sirolimus and Dyspnea

The mammalian target of rapamycin (mTOR) inhibitor class of drugs represents the newest addition to the armamentarium of therapies for hormonally driven breast cancer. It has recently been shown that the addition of mTOR inhibitor everolimus to aromatase inhibitors in hormone receptor-positive breast cancers improves progression-free survival. However, a clinically significant toxicity associated with this class of drugs is the development of noninfectious pneumonitis (NIP). Although generally mild and manageable, everolimus-induced NIP requires prompt diagnosis and management. This article will provide a brief overview of data relating to dysregulation of the phosphatidylinositol-3-kinase/protein kinase B/mTOR pathway in breast cancer; review the literature relating to the efficacy and safety of mTOR inhibitors in breast cancer; and evaluate the incidence, severity, and optimal management of mTOR inhibitor-related NIP in breast cancer.

Topics: Antineoplastic Agents; Breast Neoplasms; Cough; Dyspnea; Elafin; Everolimus; Female; Humans; Incidence; Pneumonia; Proto-Oncogene Proteins c-akt; Severity of Illness Index; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Sirolimus is an immunosuppressive medication used in transplant recipients. To our knowledge, we describe the third reported case of alveolar hemorrhage in association with sirolimus. Fever, dyspnea, hemoptysis, and lung infiltrates resolved rapidly with cessation of sirolimus therapy both initially and after reinstitution of the drug. Unlike previous reports, our patient had no evidence of lymphocytic alveolitis but rather marked macrophage hemosiderosis, suggesting that sirolimus pulmonary toxicity may manifest through 2 separate mechanisms. Our case highlights an uncommon but potentially lethal manifestation of sirolimus pulmonary toxicity.

Topics: Biopsy; Bronchoalveolar Lavage Fluid; Dyspnea; Female; Fever; Hemoptysis; Hemorrhage; Hemosiderin; Humans; Immunosuppressive Agents; Kidney Transplantation; Lung Diseases; Macrophages; Middle Aged; Pulmonary Alveoli; Sirolimus; Tomography, X-Ray Computed

Myelodysplastic syndrome (MDS) continues to cause major morbidity and mortality; thus, novel treatments are needed. The mammalian target of rapamycin (mTOR) inhibitor RAD001 (everolimus) inhibits cellular pathways important to MYC protein stability and cell growth. Pharmacodynamic biomarkers could be useful in distinguishing between (1) disease resistance that occurs even though mTOR is successfully inhibited (suggesting a need for a different treatment strategy) and (2) resistance that might respond to changes in drug dosage or schedule.. This was a small phase II trial of RAD001 in patients with low- and intermediate-1-risk MDS (n = 7). Protein S6K1 (S6) is downstream of mTOR, whereas protein kinase B (AKT) is upstream of mTOR. Therefore, to evaluate the pharmacodynamic effects of RAD001, S6 and AKT phosphorylation (pS6, pAKT) were measured by peripheral blood flow cytometry.. Sequential weeks of RAD001 produced a decrease in pS6, whereas pAKT was maintained or increased. There were no clinical responses despite the biomarker evidence of intended pharmacodynamic effect.. The pS6:pAKT ratio could be useful as a biomarker of target inhibition by RAD001 (clinicaltrials.gov identifier: NCT00809185).

Topics: Aged; Aged, 80 and over; Biomarkers; Cell Line, Tumor; Drug Administration Schedule; Dyspnea; Everolimus; Fatigue; Female; Fever; Flow Cytometry; Humans; Immunosuppressive Agents; Male; Middle Aged; Myelodysplastic Syndromes; Neutropenia; Phosphorylation; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

To retrospectively analyze the effects of treatment duration on outcomes of everolimus treatment of patients in the RAD001 Expanded-Access Clinical Trial in RCC (REACT) program.. Patients with metastatic renal cell carcinoma refractory to vascular endothelial growth factor receptor-tyrosine kinase inhibitor received everolimus (10 mg once daily), with dosing interruption or modifications allowed for toxicity. All serious and grade 3/4 adverse events and grade 1/2 adverse events leading to a change in drug administration were reported. Tumor response was evaluated using Response Evaluation Criteria In Solid Tumors.. The study stratified 1367 evaluable patients into treatment duration groups of <3 months, ≥3 and <6 months, ≥6 months and <1 year, and ≥1 year. Pneumonia, noninfectious pneumonitis, and hyperglycemia occurred more frequently in patients receiving everolimus for ≥1 year but did not result in treatment discontinuations. First occurrence of adverse events presented early in the treatment course for most patients. Treatment duration of ≥6 months was associated with improved disease control rates.. Everolimus is well tolerated in patients with metastatic renal cell carcinoma for treatment durations≥1 year and not associated with cumulative toxicity.

