sirolimus and Anorexia

With the advent of targeted agents for the treatment of renal cell carcinoma (RCC), overall survival has improved, and patients are being treated continuously for increasingly long periods of time. This has raised challenges in the management of adverse events (AEs) associated with the six targeted agents approved in RCC-sorafenib, sunitinib, pazopanib, bevacizumab (in combination with interferon alpha), temsirolimus, and everolimus. Suggestions for monitoring and managing AEs have been published, but there are few consensus recommendations. In addition, there is a risk that patients will be subjected to multiple unnecessary investigations. In this review, we aimed to identify the level of supporting evidence for suggested AE management strategies to provide practical guidance on essential monitoring and management that should be undertaken when using targeted agents. Five databases were systematically searched for relevant English language articles (including American Society of Clinical Oncology abstracts) published between January 2007 and March 2011; European Society of Medical Oncology congress abstracts were hand searched. Strategies for AE management were summarized and categorized according to the level of recommendation. A total of 107 articles were identified that describe a large number of different investigations for monitoring AEs and interventions for AE management. We identify and summarize clear recommendations for the management of dermatologic, gastrointestinal, thyroid, cardiovascular, and other AEs, based predominantly on expert opinion. However, because the evidence for the suggested management strategies is largely anecdotal, there is a need for further systematic investigation of management strategies for AEs related to targeted therapies for RCC.

Topics: Anorexia; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Bevacizumab; Carcinoma, Renal Cell; Cardiovascular System; Drug Eruptions; Europe; Everolimus; Evidence-Based Medicine; Gastrointestinal Tract; Humans; Hypothyroidism; Indazoles; Indoles; Kidney Neoplasms; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Pneumonia; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Pyrroles; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A; Weight Loss; Wound Healing

There is crosstalk between the ANG-Tie2 and the PI3K/Akt/mTOR pathways. Combined ANG1/2 and mTOR blockade may have additive anti-cancer activity. The combination of trebananib, an inhibitor of ANG1/2-Tie2 interaction, with temsirolimus was evaluated in patients with advanced solid tumors to determine tolerability, maximum tolerated dose (MTD), and preliminary antitumor activity.. Patients were enrolled using 3 + 3 design, and were given intravenous trebananib and temsirolimus on Day 1, 8, 15 and 22 of a 28-day cycle. Dose limiting toxicities (DLTs) were evaluated during cycle 1. Peripheral blood was collected for evaluation of Tie2-expressing monocytes (TEMs) and thymidine phosphorylase (TP). Sparse pharmacokinetic (PK) sampling for trebananib drug levels was performed on Day 1 and 8 of cycle 2.. Twenty-one patients were enrolled, 6 at dose level (DL) 1, 7 at DL -1, and 8 at DL -2. No effect of temsirolimus on trebananib PK was observed. The most common treatment-related adverse events (AEs) were: fatigue (81 %), edema (62 %), anorexia (57 %), nausea (52 %), rash (43 %) and mucositis (43 %). The most common grade ≥ 3 AEs included lymphopenia (28 %) and fatigue (28 %). The MTD was exceeded at DL-2. Of 18 response evaluable patients, 1 partial response was observed (ER+/HER2-/PIK3CA mutant breast cancer) and 4 patients had prolonged SD ≥ 24 weeks. No correlation with clinical benefit was observed with change in number TEMs or TP expression in TEMs with treatment.. The MTD was exceeded at trebananib 10 mg/kg weekly and temsirolimus 20 mg weekly, with frequent overlapping toxicities including fatigue, edema, and anorexia.

