Evaluating variability in fluorouracil (FU) exposure in obese and non-obese patients with colorectal cancer using full weight-based dosing.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 409-409
Author(s):  
Jai Narendra Patel ◽  
Allison Mary Deal ◽  
Howard L. McLeod ◽  
Bert H. O'Neil ◽  
Christine Marie Walko

409 Background: Approximately 30% of cancer patients are obese. Controversy exists on how to best use body weight to safely and effectively dose chemotherapy. Additionally, body surface area (BSA)-based dosing is associated with high pharmacokinetic (PK) variability and is a poor indicator of optimal drug exposure. Methods: We estimated FU exposure post cycle 1, as indicated by area under the curve (AUC), in 58 colorectal cancer patients receiving mFOLFOX6 (FU 2400 mg/m2 [BSA calculated using actual body weight (ABW)] over 46 hours) +/- bevacizumab. AUCs were determined using an immunoassay at Myriad Laboratories. The primary objective was to identify variability in FU exposure in obese and non-obese patients using body mass index (BMI), BSA, and ABW. Groups were compared using two group t-tests. Results: No significant difference in AUC was observed between obese (BMI ≥ 30 kg/m2) and non-obese (< 30 kg/m2) patients. A significantly lower AUC was observed in patients with a BSA ≥ 2.0 m2 compared to those < 2.0 m2 (p=0.02). The AUC for obese and non-obese patients ranged from 7-34 and 12-38 mg*hr/L, respectively. Only 32% and 28% of obese and non-obese patients, respectively, were within the previously reported therapeutic target AUC 20-25 mg*hr/L. Males had significantly lower AUCs compared to females (mean 18.7 v 22.4, p=0.03). FU AUC was not strongly correlated with BMI, BSA, or ABW (Pearson correlation of -0.03, -0.26, and -0.15, respectively). Conclusions: BSA-based dosing is associated with variable FU exposure. Lower AUCs in patients with a BSA ≥ 2.0 m2 supports both ASCO recommendations for full-weight-based dosing in obese patients and the value of dosing assessment across patient populations. Further study of AUC-based dosing is warranted as our data do not support a reduction in variable exposure based on BMI, BSA, or ABW dosing. [Table: see text]

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13576-13576
Author(s):  
A. Bononi ◽  
M. Gusella ◽  
G. Crepaldi ◽  
R. Padrini ◽  
E. Ferrazzi

13576 Background: It is well known that females present a significantly reduced clearance of 5FU compared to males treated with the same doses.We tested the hypothesis that it may depend on the hormonal status, so that pre-menopausal women would have different 5FU pharmacokinetics compared with both postmenopausal women and elderly women. Methods: 48 colorectal cancer patients were prospectively studied: all of them were on adjuvant treatment based on 5FU repeated boluses. On the second day of the first cycle peripheral blood was drawn after drug administration. Plasma level were detected by HPLC analysis and pharmacokinetic parameters were calculated trough a one phase exponential decay model. Results: All patients had 100–90 Karnosky Performance status score. 12 were in pre-menopausal phase (age range : 40–55 years); among the others we distinguished a younger 19 people group (age lower than 70 years old) and an elderly 17 patient group (age equal or higher than 70 years old). They received a 5FU mean dose of 406 ± 15 mg/mq, not significantly different among the three groups. After intravenous bolus injection a high interindividual variability of 5-FU pharmacokinetics was detected: AUC0-∞ (area under the curve of drug plasma levels versus time) ranged between 368 and 1236 mg × min/L and the highest values (>1000) were found in two elderly patients, considered fit; anyway there was no significant difference among AUC of the three groups. 5FU total clearance ranged between 0.53 and 1.9 L/min and means were 1.07 ± 0.3, 1.02 ± 0.3 and 0.98 ± 0.3 L/min in pre-menopausal, postmenopausal and elderly women respectively; again 5FU clearance/ BSA (body surface area), half live elimination times and peak concentration plasma levels were not significantly different among the three groups. Conclusions: It seems that sexual hormonal status do not influence 5FU total body elimination capability, and that pharmacokinetic differences between genders should be related to other factors,as for example Body Composition. Funded by AIRC-Veneto No significant financial relationships to disclose.


