sirolimus and Stomatitis--Aphthous

With the recent introduction of inhibitors of mammalian target of rapamycin (mTOR) in oncology, distinct cutaneous and oral adverse events have been identified. In fact, stomatitis and rash are documented as the most frequent and potentially dose-limiting side effects. Clinically, mTOR inhibitor-associated stomatitis (mIAS) more closely resembles aphthous stomatitis than oral mucositis due to conventional anticancer therapies. While most cases of mIAS are mild to moderate and self-limiting, more severe and persistent mIAS can become a dose-limiting toxicity. Small ulcerations may cause significant pain and mucosal sensitivity may occur in the absence of clinical changes. Use of clinical assessment tools that are primarily driven by ulceration size may underestimate mIAS, and assessment should include patient-reported outcomes. This article provides an up-to-date review of the clinical presentation, terminology, pathogenesis, assessment and management of mIAS and other mTOR inhibitor-associated oral adverse events. In addition, areas of future research are considered.

Topics: Drug-Related Side Effects and Adverse Reactions; Humans; Protein Kinase Inhibitors; Sirolimus; Stomatitis, Aphthous; TOR Serine-Threonine Kinases

Temsirolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is a new targeted therapy used in advanced renal cell carcinoma and mantle cell lymphoma and is currently tested in several other human tumors. It induces several cutaneous and mucosal side effects, including painful, dose-limiting stomatitis. We report the unusual case of a 77-year-old man who developed severe mucosal, scrotal and perianal cutaneous aphthous-like ulcerations, 6 weeks after introduction of temsirolimus therapy for advanced-stage renal cell carcinoma. Other causes of aphthous-like ulcerations were ruled out. Topical corticosteroids remained ineffective. It led to the interruption of the treatment. Introduction of colchicine resulted in a dramatic improvement within 1 month. Reintroduction of temsirolimus with concomitant colchicine therapy was followed by a delayed recurrence of the lesions. We provide here a review of the potential cutaneous and mucosal side effects of mTOR inhibitors.

Topics: Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Genital Diseases, Male; Humans; Kidney Neoplasms; Male; Protein Kinase Inhibitors; Scrotum; Sirolimus; Stomatitis, Aphthous; TOR Serine-Threonine Kinases

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

Aphthous ulceration is a common side effect of sirolimus. These lesions of the oral mucous membranes are often painful and debilitating, leading to either dose reduction or discontinuation of sirolimus in a significant number of patients. We report that the direct application of clobetasol, a high potency topical steroid, led to prompt resolution of the aphthous ulcers that developed in our renal transplant patients on sirolimus-based immunosuppression.

Topics: Adult; Anti-Inflammatory Agents; Clobetasol; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Sirolimus; Stomatitis, Aphthous

We report the clinical features and management outcomes in 7 patients with everolimus-related stomatitis.. Fifteen women with hormone-receptor-positive advanced breast cancer receiving everolimus combined with exemestane were prospectively evaluated to assess the development of stomatitis. Oral ulcers were diagnosed based on established criteria.. Seven patients developed stomatitis (46.6%). All patients were treated with topical dexamethasone solution, while everolimus was temporarily discontinued in 4 patients. Stomatitis resolved within 1-2 weeks. Two of the 4 patients, who had interrupted everolimus, developed recurrent stomatitis following drug resume and everolimus was again discontinued and restarted after 2 weeks. To date, 5 patients receive everolimus in full dose. The 2 patients, who developed recurrent stomatitis, received a reduced dose.. Everolimus-related oral ulcers were frequent and led to dose modifications. Controlled trials, endorsing a consensus in terminology, are needed to evaluate measures on prevention and management of this unique toxicity.

Topics: Aged; Androstadienes; Anti-Inflammatory Agents; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma; Dexamethasone; Everolimus; Female; Follow-Up Studies; Glucocorticoids; Humans; Middle Aged; Oral Ulcer; Prospective Studies; Recurrence; Sirolimus; Stomatitis; Stomatitis, Aphthous; TOR Serine-Threonine Kinases; Treatment Outcome

Mammalian target of rapamycine (mTOR) inhibitors are being increasingly prescribed as antitumoural drugs, and associated adverse cutaneous effects are frequent but poorly described. The aim of this study was to describe such adverse effects and to assess the quality of life of patients experiencing them.. Over a period of 18 months, 18 patients treated with mTOR inhibitors for renal carcinoma were included and 77 dermatological examinations performed. Wherever a cutaneous adverse event was present, quality of life was evaluated using the Skindex 30 questionnaire.. Fifteen of the 18 patients included presented adverse cutaneous events, consisting of buccal ulcers (61.1%), xerosis (55.5%), distal onycholysis (50%), acneiform eruption (38.8%), paronychia (22.2%) and pruritus (22.2%). Buccal ulcerations and perionyxis had an especially marked impact on quality of life, which was greatest in terms of physical score (19%), followed by emotional (9%) and functional (6%) scores.. Cutaneous adverse effects of mTOR inhibitors are frequent and have a considerable impact on quality of life, particularly as regards physical scores. Dermatological examination appears useful to allow early management of cutaneous adverse effects and improve the quality of life of these patients.

Topics: Acneiform Eruptions; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Drug Eruptions; Emotions; Everolimus; Female; Humans; Ichthyosis; Kidney Neoplasms; Male; Middle Aged; Onycholysis; Paronychia; Prospective Studies; Pruritus; Quality of Life; Severity of Illness Index; Sirolimus; Stomatitis, Aphthous; TOR Serine-Threonine Kinases

Aphthous stomatitis, a common mucocutaneous disorder, is a well accepted complication of sirolimus therapy. This association has been reported less frequently with tacrolimus.. We present an 11-year old male with Budd-Chiari syndrome who experienced profound worsening of chronic aphthous ulcers after immunosuppressive therapy was changed from tacrolimus to sirolimus.. Since these drugs are used widely in the pediatric transplantation population, this report serves to heighten awareness of this debilitating phenomenon, and to stress the importance of exercising caution when sirolimus and tacrolimus are administered in combination to pediatric patients.

Topics: Administration, Oral; Budd-Chiari Syndrome; Calcineurin Inhibitors; Child; Humans; Immunosuppressive Agents; Intracellular Signaling Peptides and Proteins; Male; Protein Serine-Threonine Kinases; Severity of Illness Index; Sirolimus; Stomatitis, Aphthous; Tongue Diseases; TOR Serine-Threonine Kinases

Mammalian target of rapamycin (mTOR) inhibitors display antiproliferative effects with less nephrotoxicity than calcineurin inhibitors. However, clinical use of mTOR inhibitors can be associated with a series of adverse events. We experienced cases of aphthous stomatitis associated with everolimus (EVL) in four Japanese heart transplant recipients treated at the target trough EVL blood level after a switch from mycophenolate mofetil between April and December 2007. All four patients developed aphthous stomatitis; three required reduction of the exposure and one, EVL discontinuation due to stomatitis as well as other side effects. All patients recovered from stomatitis after reduction or withdrawal of EVL. Thus, we considered that EVL-related stomatitis might occur commonly among the Japanese population. The proper dosage, effects, and frequency of the side effects of mTOR inhibitors may vary by ethnic population.

Topics: Adolescent; Adult; Asian People; Dose-Response Relationship, Drug; Drug Substitution; Everolimus; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Japan; Male; Sirolimus; Stomatitis, Aphthous; TOR Serine-Threonine Kinases

Topics: Everolimus; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Oral Ulcer; Sirolimus; Stomatitis, Aphthous; Tongue Diseases