sirolimus and Stomatitis

Lymphangioleiomyomatosis (LAM) is a rare, low-grade multisystem neoplastic disease. Most LAM patients are at a high risk of losing lung function at an accelerated rate and developing progressive dyspnea. Recently, several studies have reported their experience with pharmacological treatments for LAM. Therefore, we conducted a systematic review and meta-analysis to assess the efficacy and safety of these therapies.. PubMed (Medline), EMBASE, Cochrane Library, Web of Science and EBSCO Host were searched (until March 31, 2019) for eligible prospective studies regarding LAM patients treated with pharmacological treatments. Random effect models were used for quantitative analysis.. Fourteen prospective studies regarding five pharmacological treatments (including sirolimus, everolimus, doxycycline, triptorelin, and a combination therapy of sirolimus and hydroxychloroquine) were enrolled in our systematic review, and ten of them were used for the meta-analysis. Seven prospective studies reported that sirolimus was effective at improving or stabilizing lung function and alleviating renal angiomyolipoma (AML) in LAM patients. Subsequent quantitative analyses showed that during sirolimus treatment, the pooled values of lung function and 6-min walk distance (6MWD) were not significantly changed (P > 0.05), with the pooled response rate of AML being 0.62 (95% confidence intervals [CIs]: 0.43 to 0.82, I. Overall, sirolimus and everolimus were recommended for the treatment of LAM because they could stabilize lung function and alleviate renal AML. Doxycycline and triptorelin were not recommended for the treatment of LAM because no beneficial outcomes were consistently observed. The efficacy and safety of combination therapy remain to be further explored.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Clinical Trials as Topic; Drug Therapy, Combination; Enzyme Inhibitors; Everolimus; Humans; Hydroxychloroquine; Hyperlipidemias; Lymphangioleiomyomatosis; Prospective Studies; Sirolimus; Stomatitis; Treatment Outcome

Patients with metastatic breast cancer may develop oral morbidities that result from therapeutic interventions. Mammalian target of rapamycin (mTOR) inhibitor-associated stomatitis (mIAS) is a common adverse event (AE), secondary to mTOR inhibitor therapy, that can have a negative impact on treatment adherence, quality of life, and health care costs. A multidisciplinary team approach is important to minimize mIAS and to maximize treatment benefits to patients with breast cancer. In this review, we discuss the pathophysiology, diagnosis, and natural history of mIAS. Current and new management strategies for the prevention and treatment of mIAS are described in the context of fostering a coordinated team care approach to optimizing patient care.. The authors conducted a PubMed search from 2007 through 2017 using the terms "stomatitis," "mIAS," "everolimus," "mTOR," "metastatic breast cancer," and "oral care." They selected articles published in peer-reviewed journals that reported controlled trials and evidence-based guidelines.. mIAS can be distinguished from mucositis caused by cytotoxic chemotherapy or radiotherapy on the basis of cause, clinical presentation, and treatment paradigms. Specific preventive and therapeutic management strategies can be implemented across the continuum of patient oral health care.. Oral health care providers are on the frontline of oral health care for patients with metastatic breast cancer and are uniquely positioned to provide patient education, advocate accurate reporting of mIAS, and support early identification, monitoring, and prompt intervention to mitigate the severity and duration of this manageable, potentially dose-limiting AE.

Topics: Antineoplastic Agents; Breast Neoplasms; Humans; Quality of Life; Sirolimus; Stomatitis; TOR Serine-Threonine Kinases

Traditional treatment of malignancies with chemotherapeutic agents is often affected by the damage inflicted on non-cancerous cells. Toxicities of the oral cavity, such as mucositis and stomatitis, are some of the most significant and unavoidable toxicities associated with anti-cancer therapies. For such reason, in the last decades, newer targeted agents have been developed aiming to decrease the rates of side effects on healthy cells. Unfortunately, targeted anti-cancer therapies also showed significant rate of toxicity on healthy tissues. mTOR inhibitors showed some adverse events, such as hyperglycemia, hyperlipidemia, hypophosphatemia, hematologic toxicities, and mucocutaneous eruption, but the most important are still stomatitis and skin rash, often reported as dose-limiting side effects.. A search of the literature was performed by authors on the PubMed online database using the following key words: "sirolimus" OR "everolimus" OR "temsirolimus" OR "deforolimus" OR "ridaforolimus" combined with the Boolean operator AND with the terms: "stomatitis" OR "mucositis" OR "oral pain." Titles and abstracts of 382 potentially relevant studies were screened; of these, 114 studies were excluded because they did not report the inclusion criteria. In the second round, 268 studies were read full-text, but only 135 reported the inclusion criteria and were included for data extraction. Of the included studies, 95 referred to everolimus use, 16 to ridaforolimus, and 26 to temsirolimus (two studies referred to both everolimus and temsirolimus).. The incidence rate of stomatitis according to the agent used was 25.07% (3,959/15,787) for everolimus, 27.02% (724/2,679) for temsirolimus, and 54.76% (598/1,092) for ridaforolimus. All the three agents analyzed showed high rates of low-grade stomatitis (G1-G2), while the onset of severe stomatitis (G3-G4) was rare.. Analysis of the reports with patients treated with everolimus, temsirolimus, and ridaforolimus showed a clear prevalence of stomatitis grade 1 or 2. These data differ from that of patients treated with conventional chemotherapy in which mucositis is predominantly of grade 3 or 4.