2021 ◽  
pp. 001857872110557
Author(s):  
Amanda Wolfe ◽  
Jonathan Bowling ◽  
Marintha R. Short ◽  
Greg Mateyoke ◽  
Steven C. Berger

Background: Vancomycin requires therapeutic drug monitoring (TDM) based on its pharmacokinetic properties, and guidelines have shifted to analyzing area under the curve over 24 hours (AUC24) rather than trough concentrations due to nephrotoxicity concerns and correlation to efficacy. Obesity is an established risk factor for vancomycin-induced nephrotoxicity due to increased drug exposure based on dosing calculations and volume of distribution estimation. The aim of this study is to assess the relationship between AUC-based versus trough-based dosing and nephrotoxicity among obese patients receiving vancomycin. Methods: This research project was conducted as a retrospective, observational, single-centered study which included obese adults who received at least 48 hours of vancomycin. The electronic medical record provided data for patients with vancomycin pharmacokinetic consults either evaluated with trough-only or AUC-based dosing. The primary objective was to compare the development of nephrotoxicity after vancomycin initiation, while secondary objectives included vancomycin loading dose exposure, total daily dose of vancomycin, and whether target TDM was attained. Nominal data were evaluated utilizing the chi-square test and continuous data using the independent samples t-test or Mann-Whitney test. The a priori level of significance was .05. Data analysis was performed using Microsoft Excel and SAS statistical software. Results: Two hundred fifty-four patients were included in the primary analysis. Four patients in the AUC cohort (6.3%) developed nephrotoxicity compared to 32 (17.4%) in the trough cohort ( P = .035). Both cohorts received a median of 4 days of therapy; however, the median loading dose per actual body weight in the AUC cohort was 20 mg/kg as compared to 16 mg/kg in the trough cohort. Of the 130 patients with available TDM in the trough cohort, 97 (74.6%) did not meet target attainment as compared to 15 of the 57 in the AUC cohort (26.3%) ( P < .001). Conclusions: AUC dosing was associated with a statistically significant reduction in AKI occurrence despite overall higher loading dose exposure as compared to the trough cohort. Though maintenance dose exposure was similar between both cohorts, patients in the AUC cohort maintained therapeutic concentrations at a higher percentage than the trough cohort.


2008 ◽  
Vol 26 (25) ◽  
pp. 4072-4077 ◽  
Author(s):  
Jennifer K. Litton ◽  
Ana M. Gonzalez-Angulo ◽  
Carla L. Warneke ◽  
Aman U. Buzdar ◽  
Shu-Wan Kau ◽  
...  

Purpose To understand the mechanism through which obesity in breast cancer patients is associated with poorer outcome, we evaluated body mass index (BMI) and response to neoadjuvant chemotherapy (NC) in women with operable breast cancer. Patients and Methods From May 1990 to July 2004, 1,169 patients were diagnosed with invasive breast cancer at M. D. Anderson Cancer Center and received NC before surgery. Patients were categorized as obese (BMI ≥ 30 kg/m2), overweight (BMI of 25 to < 30 kg/m2), or normal/underweight (BMI < 25 kg/m2). Logistic regression was used to examine associations between BMI and pathologic complete response (pCR). Breast cancer–specific, progression-free, and overall survival times were examined using the Kaplan-Meier method and Cox proportional hazards regression analysis. All statistical tests were two-sided. Results Median age was 50 years; 30% of patients were obese, 32% were overweight, and 38% were normal or underweight. In multivariate analysis, there was no significant difference in pCR for obese compared with normal weight patients (odds ratio [OR] = 0.78; 95% CI, 0.49 to 1.26). Overweight and the combination of overweight and obese patients were significantly less likely to have a pCR (OR = 0.59; 95% CI, 0.37 to 0.95; and OR = 0.67; 95% CI, 0.45 to 0.99, respectively). Obese patients were more likely to have hormone-negative tumors (P < .01), stage III tumors (P < .01), and worse overall survival (P = .006) at a median follow-up time of 4.1 years. Conclusion Higher BMI was associated with worse pCR to NC. In addition, its association with worse overall survival suggests that greater attention should be focused on this risk factor to optimize the care of breast cancer patients.