Topics: Aged; Anemia; Antineoplastic Agents; Carcinoma, Renal Cell; Disease Progression; Dyspnea; Everolimus; Fatigue; Female; Humans; Hyperglycemia; Kidney Neoplasms; Male; Middle Aged; Pneumonia; Sirolimus; Stomatitis; Time Factors; Treatment Outcome

Pemetrexed is an established second-line therapy for non-small cell lung cancer (NSCLC). Everolimus has previously been shown to have some clinical activity when used as a single agent in NSCLC. The aim of this phase I study was to evaluate the safety and feasibility of combining pemetrexed with everolimus in patients with NSCLC who had disease progression after one previous treatment.. Patients with stage IIIb/IV NSCLC and one previous chemotherapy regimen were enrolled. A Bayesian dose-escalation model was used to determine the feasible doses of daily or weekly everolimus combined with pemetrexed (500 mg/m q3w). The primary end point was rate of cycle 1 dose-limiting toxicities (DLTs). Secondary end points included safety, relative dose intensity of pemetrexed, pharmacokinetics, and tumor response.. Twenty-four patients received daily everolimus (2.5, 5, 7.5, or 10 mg) and 19 received weekly everolimus (30 or 50 mg) with pemetrexed. Cycle 1 DLTs in the daily regimen included febrile neutropenia, neutropenia, rash/pruritus, and thrombocytopenia; in the weekly regimen, DLTs included neutropenia and stomatitis. The most frequent grade 3/4 adverse events were neutropenia, dyspnea, and thrombocytopenia. Three partial responses were observed with everolimus 5 mg/d and two with 50 mg/wk. Pharmacokinetics did not suggest an influence of everolimus on pemetrexed parameters; pemetrexed resulted in a minor decrease in everolimus exposure with both daily and weekly regimens.. Everolimus 5 mg/d or 50 mg/wk with the standard regimen of pemetrexed are feasible dosages in patients with stage IIIb/IV NSCLC.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bayes Theorem; Carcinoma, Non-Small-Cell Lung; Drug Eruptions; Dyspnea; Everolimus; Female; Glutamates; Guanine; Humans; Lung Neoplasms; Male; Middle Aged; Neutropenia; Pemetrexed; Pruritus; Sirolimus; Stomatitis; Thrombocytopenia; Treatment Outcome

Topics: Adolescent; Biopsy; Bone Density Conservation Agents; Dyspnea; Exudates and Transudates; Humans; Imaging, Three-Dimensional; Male; Membrane Glycoproteins; Osteolysis, Essential; Pleural Effusion; Ribs; Sirolimus; Tomography, X-Ray Computed; Zoledronic Acid

Topics: Chest Pain; Cough; Diagnosis, Differential; Dyspnea; Female; Humans; Lung; Lung Diseases, Fungal; Lung Neoplasms; Lymphangioleiomyomatosis; Magnetic Resonance Imaging; Pneumonia, Bacterial; Pneumothorax; Radiography, Thoracic; Risk Factors; Shock; Sirolimus; Thoracostomy; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Young Adult

Topics: Adult; Antibiotics, Antineoplastic; Chest Pain; Dyspnea; Female; Forced Expiratory Volume; Humans; Lung; Lung Neoplasms; Lymphangioleiomyomatosis; Pleurodesis; Sirolimus; Tomography, X-Ray Computed

Topics: Child, Preschool; Dyspnea; Female; Humans; Osteolysis; Osteolysis, Essential; Pleural Effusion; Radiography, Thoracic; Respiration; Respiratory Rate; Sirolimus; Skin

Topics: Adult; Biopsy; Carbon Monoxide; Cell Proliferation; Dyspnea; Female; Genotype; Humans; Lung; Lung Diseases; Respiratory Function Tests; Sirolimus; Tomography, X-Ray Computed; Treatment Outcome; Vital Capacity

Topics: Bronchoscopy; Disease Progression; Dyspnea; Female; Hemorrhage; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lung Diseases; Middle Aged; Pulmonary Alveoli; Sirolimus

Topics: Cough; Dyspnea; Forced Expiratory Volume; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Sirolimus; Surgical Stapling; Surgical Wound Dehiscence; Sutures