Topics: Antineoplastic Agents; Everolimus; Humans; Severity of Illness Index; Sirolimus; Stomatitis; TOR Serine-Threonine Kinases

Inhibitors of the mammalian target of rapamycin (mTOR) pathway including everolimus and temsirolimus have been used extensively in cancer patients. Their use is associated with stomatitis, an adverse event resulting in morbidity and treatment interruptions or discontinuation. This study was conducted to determine the overall incidence and risk of stomatitis in cancer patients treated with the mTOR inhibitors by a meta-analysis of randomized controlled clinical trials (RCTs).. Databases from PubMed and abstracts presented at the American Society of Clinical Oncology annual meetings up to October 2013 were searched for relevant studies. Eligible studies included RCTs using everolimus and temsirolimus at approved doses in cancer patients. Summary incidences, relative risks (RR), and 95% confidence intervals (CI) were calculated using a random- or fixed-effects model depending on the heterogeneity of the included trials.. A total of 11 RCTs with 4,752 patients (mTORs: 2,725, controls: 2,027) with a variety of solid tumors were included in the analysis. The incidences of all-grade (grade 1-4) and high-grade stomatitis (grade 3-4) were 33.5% (95% CI: 21.9-47.6%) and 4.1% (95% CI: 2.6-6.3%), respectively. The incidence of high-grade stomatitis significantly varied with tumor types (p=.004), and mTOR inhibitors (temsirolimus vs. everolimus, p<.001). In comparison with controls, mTOR inhibitors significantly increased the risk for developing all-grade stomatitis (RR: 4.04, 95% CI: 3.13-5.22, p<.001) and high-grade stomatitis (RR: 8.84, 95% CI: 4.07-19.22, p<.001).. The mTOR inhibitors everolimus and temsirolimus significantly increased the risk of high-grade stomatitis in cancer patients. Efforts towards the prevention, treatment, and identification of individuals at risk may allow for improved quality of life and consistent dosing.

Topics: Everolimus; Humans; Incidence; Neoplasms; Randomized Controlled Trials as Topic; Risk Factors; Sirolimus; Stomatitis; TOR Serine-Threonine Kinases

The authors performed a systematic review and meta-analysis of diarrhea and stomatitis associated with the use of everolimus, temsirolimus or ridaforolimus in patients with solid tumors.. Eligible studies included randomized trials of patients with solid tumors on everolimus, temsirolimus or ridaforolimus, describing the events of diarrhea and stomatitis.. After exclusion of ineligible studies, a total of 18 clinical trials including 8143 patients were considered eligible for the meta-analysis. The relative risk ratios of all-grade diarrhea and stomatitis were 1.94 (95% CI: 1.6-2.36; p < 0.00001) and 3.54 (95% CI: 2.59-4.84; p < 0.00001), respectively, while the relative risk ratios of high-grade diarrhea and stomatitis were 3.49 (95% CI: 2.39-5.09; p < 0.00001) and 6.98 (95% CI: 4.76-10.26; p < 0.00001), respectively. On subgroup analysis, there was no statistically significant difference between everolimus and temsirolimus in the risk of relevant adverse events.. This meta-analysis demonstrated that regimens containing everolimus, temsirolimus or ridaforolimus for the treatment of solid tumors are associated with a significantly increased risk of all-grade and high-grade diarrhea and stomatitis. Close clinical monitoring is required when administering these drugs.