2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Tao Chen

Abstract Recent studies have shown that obesity is a major risk factor for idiopathic hyperaldosteronism (IHA). IHA patients have greater AGV than normal controls. However, it is unclear whether such changes are caused by obesity and whether losing weight could reverse the morphological and functional abnormalities of the adrenal gland. This study was to investigate the association of obesity with adrenal gland volume (AGV) and the effects of weight loss on AGV. This study recruited obese patients (N=25) who underwent sleeve gastrectomy and age- and sex-matched normal-weight (N=25) and overweight healthy volunteers (HV) (N=21). Thin-slice computed tomography was used to evaluate adrenal morphological changes. AGV was measured semiautomatically based on the digital imaging and communications in medicine (DICOM) image. The effects of weight loss on AGV were evaluated in patients for one year or more after sleeve gastrectomy. The results showed that left, right and total AGV were larger in obese patients than those in overweight and normal- weight HVs (6.77±0.36, 5.76±0.31, and 12.53±0.64 cm3 vs. 3.88±0.14, 3.09± 0.13 and 6.97± 0.24 cm3 vs. 3.38±0.23, 2.67±0.15 and 6.04±0.36 cm3). No statistically significant difference was identified between overweight and normal-weight HVs. Sleeve gastrectomy significantly reduced body weight (-27.1±2.5 kg), left AGV (-0.80±0.26 cm3), and right AGV (-0.88±0.20 cm2). However, the adrenal volume in five patients was not reduced, despite significant weight loss postsurgery. In brief, obesity leads to increased AGV, and in some cases, this effect seems to be irreversible. We speculate that obesity causes permanently adrenal morphological changes (increased volume or hyperplasia), and under certain circumstances, it results in excessive aldosterone secretion via altered adipokines (leptin, CTRP1, etc.).


2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Kristen L. Bunnell ◽  
Manjunath P. Pai ◽  
Monica Sikka ◽  
Susan C. Bleasdale ◽  
Eric Wenzler ◽  
...  

ABSTRACT A recommended total-body-weight (TBW) dosing strategy for telavancin may not be optimal in obese patients. The primary objective of this study was to characterize and compare the pharmacokinetics (PK) of telavancin across four body size groups: normal to overweight and obese classes I, II, and III. Healthy adult subjects ( n = 32) received a single, weight-stratified, fixed dose of 500 mg ( n = 4), 750 mg ( n = 8), or 1,000 mg ( n = 20) of telavancin. Noncompartmental PK analyses revealed that subjects with a body mass index (BMI) of ≥40 kg/m 2 had a higher volume of distribution (16.24 ± 2.7 liters) than subjects with a BMI of <30 kg/m 2 (11.71 ± 2.6 liters). The observed area under the concentration-time curve from time zero to infinity (AUC 0–∞ ) ranged from 338.1 to 867.3 mg · h/liter, with the lowest exposures being in subjects who received 500 mg. AUC 0–∞ values were similar among obese subjects who received 1,000 mg. A two-compartment population PK model best described the plasma concentration-time profile of telavancin when adjusted body weight (ABW) was included as a predictive covariate. Fixed doses of 750 mg and 1,000 mg had similar target attainment probabilities for efficacy as doses of 10 mg/kg of body weight based on ABW and TBW, respectively. However, the probability of achieving a target area under the concentration-time curve from time zero to 24 h of ≥763 mg · h/liter in association with acute kidney injury was highest (19.7%) with TBW-simulated dosing and lowest (0.4%) at the 750-mg dose. These results suggest that a fixed dose of 750 mg is a safe and effective alternative to telavancin doses based on TBW or ABW for the treatment of obese patients with normal renal function and Staphylococcus aureus infections. (This study has been registered at ClinicalTrials.gov under identifier NCT02753855.)


2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Chaoran Yu ◽  
Yujie Zhang

Abstract Background This study aimed to establish nomogram models of overall survival (OS) and cancer-specific survival (CSS) in elderly colorectal cancer (ECRC) patients (Age ≥ 70). Methods The clinical variables of patients confirmed as ECRC between 2004 and 2016 were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate analysis were performed, followed by the construction of nomograms in OS and CSS. Results A total of 44,761 cases were finally included in this study. Both C-index and calibration plots indicated noticeable performance of newly established nomograms. Moreover, nomograms also showed higher outcomes of decision curve analysis (DCA) and the area under the curve (AUC) compared to American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) stage and SEER stage. Conclusions This study established nomograms of elderly colorectal cancer patients with distinct clinical values compared to AJCC TNM and SEER stages regarding both OS and CSS.