Topics: Adult; Aged; Anorexia; Antineoplastic Combined Chemotherapy Protocols; Edema; Fatigue; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Recombinant Fusion Proteins; Sirolimus; Treatment Outcome

LY2584702 tosylate (hereafter referred to as LY2584702) is an oral, selective ATP competitive inhibitor of p70 S6 kinase. Preclinical studies with LY2584702 demonstrated significant synergistic activity with erlotinib and everolimus. The primary objective was to determine a phase II dose and schedule. Secondary objectives included evaluation of safety, toxicity and pharmacokinetics of LY2584702 in combination with erlotinib or everolimus.. Patients with advanced solid tumours were treated with a total daily dose of 50-200mg of LY2584702 in combination with erlotinib 150 mg once daily (Arm A) or everolimus 10mg once daily (Arm B). Dose escalation was based on 3+3 design and used the Common Terminology Criteria for Adverse Events Version 4.0.. Twenty-nine patients were enrolled, 17 in Arm A and 12 in Arm B. Dose limiting toxicities (DLTs) in cycle 1 were observed in Arm A in four patients and consisted of Grade 3 vomiting, hypophosphataemia, pulmonary embolism and decreased clotting factor V. No DLTs were observed in Arm B at cycle 1, and the most frequent treatment-emergent adverse events related to study drug were: fatigue, anorexia, diarrhoea, nausea and vomiting. Seven patients received ≥4 cycles (3 in A, 4 in B). Best overall response was stable disease. Exposure accumulation of LY2584702 occurred with BID (twice daily) dosing. Exposure of erlotinib increased when administered in combination with LY2584702.. LY2584702 was not well tolerated when administered with erlotinib, therefore this combination is not feasible. The combination with everolimus was better tolerated but yielded very limited clinical benefit.

Topics: Adaptor Proteins, Signal Transducing; Adult; Aged; Anorexia; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Erlotinib Hydrochloride; Everolimus; Fatigue; Female; Humans; Male; Metabolic Clearance Rate; Middle Aged; Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyrimidines; Quinazolines; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus; Time Factors; Treatment Outcome; Vomiting

Subependymal giant cell astrocytomas (SEGA) appear in 5-20% of patients with tuberous sclerosis complex (TSC) and are the most common brain tumours in TSC. They are benign tumours, of a glioneural stock, that develop mainly in the first two decades of life, generally close to the foramen of Monro, and can trigger hydrocephalus and intracranial hypertension. It is one of the leading causes of death in TSC. Recently mTOR inhibitors have proved to be a therapeutic alternative to surgical excision. AIM. To describe our experience of using everolimus to treat patients with SEGA and TSC.. We conducted a prospective study of the responses of patients with TSC and at least one SEGA undergoing growth.. Three females and three males with a mean age of 12.3 years received treatment. One patient had previously undergone surgery due to SEGA with hydrocephalus. The maximum mean diameter of the SEGA on beginning treatment was 15.3 mm (range: 11.3-24.8 mm). Treatment was established with everolimus, 2.5 mg/day administered orally in patients with a body surface area < 1.2 m2, and 5 mg/day in patients with a body surface area > 1.2 m2. Two patients presented hypertriglyceridemia; one, anorexia; another, a mouth ulcer; and one, amenorrhoea. The mean reduction in the volume of the SEGA at three months of treatment was 46%, and the reduction remained steady in later control examinations (6-25 months).. Treatment with everolimus reduces the size of SEGA associated with TSC with an adequate safety profile, and constitutes an alternative to surgery in certain cases.. Respuesta a everolimus en pacientes con astrocitoma de celulas gigantes asociado al complejo esclerosis tuberosa.. Introduccion. Los astrocitomas subependimarios de celulas gigantes (SEGA) se presentan en el 5-20% de los pacientes con complejo esclerosis tuberosa (CET) y son los tumores cerebrales mas comunes en el CET. Son tumores benignos, de estirpe glioneural, que se desarrollan fundamentalmente en las primeras dos decadas de la vida, en general cercanos al foramen de Monro, y pueden ocasionar hidrocefalia e hipertension intracraneal. Constituyen la principal causa de muerte en el CET. Recientemente, los inhibidores mTOR han demostrado ser una alternativa terapeutica a la reseccion quirurgica. Objetivo. Describir nuestra experiencia con everolimus para el tratamiento de pacientes con SEGA y CET. Pacientes y metodos. Estudio prospectivo de la respuesta de los pacientes con CET y al menos un SEGA en crecimiento. Resultados. Recibieron tratamiento tres mujeres y tres varones con una edad media de 12,3 años. Un paciente habia sido previamente intervenido quirurgicamente por SEGA con hidrocefalia. El diametro maximo medio del SEGA al inicio del tratamiento era de 15,3 mm (rango: 11,3-24,8 mm). Se inicio tratamiento con everolimus, 2,5 mg/dia por via oral en pacientes con superficie corporal < 1,2 m2 y 5 mg/dia en pacientes con superficie corporal > 1,2 m2. Dos pacientes presentaron hipertrigliceridemia; uno, anorexia; otro, un afta; y una paciente, amenorrea. La reduccion media del volumen del SEGA a los tres meses de tratamiento fue del 46%, y la reduccion se mantuvo estable en controles posteriores (6-25 meses). Conclusiones. El tratamiento con everolimus disminuye el tamaño de los SEGA asociados a CET con un perfil de seguridad adecuado, y constituye una alternativa a la cirugia en casos seleccionados.