Topics: Antineoplastic Agents; Diarrhea; Everolimus; Humans; Intestinal Mucosa; Mouth Mucosa; Neoplasms; Sirolimus; Stomatitis

Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved for the treatment of advanced renal cell carcinoma, pancreatic neuroendocrine tumors, subependymal giant cell astrocytoma associated with tuberous sclerosis complex, renal angiomyolipoma and tuberous sclerosis complex, and, in combination with exemestane, for hormone receptor-positive HER2-negative advanced breast cancer after failure of treatment with letrozole or anastrozole. Results from the phase III BOLERO-2 trial demonstrated that everolimus in combination with exemestane provided significant clinical benefit to patients with advanced hormone receptor-positive breast cancer. Although everolimus is generally well tolerated, as with most therapies administered in an advanced cancer setting, drug-related adverse events (AEs) inevitably occur. Most common AEs observed in the everolimus studies include stomatitis, rash, infection, noninfectious pneumonitis, and hyperglycemia. Clinical awareness and early identification of such AEs by oncology nurses are essential to dosing (interruptions, reduction, and treatment discontinuation); quality of life; and, ultimately, patient outcomes. Because everolimus has already been shown to significantly improve clinical efficacy in patients with advanced breast cancer, a proactive approach to the practical management of AEs associated with this mTOR inhibitor as well as other most common AEs observed in this patient population has been reviewed and outlined here.

Topics: Adult; Androstadienes; Antineoplastic Agents; Breast Neoplasms; Clinical Trials, Phase III as Topic; Everolimus; Exanthema; Female; Humans; Hyperglycemia; Pneumonia; Sirolimus; Stomatitis; Treatment Outcome

Everolimus is an orally available inhibitor of the mammalian target of rapamycin (mTOR), which has been approved in combination with exemestane for hormone receptor-positive (HR) breast cancer after failure of treatment with non-steroidal aromatase inhibitors. Everolimus is generally very well tolerated with most common side effects including stomatitis, rash, fatigue, hyperglycemia, hyperlipidemia, and myelosuppression. Most of these side effects are mild and resolve with dose interruptions or dose reductions. Symptomatic non-infectious pneumonitis is a relatively uncommon class effect of mTOR inhibitors, which can be life threatening. Given the efficacy of everolimus in HR-positive metastatic breast cancer, it is crucial for physicians to recognize toxicities related to everolimus and start timely interventions. This review will focus on the adverse events reported with everolimus in breast cancer trials and will provide practical guidelines for the management of these adverse events.

Topics: Antineoplastic Agents; Breast Neoplasms; Everolimus; Fatigue; Female; Humans; Hyperglycemia; Hyperlipidemias; Pneumonia; Sirolimus; Stomatitis; TOR Serine-Threonine Kinases

We conducted a systematic review of the literature and performed a meta-analysis to determine the risk of developing skin rash and stomatitis among patients receiving temsirolimus.. Databases from PubMed and Web of Science from January, 1998 until June, 2011 and abstracts presented at the American Society of Clinical Oncology annual meetings from 2004 through 2011 were searched to identify relevant studies. The incidence and relative risk (RR) of skin rash and stomatitis were calculated using random-effects or fixed-effects model depending on the heterogeneity of included studies.. A total of 779 patients from 10 clinical trials were included in this analysis. The overall incidence of all-grade rash was 45.8% (95% confidence interval (CI): 35.6-56.3%), with a RR of 7.6 (95%CI: 4.4-13.3; p<0.001). The overall incidence of high-grade rash was 3.3% (95%CI: 1.9-5.6%), with a RR of 13.70 (95%CI: 0.82-227.50, p=0.07). The overall incidence of all-grade stomatitis was 44.3% (CI: 32.1-57.1%), with a RR of 11.10, 95%CI: 5.60-22.00; p<0.001). The overall incidence of high-grade stomatitis was 3.2% (95%CI: 1.9-5.4%), with a RR of 13.2 (95%CI: 0.80-218.50, p=0.07).. There is a significant risk of developing skin rash and stomatitis in cancer patients receiving temsirolimus. The risk is independent of underlying tumour. Adequate monitoring and early intervention are recommended to prevent debilitating toxicity and suboptimal dosing.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Exanthema; Humans; Incidence; Protein Kinase Inhibitors; Risk Factors; Sirolimus; Stomatitis

Everolimus (RAD001), a mTOR inhibitor, was initially used as an immunosuppressant in organ transplant patients; however, it also has significant antineoplastic properties. In patients with subependymal giant cell astrocytomas (SEGAs) associated with tuberous sclerosis complex who are not candidates for surgery, single-agent everolimus has demonstrated the ability to significantly reduce SEGA volume with good tolerability. In the Phase III, randomized, placebo-controlled trial, everolimus was associated with a SEGA response rate of 35% compared with 0% in the placebo group. The most common adverse events in clinical trials were stomatitis/mouth ulceration and upper respiratory tract infections, and most adverse events were grade 1 or 2; grade 4 events were rare.

