotherapy regimens. Moreover, the 'prophylactic' setting was demonstrated to be more effective than the 'curative' one.
The progression of the neoplastic disease is characterized by specific alterations of energy metabolism and by symptoms like fatigue, anorexia, nausea, anaemia, immunodepression and poor performance ...status (PS). The main cause of these symptoms and metabolic abnormalities is the chronic action of proinflammatory cytokines released both by tumour and immune cells. The present study aimed to assess the relationship between markers of inflammation (C-Reactive Protein, Fibrinogen, proinflammatory cytokines) and energy metabolic status (BMI, leptin, oxidative stress) according to clinical parameters in 104 ovarian cancer patients at different stage and, moreover, to evaluate prospectively the changes of these parameters in accordance to tumour response in a subgroup of 70 advanced stage ovarian cancer patients. Advanced stage and poor PS were associated to high-grade inflammation and impaired energy metabolism. Among inflammatory mediators, interleukin (IL)-6 had a central role as predictive factor of leptin, reactive oxygen species and glutathione peroxidase. In turn, leptin considered the key marker of the nutritional status and energy metabolism, was independently determined from stage and IL-6, not only from BMI. Moreover, the evaluation of the changes of these parameters during the course of the neoplastic disease in the subgroup of advanced ovarian cancer patients clearly unveils the central role of IL-6 and leptin as early markers of the metabolic alterations and symptoms associated to disease progression in advanced stage ovarian cancer. Their assessment should be included in monitoring disease outcome, especially when cancer is no longer curable and quality of life becomes the primary endpoint.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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