levoleucovorin and Cachexia

Cancer progression is associated with significant systemic clinical manifestations including cachexia induced weight loss and anorexia. Pentoxifylline (PTX) is a drug that has been shown to have multiple beneficial effects in cancer patients through its anti-inflammatory properties.. To evaluate PTX effects on colon cancer patients treated with chemotherapy.. Forty metastatic colon cancer patients receiving chemotherapy were enrolled in this randomized study. 17 patients were treated with a full dose of PTX (400 mg TID), 9 patients with a reduced dose PTX (200 mg TID) and 23 served as controls (no PTX).. Follow-up evaluations of patients included the following: physical examination; leukopenia determination; weight determination; stomatitis determination; and survival rate. Patients treated with PTX (both full and reduced doses), experienced a significant increase in weight and a reduction in stomatitis relative to the control group. Treatment with PTX also significantly increased patient survival rate. All patients treated with PTX, had a median overall survival (OS) rate of 20.4 months as compared to 13.2 months in the control group.. PTX treatment of colon cancer patients, in addition to chemotherapy, significantly improved survival rates, induced weight gain and reduced stomatitis occurrence -all important parameters of cachexia.

Topics: Aged; Antineoplastic Agents; Cachexia; Colonic Neoplasms; Disease Progression; Female; Fluorouracil; Humans; Leucovorin; Leukopenia; Male; Middle Aged; Pentoxifylline; Stomatitis; Weight Gain

Omega-3 fatty acids may improve cancer cachexia, but only in patients with pancreatic and bile duct cancer. Patients with pancreatic cancer commonly suffer from exocrine pancreatic insufficiency, and the ingestion of digestive enzyme supplements may improve absorption.. Racol®, an enteral nutrient formulated with omega-3 fatty acids, was administered to patients with unresectable pancreatic and bile duct cancer. The skeletal muscle mass and blood test data were taken pre-administration and at 4 and 8 weeks after. Patients with pancreatic cancer were given the digestive enzyme supplement LipaCreon® from the fifth week after the start of administration.. In all 27 patients, skeletal muscle mass was significantly increased at both 4 and 8 weeks after the start of administration versus pre-administration (p=0.006, p=0.002, respectively).. Omega-3 fatty acid supplementation in patients with unresectable pancreatic and bile duct cancer may improve cancer cachexia.

Topics: Aged; Aged, 80 and over; Albumins; Antineoplastic Combined Chemotherapy Protocols; Bile Duct Neoplasms; Cachexia; Camptothecin; Combined Modality Therapy; Deoxycytidine; Dietary Supplements; Drug Combinations; Fatty Acids, Omega-3; Female; Fluorouracil; Gemcitabine; Humans; Leucovorin; Male; Middle Aged; Nutritional Support; Organoplatinum Compounds; Oxonic Acid; Paclitaxel; Pancreatic Neoplasms; Pyridines; Tegafur

Topics: Animals; Blotting, Western; Cachexia; Cells, Cultured; Cisplatin; Drug Therapy, Combination; Fluorouracil; Leucovorin; Muscle Fibers, Skeletal; Muscle Proteins; Myosin Heavy Chains; Rats; Tropomyosin; Troponin

