levoleucovorin and Obesity

Obesity is a risk factor for the development of colon carcinoma. The influence of body mass index (BMI) on long-term outcomes and treatment-related toxicity in patients with colon carcinoma has not been well characterized.. This cohort study was conducted within a large, randomized adjuvant chemotherapy trial of 3759 men and women with high-risk, Stage II and Stage III colon carcinoma who were treated between 1988 and 1992 throughout the United States. With a median follow-up of 9.4 years, the authors examined the influence of BMI on disease recurrence, overall survival, and treatment-related toxicity.. Compared with women of normal weight (BMI, 21.0-24.9 kg/m(2)), obese women with colon carcinoma (BMI > or = 30.0 kg/m(2)) experienced significantly worse overall mortality (hazard ratio [HR], 1.34; 95% confidence interval [95% CI], 1.07-1.67) and a nonsignificant increase in the risk of disease recurrence (HR, 1.24; 95% CI, 0.98-1.59). The influence of BMI among women was not related to any differences in chemotherapy dose-intensity across categories of BMI. In contrast, BMI was not related significantly to long-term outcomes among male patients in this cohort. Among all study participants, obese patients had significantly lower rates of Grade 3-4 leukopenia and lower rates of any Grade > or = 3 toxicity compared with patients of normal weight.. Among women with Stage II-III colon carcinoma, obesity was associated with a significant increase in overall mortality as well as a borderline significant increase in disease recurrence. Nonetheless, obesity was not associated with any increase in chemotherapy-related toxicity.

Topics: Antineoplastic Combined Chemotherapy Protocols; Body Mass Index; Body Weight; Chemotherapy, Adjuvant; Cohort Studies; Colonic Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Levamisole; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Obesity; Risk Factors; Survival Rate; Treatment Outcome; United States

Great heterogeneity exists in the ability of adults with cancer to tolerate chemotherapy. Variability in body composition may affect rates of metabolism of cytotoxic agents and contribute to the variable chemotherapy toxicity observed. The objective of this exploratory study was to examine the association of low skeletal muscle, commonly known as sarcopenia, on the pharmacokinetics (PKs) of 5-fluorouracil (5FU) in patients receiving FOLFOX for colorectal cancer.. We performed a secondary analysis of a completed multicenter trial that investigated PK-guided 5FU dosing in patients receiving mFOLFOX6 +/- bevacizumab for colorectal cancer. Cycle 1 PK samples were obtained 2-44 h after the start of the 5FU infusion (steady state).. No significant differences in first cycle 5FU area-under-the-concentration-time-curve (AUC) were found between sarcopenic and non-sarcopenic patients (17.3 vs. 19.3 AUC, p = 0.43). Patients with grade 3/4 toxicity had a higher dose of 5FU per kg lean body mass (LBM) (105 vs. 93 mg/kg, p = 0.06), most notably for hematological toxicities (110 vs. 94 mg/kg, p = 0.002); however, no correlation between the dose/LBM and 5FU AUC was found.. Although our results did not confirm the impact of low skeletal muscle on PKs of 5FU, further research exploring the impact of body composition on chemotherapy PKs and related toxicities is warranted with the potential for alternative dosing strategies in sarcopenic patients to reduce unnecessary toxicities while maintaining efficacy.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Colorectal Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Muscle, Skeletal; Obesity; Organoplatinum Compounds; Sarcopenia; Tomography, X-Ray Computed