Treatment options are scarce in pretreated advanced non-small-cell lung cancer (NSCLC) patients. RAD001, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown phase I efficacy in NSCLC.. Stage IIIb or IV NSCLC patients, with two or fewer prior chemotherapy regimens, one platinum based (stratum 1) or both chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitors (stratum 2), received RAD001 10 mg/day until progression or unacceptable toxicity. Primary objective was overall response rate (ORR). Analyses of markers associated with the mTOR pathway were carried out on archival tumor from a subgroup using immunohistochemistry (IHC) and direct mutation sequencing.. Eighty-five patients were enrolled, 42 in stratum 1 and 43 in stratum. ORR was 4.7% (7.1% stratum 1; 2.3% stratum 2). Overall disease control rate was 47.1%. Median progression-free survivals (PFSs) were 2.6 (stratum 1) and 2.7 months (stratum 2). Common > or =grade 3 events were fatigue, dyspnea, stomatitis, anemia, and thrombocytopenia. Pneumonitis, probably or possibly related, mainly grade 1/2, occurred in 25%. Cox regression analysis of IHC scores found that only phospho AKT (pAKT) was a significant independent predictor of worse PFS.. RAD001 10 mg/day was well tolerated, showing modest clinical activity in pretreated NSCLC. Evaluation of RAD001 plus standard therapy for metastatic NSCLC continues.

Topics: Adult; Aged; Anemia; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Dyspnea; ErbB Receptors; Everolimus; Fatigue; Female; Follow-Up Studies; Humans; Immunohistochemistry; Immunosuppressive Agents; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Pneumonia; Proto-Oncogene Proteins c-akt; Regression Analysis; Sirolimus; Stomatitis; Thrombocytopenia; Time Factors; Treatment Outcome

A 23-year-old Caucasian woman, with cystic fibrosis, bilateral lung-transplantation and immunosuppressive therapy with prednisolone, tacrolimus and sirolimus, presented with clinical symptoms of a chronic transplant rejection.. Since constant sufficient blood level of tacrolimus and sirolimus had never been achieved, a genetic analysis was carried out to clarify drug metabolism.. The genetic analysis for polymorphisms of cytochrome P450 (CYP) 3A4,5,7 revealed no sequence alterations in the CYP 3A4,5,7 gene. Thus, drug intake was scrutinized in detail, disclosing a missing interval between the intake of both immunosuppressive agents. After a correct drug intake the woman's condition ameliorated and the blood levels reached normal range.. This case report highlights the crucial importance of basic medical skills like an accurate and dainty drug anamnesis before high tech approaches were applied.

Topics: Adult; Drug Monitoring; Drug Therapy, Combination; Dyspnea; Female; Graft Rejection; Humans; Immunosuppressive Agents; Lung Transplantation; Medical History Taking; Patient Compliance; Patient Education as Topic; Prednisolone; Sirolimus; Tacrolimus

Topics: Adult; Angioplasty, Balloon, Coronary; Cardiomyopathy, Hypertrophic; Combined Modality Therapy; Coronary Disease; Drug Implants; Dyspnea; Ethanol; Heart Septum; Humans; Magnetic Resonance Imaging; Male; Mitral Valve Insufficiency; Physical Exertion; Recurrence; Sclerosing Solutions; Sirolimus; Stents; Tomography, Spiral Computed; Ultrasonography

Idiopathic pulmonary fibrosis (IPF) is a progressive chronic disorder of the lower respiratory tract. The main clinical feature is a progressive shortness of breath, particularly on exercise. An overproduction and deposition of collagen and a proliferation of mesenchymal cells are the histopathologic characteristics. Rapamycin is an immunosuppressive agent with antiproliferative effects on mesenchymal cells including fibroblasts. It was this rationale that prompted the authors to administer rapamycin in a case of rapidly progressive IPF.. In a 73-year-old female with a 2-month history of IPF, treatment with steroids and interferon gamma-1b did not improve the detrimental clinical course. Treatment with rapamycin was started; subsequently, clinical condition and objective findings improved markedly within weeks. She is now under treatment for 18 months.. The authors presume that partial remission is related to rapamycin which may be effective in blocking the progressive fibrosis and increased collagen synthesis thought to be pathophysiologically relevant in this disease. Further studies have to show whether rapamycin may be a treatment option in idiopathic pulmonary fibrosis.

Topics: Aged; Dyspnea; Exercise Test; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Long-Term Care; Pulmonary Fibrosis; Retreatment; Sirolimus; Tomography, X-Ray Computed; Treatment Failure