Topics: Administration, Oral; Adolescent; Amenorrhea; Anorexia; Astrocytoma; Brain Neoplasms; Child; Everolimus; Female; Giant Cells; Humans; Hypertriglyceridemia; Male; Neoplasm Proteins; Prospective Studies; Sirolimus; Stomatitis, Aphthous; TOR Serine-Threonine Kinases; Treatment Outcome; Tuberous Sclerosis; Tuberous Sclerosis Complex 2 Protein; Tumor Burden; Tumor Suppressor Proteins

The authors have previously demonstrated that a low and intermittent peripheral dose of rapamycin (1 mg/kg three times/week) to rats inhibited mTORC1 signalling, but avoided the hyperlipidemia and diabetes-like syndrome associated with higher doses of rapamycin. The dosing regimen reduced food intake, body weight, adiposity, serum leptin and triglycerides. mTORC1 signalling was inhibited in both liver and hypothalamus, suggesting some of the actions, in particular the decrease in food intake, may be the results of a central mechanism. To test this hypothesis, rapamycin (30 μg/day for 4 weeks) was infused into 23-25-month-old F344xBN rats by intracerebroventricular (icv) mini pumps. Our results demonstrated that central infusion did not alter food intake or body weight, although there was a tendency for a decrease in body weight towards the end of the study. mTORC1 signalling, evidenced by decreased phosphorylation of S6 protein at end of 4 weeks, was not activated in liver, hypothalamus or hindbrain. Fat and lean mass, sum of white adipose tissues, brown adipose tissue, serum glucose, insulin and leptin levels remained unchanged. Thus, these data suggest that the anorexic and body weight responses evident with peripheral rapamycin are not the result of direct central action. The tendency for decreased body weight towards the end of study, suggests that there is either a slow transport of centrally administered rapamycin into the periphery, or that there is delayed action of rapamycin at sites in the brain.

Topics: Animals; Anorexia; Body Weight; Eating; Energy Intake; Rats; Sirolimus; Treatment Outcome

Metastatic renal cell carcinoma (mRCC) has historically been refractory to cytotoxic and hormonal agents. IL-2 and IFN-α provide response in a minority of patients. Small molecule tyrosine kinase inhibitors and monoclonal antibodies have established a role in the setting of mRCC. However, there is a lack of data from the Indian subcontinent. The aim of this study was to look whether our patients behave similarly as reported in the Western data to targeted agents, especially sunitinib.. The study was a prospective observational study conducted for a period of 5 years from 2011 to 2016. Sixty-three patients received targeted agents and were recruited in the study. Five patients were excluded for various reasons, and three were lost to follow-up. Fifty-five patients were properly studied and followed up. Fifty patients received sunitinib, four patients received sorafenib, and one patient received parenteral temsirolimus. Patients were followed for AEs and survival.. The most common AEs in patients taking sunitinib were fatigue (70 %), hand-foot syndrome (62 %), skin rash (58 %), mucosal inflammation (58 %), anorexia (42 %), skin discoloration (42 %), followed by dry mouth, dysgeusia, dyspepsia, dry skin, dry mouth, hair color changes, hypothyroidism, alopecia, oral pain/stomatitis, hypertension, decreased weight, photosensitivity, peripheral edema, erythema, and others. The median overall survival in our patients was 13.2 (95 % CI 10.1-16.5), progression-free survival was 8.1 months (95 % CI 6.4-10.5), and objective response was seen in 36 %.. Non-Western patients behave differently with sunitinib therapy compared to Western patients. Our patients have more mucocutaneous side effects and lesser overall survival.