Cancer cachexia is a metabolic disorder involving perturbed energy balance and altered mitochondrial function. Chemotherapy is a primary treatment option for many types of cancer, but there is substantial evidence that some chemotherapeutic agents can also lead to the development and progression of cachexia. In this study, we apply a comprehensive and systems level metabolomics approach to characterize the metabolic perturbations in murine models of cancer-induced and chemotherapy-induced cachexia. Knowledge of the unique pathways through which cancer and chemotherapy drive cachexia is necessary in order to develop effective treatments.. The murine Colon26 (C26) adenocarcinoma xenograft model was used to study the metabolic derangements associated with cancer-induced cachexia. In vivo administration of Folfiri (5-fluorouracil, irinotecan, and leucovorin) was used to model chemotherapy-induced cachexia. Comprehensive metabolic profiling was carried out using both nuclear magnetic resonance-based and mass spectrometry-based platforms. Analyses included plasma, muscle, and liver tissue to provide a systems level profiling.. The study involved four groups of CD2F1 male mice (n = 4-5), including vehicle treated (V), C26 tumour hosts (CC), Folfiri treated (F), and C26 tumour hosts treated with Folfiri (CCF). Significant weight loss including skeletal muscle was observed for each of the experimental groups with the tumour hosts showing the most dramatic change (-3.74 g vs. initial body weight in the CC group). Skeletal muscle loss was evident in all experimental groups compared with V, with the CCF combination resulting in the most severe depletion of quadriceps mass (-38% vs. V; P < 0.001). All experimental groups were characterized by an increased systemic glucose demand as evidenced by decreased levels of circulating glucose (-47% in CC vs. V; P < 0.001) and depletion of liver glucose (-51% in CC vs. V; P < 0.001) and glycogen (-74% in CC vs. V; P < 0.001). The cancer-induced and chemotherapy-induced cachexia models displayed unique alterations in flux through the tricarboxylic acid cycle and β-oxidation pathways. Cancer-induced cachexia was uniquely characterized by a dramatic elevation in low-density lipoprotein particles (+6.9-fold vs. V; P < 0.001) and a significant increase in the inflammatory marker, GlycA (+33% vs. V; P < 0.001).. The results of this study demonstrated for the first time that cancer-induced and chemotherapy-induced cachexia is characterized by a number of distinct metabolic derangements. Effective therapeutic interventions for cancer-induced and chemotherapy-induced cachexia must take into account the specific metabolic defects imposed by the pathological or pharmacological drivers of cachexia.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cachexia; Camptothecin; Cell Line, Tumor; Energy Metabolism; Fluorouracil; Glucose; Leucovorin; Liver; Male; Metabolomics; Mice; Muscle Strength; Muscle, Skeletal; Neoplasms; Reactive Oxygen Species; Receptors, LDL

By the traditional definition of unintended weight loss, cachexia develops in ~80% of patients with pancreatic ductal adenocarcinoma (PDAC). Here, we measure the longitudinal body composition changes in patients with advanced PDAC undergoing 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin therapy.. We performed a retrospective review of 53 patients with advanced PDAC on 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin as first line therapy at Indiana University Hospital from July 2010 to August 2015. Demographic, clinical, and survival data were collected. Body composition measurement by computed tomography (CT), trend, univariate, and multivariate analysis were performed.. Among all patients, three cachexia phenotypes were identified. The majority of patients, 64%, had Muscle and Fat Wasting (MFW), while 17% had Fat-Only Wasting (FW) and 19% had No Wasting (NW). NW had significantly improved overall median survival (OMS) of 22.6 months vs. 13.0 months for FW and 12.2 months for MFW (P = 0.02). FW (HR = 5.2; 95% confidence interval = 1.5-17.3) and MFW (HR = 1.8; 95% confidence interval = 1.1-2.9) were associated with an increased risk of mortality compared with NW. OMS and risk of mortality did not differ between FW and MFW. Progression of disease, sarcopenic obesity at diagnosis, and primary tail tumours were also associated with decreased OMS. On multivariate analysis, cachexia phenotype and chemotherapy response were independently associated with survival. Notably, CT-based body composition analysis detected tissue loss of >5% in 81% of patients, while the traditional definition of >5% body weight loss identified 56.6%.. Distinct cachexia phenotypes were observed in this homogeneous population of patients with equivalent stage, diagnosis, and first-line treatment. This suggests cellular, molecular, or genetic heterogeneity of host or tumour. Survival among patients with FW was as poor as for MFW, indicating adipose tissue plays a crucial role in cachexia and PDAC mortality. Adipose tissue should be studied for its mechanistic contributions to cachexia.

Topics: Adipose Tissue; Aged; Antineoplastic Combined Chemotherapy Protocols; Body Composition; Body Weights and Measures; Cachexia; Carcinoma, Pancreatic Ductal; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms; Phenotype; Prognosis; Retrospective Studies; Tomography, X-Ray Computed

