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Sjoblom B.,Innlandet Hospital Trust | Sjoblom B.,University of Oslo | Gronberg B.H.,Norwegian University of Science and Technology | Gronberg B.H.,European Palliative Care Research Center | And 9 more authors.
Lung Cancer | Year: 2015

Background: Recent research suggests a significant relationship between lean body mass (LBM) and toxicity from chemotherapeutic agents. We investigated if higher drug doses per kg LBM were associated with increased toxicity in stage IIIB/IV non-small cell lung cancer (NSCLC) patients receiving a first-line chemotherapy regimen dosed according to body surface area (BSA). Methods: Data from patients randomised to receive intravenous gemcitabine 1000mg/m2 plus orally vinorelbine 60mg/m2 days 1 and 8 in a phase III trial comparing two chemotherapy regimens were analysed. LBM was estimated from assessment of the cross-sectional muscle area at the third lumbar level (L3) on computed tomography images obtained before chemotherapy commenced. Common terminology criteria for adverse events (CTCAE) grade 3-4 haematological toxicity and dose reduction and/or stop of treatment after the first course of chemotherapy were defined as primary and secondary toxicity outcomes. Results: The study sample included 153 patients, mean age was 66 years, 55% were men, 87% had disease stage IV and 75% had performance status (PS) 0-1. Gemcitabine doses per kg LBM varied from 23.2 to 53.1. mg/kg LBM, and vinorelbine doses from 1.5 to 3.3. mg/kg LBM. Higher doses of gemcitabine per kg LBM were significantly associated with grade 3-4 haematological toxicity in bivariate (OR = 1.12, 95% CI 1.03-1.23, p = 0.008) and multivariate analyses (OR = 1.15, 95% CI 1.01-1.29, p = 0.018), as were also higher doses of vinorelbine per kg LBM. No significant association was found between drug doses per kg LBM and dose reduction and/or stop of treatment. Conclusion: The study showed that dose estimates according to BSA lead to a substantial variation in drug dose per kg LBM, and higher doses per kg LBM are a significant predictor for chemotherapy-induced haematological toxicity. The results indicate that taking LBM into account may lead to a better dose individualisation of chemotherapy. © 2015 Elsevier Ireland Ltd. Source

Solheim T.S.,Norwegian University of Science and Technology | Solheim T.S.,European Palliative Care Research Center | Blum D.,Norwegian University of Science and Technology | Blum D.,European Palliative Care Research Center | And 8 more authors.
Acta Oncologica | Year: 2014

Background. How to assess cachexia is a barrier both in research and in clinical practice. This study examines the need for assessing both reduced food intake and loss of appetite, to see if these variables can be used interchangeably. A secondary aim is to assess the variance explained by food intake, appetite and weight loss by using tumor-related factors, symptoms and biological markers as explanatory variables. Material and methods. One thousand and seventy patients with incurable cancer were registered in an observational, cross sectional multicenter study. A total of 885 patients that had complete data on food intake (PG-SGA), appetite (EORTC QLQ-C30) and weight loss were included in the present analysis. The association between reduced food intake and appetite loss was assessed using Spearman's correlation. To find the explained variance of the three symptoms a multivariate analysis was performed. Results. The mean age was 62 years with a mean survival of 247 days and a mean Karnofsky performance status of 72. Thirteen percent of the patients who reported eating less than normal had good appetite and 25% who had unchanged or increased food intake had reduced appetite. Correlation between appetite loss and food intake was 0.50. Explained variance for the regression models was 44% for appetite loss, 27% for food intake and only 13% for weight loss. Conclusion. Both appetite loss and food intake should be assessed in cachectic patients since conscious control of eating may sometimes overcome appetite loss. The low explained variance for weight loss is probably caused by the need for more knowledge about metabolism and inflammation, and is consistent with the cancer cachexia definition that claims that in cachexia weight loss is not caused by reduced food intake alone. The questions concerning appetite loss from EORTC-QLQ C30 and food intake from PG-SGA seem practical and informative when dealing with advanced cancer patients. © 2014 Informa Healthcare. Source

Laird B.J.,European Palliative Care Research Center | Laird B.J.,University of Edinburgh | Kaasa S.,European Palliative Care Research Center | Kaasa S.,Norwegian University of Science and Technology | And 7 more authors.
Clinical Cancer Research | Year: 2013