2014 ◽  
Vol 29 (3) ◽  
pp. 261-267 ◽  
Author(s):  
Violetta Dymicka-Piekarska ◽  
Aleksandra Korniluk ◽  
Mariusz Gryko ◽  
Elzbieta Siergiejko ◽  
Halina Kemona

Platelet activation observed in cancer patients is associated with the release of various cytokines, including P-selectin and CD40 ligand (CD40L). We analyzed the plasma levels of sCD40L in association with adhesion molecules (sP-selectin and sVCAM-1) to check the hypothesis of a possible involvement in cancer progression. Blood samples were obtained from 59 patients with different stages of colorectal cancer (CRC) and 29 age and gender-matched control subjects. Plasma sCD40L, sP-selectin, and sVCAM-1 concentrations were measured with quantitative sandwich enzyme-linked immunoassay. All patients with CRC had significantly higher levels of sCD40L (p<0.001), sP-selectin (p<0.02), and sVCAM-1 (p<0.03), as compared to healthy subjects. The level of sCD40L significantly correlated with sP-selectin (p<0.05) in patients with distant metastases to the liver. We also observed a high negative correlation between sP-selectin and platelets count (p<0.02) in patients with lymph node metastasis. The receiver-operator curve for CRC patients indicated that the area under the curve for sCD40L was 0.915, which may indicate its high efficiency as an inflammatory marker. In our study, the sCD40L correlated with sP-selectin in patients with advanced stage of CRC, which might indicate its possible participation in metastasis formation.


2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4036-4036
Author(s):  
A. M. Glas ◽  
P. Roepman ◽  
R. Salazar ◽  
G. Capella ◽  
V. Moreno ◽  
...  

4036 Background: Between 25 and 35% of stage II CRC patients will experience a recurrence of their disease and may benefit from adjuvant chemotherapy. Official guidelines give suggestions but no clear recommendation for best risk stratification. Here we describe the development a robust signature that predicts disease relapse and can assist in treatment decisions. Methods: Fresh frozen tumor tissues from 180 patients with stage I, II and III colorectal cancer undergoing surgery were analyzed using high density Agilent 44K oligonucleotide arrays. Median FU was 70.2 months; 85% of patients did not receive adjuvant chemotherapy. Unsupervised hierarchical clustering based on full-genome gene expression measurement indicated the existence of 3 main colon molecular subclasses. Survival analysis of the 3 classes showed that subtype C (n= 27) had a poor outcome and subtype A (n= 48) good outcome. Only the intermediate group B (n=104) was used to develop a signature by using a cross validation procedure to score all genes for their association with 5-yr distant metastasis free survival (DMFS) and subsequently applied to all samples (n=180). The obtained gene signature was further validated on an independent cohort of 178 stage II + III colon samples. Results: A set of 38 prognosis related gene probes showed robust DMFS association in over 50% of all iterations in the Training Set of 180 samples. The gene signature was validated on an independent cohort of 178 samples from stage II + III colon cancer patients. The profile classified 61% of the validation samples as low-risk and 39% as high-risk. The low- and high-risk samples showed a significant difference in DMFS with a HR of 3.19 (P= 8.5e-4). Five-year DMFS rates were 89% (95%CI 83–95) for low-risk and 62% (95%CI 50–77) for high-risk samples. Moreover, the profile showed a significant performance within stage II (P=0.0058) and III (P=0.036) only samples. The performance of the profile was significant for both untreated (P=0.0082) and treated patients (P=0.016) suggesting that its power is independent of treatment benefits. Conclusions: ColoPrint is able to predict the prognosis of stage II and III colon cancer patients and facilitates the identification of patients who would benefit from adjuvant chemotherapy. [Table: see text]


2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15017-e15017
Author(s):  
M. G. Zalis ◽  
F. M. Vieira ◽  
I. Zalcberg-Renault ◽  
M. H. Bonamino ◽  
C. G. Ferreira ◽  
...  