Chemotherapy promotes the development of cachexia, a debilitating condition characterized by muscle and fat loss. ACVR2B/Fc, an inhibitor of the Activin Receptor 2B signaling, has been shown to preserve muscle mass and prolong survival in tumor hosts, and to increase bone mass in models of osteogenesis imperfecta and muscular dystrophy. We compared the effects of ACVR2B/Fc on muscle and bone mass in mice exposed to Folfiri. In addition to impairing muscle mass and function, Folfiri had severe negative effects on bone, as shown by reduced trabecular bone volume fraction (BV/TV), thickness (Tb.Th), number (Tb.N), connectivity density (Conn.Dn), and by increased separation (Tb.Sp) in trabecular bone of the femur and vertebra. ACVR2B/Fc prevented the loss of muscle mass and strength, and the loss of trabecular bone in femurs and vertebrae following Folfiri administration. Neither Folfiri nor ACVR2B/Fc had effects on femoral cortical bone, as shown by unchanged cortical bone volume fraction (Ct.BV/TV), thickness (Ct.Th) and porosity. Our results suggest that Folfiri is responsible for concomitant muscle and bone degeneration, and that ACVR2B/Fc prevents these derangements. Future studies are required to determine if the same protective effects are observed in combination with other anticancer regimens or in the presence of cancer.

Topics: Activin Receptors, Type II; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone and Bones; Bone Density; Cachexia; Camptothecin; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Female; Femur; Fluorouracil; Induction Chemotherapy; Leucovorin; Male; Mice; Mice, Inbred Strains; Muscle, Skeletal; Muscular Dystrophies

Cachexia affects the majority of cancer patients, with currently no effective treatments. Cachexia is defined by increased fatigue and loss of muscle function resulting from muscle and fat depletion. Previous studies suggest that chemotherapy may contribute to cachexia, although the causes responsible for this association are not clear. The purpose of this study was to investigate the mechanism(s) associated with chemotherapy-related effects on body composition and muscle function. Normal mice were administered chemotherapy regimens used for the treatment of colorectal cancer, such as Folfox (5-FU, leucovorin, oxaliplatin) or Folfiri (5-FU, leucovorin, irinotecan) for 5 weeks. The animals that received chemotherapy exhibited concurrent loss of muscle mass and muscle weakness. Consistently with previous findings, muscle wasting was associated with up-regulation of ERK1/2 and p38 MAPKs. No changes in ubiquitin-dependent proteolysis or in the expression of TGFβ-family members were detected. Further, marked decreases in mitochondrial content, associated with abnormalities at the sarcomeric level and with increase in the number of glycolytic fibers were observed in the muscle of mice receiving chemotherapy. Finally, ACVR2B/Fc or PD98059 prevented Folfiri-associated ERK1/2 activation and myofiber atrophy in C2C12 cultures. Our findings demonstrate that chemotherapy promotes MAPK-dependent muscle atrophy as well as mitochondrial depletion and alterations of the sarcomeric units. Therefore, these findings suggest that chemotherapy potentially plays a causative role in the occurrence of muscle loss and weakness. Moreover, the present observations provide a strong rationale for testing ACVR2B/Fc or MEK1 inhibitors in combination with anticancer drugs as novel strategies aimed at preventing chemotherapy-associated muscle atrophy.

Topics: Activin Receptors, Type II; Animals; Antineoplastic Combined Chemotherapy Protocols; Body Composition; Cachexia; Camptothecin; Cell Line; Colorectal Neoplasms; Flavonoids; Fluorouracil; Humans; Leucovorin; Male; MAP Kinase Kinase 1; MAP Kinase Signaling System; Mice; Mitochondria; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Muscle Fatigue; Muscle, Skeletal; Muscular Atrophy; Myoblasts; Myostatin; Organoplatinum Compounds; p38 Mitogen-Activated Protein Kinases; Protein Kinase Inhibitors; Up-Regulation

There are different types of skin changes associated with internal malignancy. One type is the skin involvement as a result of cutaneous metastasis from an internal tumor. The skin is an uncommon site for distant metastasis; when it is present the most common sources are breast, lung, and colon. Metastasis generally occurs after an internal malignancy had been discovered and signifies disseminated disease with a poor prognosis. We report an exuberant and rare case of cutaneous metastasis from gastric adenocarcinoma as the first sign of this serious visceral cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cachexia; Carcinoma, Signet Ring Cell; Etoposide; Fluorouracil; Humans; Leucovorin; Lung Neoplasms; Male; Middle Aged; Skin Neoplasms; Spinal Neoplasms; Stomach Neoplasms; Treatment Failure