Purpose: In advanced cancer, oncological treatment is influenced by performance status (PS); however, this has limitations. Biomarkers of systemic inflammation may have prognostic value in advanced cancer. The study compares key factors in prognosis (performance status, patient-reported outcomes; PRO) with an inflammation-based score (Glasgow Prognostic Score, mGPS). A new method of prognosis in advanced cancer (combining performance status and mGPS) is tested and then validated. Experimental Design: Two international biobanks of patients with advanced cancer were analyzed. Key prognostic factors [performance status, PROs (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C-30), and mGPS (using C-reactive protein and albumin concentrations)] were examined. The relationship between these and survival was examined using Kaplan-Meier and Cox regression methods, in a test sample before independent validation. Results: Data were available on 1,825 patients (test) and 631 patients (validation). Median survival ranged from 3.2 months (test) to 7.03 months (validation). On multivariate analysis, performance status (HR 1.62-2.77) and mGPS (HR 1.51-2.27) were independently associated with, and were the strongest predictors of survival (P < 0.01). Survival at 3 months varied from 82% (mGPS 0) to 39% (mGPS 2) and from 75% (performance status 0-1) to 14% (performance status 4). When used together, survival ranged from 88% (mGPS 0, PS 0-1) to 10% (mGPS 2, performance status 4), P < 0.001. Conclusion: A systemic inflammation-based score, mGPS, and performance status predict survival in advanced cancer. The mGPS is similar to performance status in terms of prognostic power. Used together, performance status and mGPS act synergistically improving prognostic accuracy. This new method may be of considerable value in the management of patients with advanced cancer. © 2013 American Association for Cancer Research. Source

Barratt D.T.,University of Adelaide | Bandak B.,University of Adelaide | Bandak B.,Copenhagen University | Klepstad P.,Norwegian University of Science and Technology | And 5 more authors.
Pharmacogenetics and Genomics | Year: 2014

Objective: This study aimed to investigate whether CYP3A4/5 genetic variants, together with clinical and patient factors, influence serum fentanyl and norfentanyl concentrations and their ratio in cancer pain patients receiving transdermal fentanyl. Methods: CYP3A4*22 and CYP3A5*3 polymorphisms were analysed in 620 cancer pain patients receiving transdermal fentanyl (12.5-700 μg/h) from the European Pharmacogenetic Opioid Study. Using stepwise linear regression, CYP3A4/5 genetic variability was examined in combination with patient factors relating to organ drug elimination function and ABCB1 genetics for their association with serum fentanyl and norfentanyl concentrations and metabolic ratio (MR) (norfentanyl: fentanyl). Results: Delivery rate-adjusted serum fentanyl concentrations (0.0012-1.1 nmol/l/μg.h) and MRs (0.08-499) varied widely. Only 43% of variability in serum fentanyl concentrations was accounted for by delivery rate and less than 50% by CYP3A4/5 genotypes and clinical variables (delivery rate, sex, comedications, kidney disease, BMI, serum albumin). CYP3A4*22 and CYP3A5*3 variants, CYP3A inhibitors and variables relating to liver and kidney function (serum albumin, glomerular filtration rate, kidney disease, BMI) were associated with MR, but accounted for only 14% of variability. Conclusion: Serum fentanyl concentrations and MR vary considerably between cancer pain patients on transdermal fentanyl patches. CYP3A4*22 and CYP3A5*3 genotypes, and multiple clinical factors, combine to influence transdermal fentanyl pharmacokinetics, but accounted for only a small proportion of variability in this study. Identification of the remaining factors determining serum fentanyl concentrations, and their relationship to efficacy and adverse effects may aid in improving the safety and effectiveness of transdermal fentanyl. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

Scarpi E.,Biostatistics and Clinical Trials Unit | Calistri D.,Biosciences Laboratory | Klepstad P.,Norwegian University of Science and Technology | Klepstad P.,European Palliative Care Research Center | And 7 more authors.
Oncologist | Year: 2014

Objective. The study objective was to evaluate whether there are clinical or genetic differences between patients with cancer-induced bone pain (CIBP) and patients with non-CIBP, and, in the CIBP group, in those with good versus poor opioid response.Materials and Methods. A total of 2,294 adult patients with cancer who were receiving opioids for moderate or severe pain were included in the European Pharmacogenetic Opioid Study. Pain intensity and pain relief were measured using the Brief Pain Inventory. Linkage disequilibrium of 112 single nucleotide polymorphisms was evaluated in 25 candidate genes, and 43 haplotypes were assessed. Correlations among demographical factors, disease-related factors, genetic factors, CIBP, and pain relief were analyzed by logistic regression models corrected for multiple testing. Patients with bone metastases and bone/soft tissue pain were defined as having prevalent bone pain (CIBP population). This population was compared with patients who had other types of cancer pain (non-CIBP).Results. A total of 577 patients (26.2%) had CIBP, and 1,624 patients (73.8%) had non-CIBP. Patients with CIBP had more breakthrough cancer pain episodes (64.2% vs. 56.4%, p = .001), had significantly higher pain interference in“walkingability in the past 24 hours” (p < .0001), used more adjuvant drugs (84.1% vs. 78.3%, p = .003), and had a higher, albeit nonsignificant, median overall survival (3.8 vs. 2.9 months, p = .716) than patients with non-CIBP. None of the examined haplotypes exceeded p values corrected for multiple testing for the investigated outcomes.Conclusion. Patients with CIBP who were taking opioids had a clinical profile slightly different from that of the non-CIBP group. However, no specific genetic pattern emerged for CIBP versus non-CIBP or for responsive versus nonresponsive patients with CIBP. The Oncologist 2014;19:1276–1283 © AlphaMed Press 2014. Source

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