e15017 Background: KRAS mutation is common event in colorectal cancer occurring in around 40% of the patients. It is well- known that patients harboring the KRAS mutation do not derive benefit from cetuximab. However data available KRAS mutation profile is limited to Caucasian and Asian individuals and there is a lack of data in the population from Latin America. Brazilian population has a heterogeneous genetic background and this may have pharmacogenetic implications (Suarez-Kurtz, 2006). Methods: Between July and November 2008, we analyzed 989 consecutive patient samples sent to our laboratory for KRAS genotyping as a screening for cetuximab use. DNA was extracted from paraffin-embedded tissue, exons 1 were amplified by PCR and submitted to automatic sequencing. Codons 12 and 13 were analyzed. Results: The median age was 59 years and 53% of the patients were male and 47% female. The percentage of wild-type and mutated KRAS was 62 and 38%, respectively. Among the 375 mutated cases, 87% were in codon 12 versus 13% in codon 13. Mutation Gly12Asp was the most common being detected in 39% of the mutated cases. Due to the sample size a comparison among patients from different regions of Brazil was possible. However, no significant difference was observed in relation to the type or percentage of patients harboring the KRAS mutation. Interestingly, a significant difference in the percentage of mutated KRAS patients was observed between male and female (41 versus 35%, p= 0.05). Conclusions: The profile of KRAS mutation in the Brazilian population is similar to that reported for Caucasian and Asian populations. This is one of the largest cohorts of KRAS genotyping in colorectal cancer patients ever reported. To the best of our knowledge our data is the first to put forward the issue of a potential difference in the mutation rate according to gender. The observed higher incidence of KRAS-mutation in male than female deserves further investigation. No significant financial relationships to disclose.


2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14186-e14186
Author(s):  
Shivi Jain ◽  
Kireet Agrawal ◽  
Shinoj Pattali ◽  
Abhijai Singh ◽  
Kamal Agrawal ◽  
...  

e14186 Background: Overall survival in colorectal cancer is influenced by obesity, age, gender and stage at diagnosis. However, in minority based populations, effect of the above factors on overall survival has not been studied in any detail. Hence, we undertook this retrospective study to evaluate effect of above factors on overall survival in young colorectal cancer patients. Methods: 1,195 subjects with colorectal cancer treated at John H. Stroger Hospital of Cook County between 2000 and 2008 were retrospectively analyzed. 179 subjects with age 50 years and younger were identified. 146 of 179 subjects with available Body Mass Index (BMI) in kg/m2 were included in the study. Effect of BMI, age, sex, race, LDH and CEA levels, stage, site of tumor, smoking and family history on overall survival was evaluated using standard statistical multivariate analysis. Results: In our population, 22 of 146(15%) were underweight (BMI<20), 56 of 146(38.4%) were normal weight (BMI 20-24.9), 46 of 146(31.5%) were overweight (BMI 25-29.9) and 22 of 146(15%) were obese (BMI >30). Male: female ratio was 1.4:1. 75 of 146(51.7%) were African American, 23 of 146(15.9%) were Caucasians. 50 of 146(34.2%) were stage IV colorectal cancer at diagnosis. On univariate analysis, BMI<20(p=0.031, HR 2.1, 95% CI 1.15-3.82), CEA >4ng/ml (p=0.005, HR 1.93, 95% CI 1.21-3.08) and stage IV colorectal cancer (p<0.001, HR 6.1, 95% CI 2.42-15.53) were significantly associated with decreased overall survival. LDH<200 U/L was significantly associated with improved overall survival (p 0.029, HR 0.6, 95% CI 0.391-0.950). On multivariate analysis, stage IV colorectal cancer was a single significant independent predictor of overall survival (p=0.001, 95% CI 2.47-27.78). CEA>4ng/ml was marginally significant for decreased overall survival (p=0.06, 95% CI 0.978-3.015). On the contrary, no statistically significant difference was found on overall survival with age, BMI>20, gender, race, tumor location, smoking and family history. Conclusions: Advanced stage and CEA >4ng/ml are independent prognostic variables for decreased overall survival in minority based population of young colorectal cancer.


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