Topics: Adult; Aged; Aged, 80 and over; Anorexia; Antineoplastic Agents; Carcinoma, Renal Cell; Developing Countries; Disease-Free Survival; Fatigue; Female; Follow-Up Studies; Hand-Foot Syndrome; Humans; India; Indoles; Kidney Neoplasms; Male; Middle Aged; Mucositis; Niacinamide; Phenylurea Compounds; Pigmentation Disorders; Prospective Studies; Pyrroles; Response Evaluation Criteria in Solid Tumors; Sirolimus; Sorafenib; Sunitinib; Survival Rate; White People; Young Adult

Anorexia-cachexia syndrome (ACS) is a major determinant of cancer-related death that causes progressive body weight loss due to depletion of skeletal muscle mass and body fat. Here, we report the development of a novel preclinical murine model of ACS in which lymphomas harbor elevated Myc and activated mTOR signaling. The ACS phenotype in this model correlated with deregulated expression of a number of cytokines, including elevated levels of interleukin-10 which was under the direct translational control of mTOR. Notably, pharmacologic intervention to impair protein synthesis restored cytokine production to near-normal levels, delayed ACS progression, and extended host survival. Together, our findings suggest a new paradigm to treat ACS by strategies which target protein synthesis to block the production of procachexic factors.

Topics: Animals; Anorexia; Antineoplastic Agents; Body Weight; Cachexia; Cell Line, Tumor; Colonic Neoplasms; Disease Models, Animal; Female; Harringtonines; Homoharringtonine; Humans; Interleukin-10; Kaplan-Meier Estimate; Lymphoma; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Protein Biosynthesis; Proto-Oncogene Proteins c-myc; Signal Transduction; Sirolimus; Syndrome; TOR Serine-Threonine Kinases

The aim of the present study was to obtain evidence for the possible modulatory effect of leptin on glucosensing capacity in hypothalamus and hindbrain of rainbow trout. In a first experiment, trout were injected ICV with saline alone or containing increased doses of leptin (0.3-30 microg microl(-1)). Leptin induced in general in both hypothalamus and hindbrain dose-dependent changes in parameters related to glucosensing (increased glycogenic and glycolytic potentials together with increased GK activity, and increased mRNA levels of genes involved in glucosensing response) compatible with those occurring under hyperglycemic conditions, a situation that is known to produce anorexia. The anorectic action of leptin in our experimental conditions was observed in a second experiment. The specificity of leptin action was tested in a third experiment in which trout were injected ICV with saline, or leptin alone, or leptin plus agents known to inhibit leptin signaling pathways in mammals. The results obtained suggest that the central action of leptin on glucosensing system can be related to the JAK/STAT and IRS-PI(3)K pathways. Finally, we also provide evidence for a peripheral effect of central leptin treatment (increased liver glycogenolytic potential), which could be associated with increased sympathetic activity.

Topics: Animals; Anorexia; ATP-Binding Cassette Transporters; Brain; Energy Metabolism; Glucokinase; Glucose; Hypothalamus; Injections, Intraventricular; Leptin; Liver Glycogen; Milrinone; Oncorhynchus mykiss; Potassium Channels, Inwardly Rectifying; Pyruvate Kinase; Receptors, Drug; Rhombencephalon; RNA, Messenger; Sirolimus; Sulfonylurea Receptors