This study aimed to clarify the predictive impact of visceral fat on response to bevacizumab in patients with metastatic colorectal cancer (mCRC).. Pretreatment computed tomography was used to measure visceral fat area (VFA) and patients with mCRC receiving first-line chemotherapy with/without bevacizumab were divided by median VFA value into two groups: high VFA and low VFA.. In the bevacizumab-treated group, patients with low VFA had significantly shorter overall survival (OS) than patients with high VFA in univariate (median=21.1 vs. 38.9 months; hazard ratio=1.70, 95% confidence interval=1.06-2.70, p=0.03) and multivariate analysis (hazard ratio=1.85, 95% confidence interval=1.15-3.03, p=0.01). No significant differences were seen in OS between groups treated with chemotherapy alone. The VFA had a marginally significant modifying effect on the relationship between bevacizumab and OS (p for interaction=0.07).. Our findings provide the first evidence that a low VFA might be a negative predictive marker for response to bevacizumab in patients with mCRC.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biomarkers, Tumor; Camptothecin; Colorectal Neoplasms; Female; Fluorouracil; Humans; Intra-Abdominal Fat; Leucovorin; Male; Middle Aged; Obesity; Organoplatinum Compounds; Retrospective Studies; Young Adult

The purpose of this study was to elucidate the effect of decreased muscle mass on the toxicity and survival of patients with colon cancer treated with adjuvant chemotherapy after surgery.. We reviewed the data of 229 consecutive patients with stage III colon cancer who received adjuvant oxaliplatin, 5-fluorouracil, and leucovorin chemotherapy at a single center between 2003 and 2010. Baseline muscle mass was assessed by measuring the cross-sectional area of the psoas muscle at the level of the fourth lumbar vertebra on computed tomography images. Effects of muscle mass on toxicity of chemotherapy and survival were assessed.. The median age of the 229 patients was 61 years (range, 28-80) and 134 (58.5 %) were men. The mean psoas muscle mass index (PI, psoas muscle area divided by height(2) [mm(2)/m(2)]) was 548.3. A 1 SD decrement in the PI was associated with an increase in all grade 3-4 toxicities in univariate (OR = 1.69, 95 % CI = 1.18-2.27) and multivariate (OR = 1.56, 95 % CI = 1.05-2.38) analyses. In univariate analysis, the PI was not associated with overall survival. However, multivariate analysis showed that a 1 SD decrement in the PI increased the hazard of overall mortality by 85 % (HR = 1.85, 95 % CI = 1.10-3.13). This effect of the PI on mortality was maintained in subgroup analyses, especially in older and obese patients.. Decreased muscle mass was associated with increased risk of grade 3-4 toxicity and poor prognosis in patients with stage III colon cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Body Composition; Chemotherapy, Adjuvant; Colonic Neoplasms; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Muscle, Skeletal; Obesity; Organoplatinum Compounds; Oxaliplatin; Sarcopenia

Toxicity from intermediate-dose methotrexate (MTX) is unusual. A severely obese adolescent with acute lymphoblastic leukemia experienced significant, delayed nephrotoxicity from intermediate-dose MTX. Altered MTX disposition may occur as a consequence of other ingestions or conditions such as obesity. The use of radioisotope renography established the diagnosis and followed the resolution of the patient's MTX-induced nephrotoxicity.

Topics: Adolescent; Antimetabolites, Antineoplastic; Humans; Kidney Diseases; Leucovorin; Male; Methotrexate; Obesity; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Radioisotope Renography

The disposition of many drugs in obesity is altered, although little is known of the effect of obesity on the pharmacokinetics of anti-cancer drugs. In this report the authors describe the pharmacokinetics of high-dose methotrexate in an obese woman (184% ideal body weight) with osteosarcoma. For this patient, both the volume of distribution at steady-state (0.398 l/kg) and systemic clearance (0.0956 l/h/kg) of methotrexate were increased compared with values observed in adult patients with osteosarcoma. The terminal elimination half-life (9.29 hours) of methotrexate was similar to other reported values in adult patients, thus indicating that increases in methotrexate volume of distribution and clearance may offset each other in obesity. Based on the experience gained from this patient, the authors suggest that renal function and methotrexate serum concentrations should be monitored in obese patients receiving high-dose methotrexate with leucovorin rescue.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Bone Neoplasms; Cyclophosphamide; Dactinomycin; Doxorubicin; Female; Half-Life; Humans; Leucovorin; Methotrexate; Obesity; Osteosarcoma; Tibia; Vincristine