Topics: Animals; Antineoplastic Agents; Astrocytoma; Clinical Trials as Topic; Everolimus; Humans; Oral Ulcer; Sirolimus; Stomatitis; TOR Serine-Threonine Kinases; Tuberous Sclerosis

In April 2009, an expert group of 11 physicians and clinical nurses met to discuss the management of selected adverse events associated with the use of everolimus for the treatment of metastatic renal cell carcinoma (mRCC). Everolimus is an orally administered inhibitor of the mammalian target of rapamycin that recently received approval from the European Medicines Agency for the treatment of advanced RCC that has progressed on or after treatment with vascular endothelial growth factor (VEGF)-targeted therapy, and from the United States Food and Drug Administration for treatment of advanced RCC after failure of sorafenib or sunitinib. Before the approval of everolimus, no standard therapy existed for the treatment of mRCC after failure of VEGF-targeted therapy. RECORD-1 (Renal Cell cancer treatment with Oral RAD001 given Daily) was the pivotal multicenter, phase III, randomised, double-blind, placebo-controlled trial of everolimus that led to approval for patients with disease progression on or after treatment with VEGF-targeted agents. Safety data from RECORD-1 were reviewed by these clinicians, all of whom had experience using everolimus in patients with mRCC. Adverse events discussed were non-infectious pneumonitis, infections, stomatitis and metabolic abnormalities.. The outcome of this discussion is summarised here. Guidance for management of these adverse events is provided. Both clinicians and patients should be aware of the potential side-effects of everolimus and understand that these side-effects are manageable with standard care to optimise patient benefit.

Topics: Aged; Carcinoma, Renal Cell; Clinical Trials as Topic; Disease Progression; Everolimus; Humans; Immunosuppressive Agents; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Placebos; Pneumonia; Randomized Controlled Trials as Topic; Research Design; Risk; Sirolimus; Stomatitis; Time Factors; Treatment Outcome

Although surgery remains the primary curative treatment for renal cell carcinoma (RCC), systemic therapy also is indicated in the advanced disease setting. This article reviews the role of mammalian target of rapamycin inhibitors in the treatment of metastatic RCC. A case study is presented to illustrate side-effect management issues commonly encountered by oncology nurses in clinical practice.

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Drug Eruptions; Drug Monitoring; Everolimus; Female; Humans; Intracellular Signaling Peptides and Proteins; Kidney Neoplasms; Middle Aged; Oncology Nursing; Pneumonia; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Sirolimus; Stomatitis; TOR Serine-Threonine Kinases

Stomatitis is one of the main reasons to discontinue everolimus in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC). To decrease stomatitis and subsequently early treatment discontinuations or dose reductions, the DESIREE trial investigated the use of a stepwise dose-escalation schedule of everolimus (EVE esc).. DESIREE is a phase II, multicentre, randomised, double-blind, placebo-controlled trial in patients with HR+/HER2- mBC and progression/relapse after nonsteroidal aromatase inhibitor treatment. Patients were randomised to EVE esc (2.5 mg/day, week 1; 5 mg/day, week 2; 7.5 mg/day, week 3; 10 mg/day, weeks 4-24) or everolimus 10 mg/day (EVE 10mg) for 24 weeks plus exemestane. The primary endpoint was the incidence of stomatitis episodes grade ≥2 within 12 weeks of treatment. The secondary endpoints included toxicity, relative total dose intensity (RTDI) and quality of life (QoL).. A total of 160 patients were randomised and 156 started treatment (EVE esc: 80; EVE 10mg: 76). The median age of patients was 64 years (range 33-85), 56.3% patients in the EVE esc arm versus 42.1% in the EVE 10mg arm had liver metastasis (P = 0.081) and 62.5% versus 51.3% received over one metastatic therapy line (P = 0.196). Within 12 weeks, the incidence of stomatitis episodes grade ≥2 was significantly lower in the EVE esc arm compared with the EVE 10mg arm (28.8% versus 46.1%; odds ratio 0.47, 95% confidence interval 0.24-0.92; P = 0.026). Toxicity was in line with the known safety profile without new safety concerns. The median RTDI was 91.1% in the EVE esc arm versus 80.0% in the EVE 10mg arm (P = 0.329). Discontinuation rate in the first 3 weeks was 6.3% versus 15.8%, respectively (P = 0.073). QoL was comparable between the two treatment arms.. A dose-escalation schema of everolimus over 3 weeks can be successfully used to reduce the incidence of high-grade stomatitis in the first 12 weeks of treatment in patients with HR+/HER2- mBC.. ClinicalTrials.govNCT02387099; https://clinicaltrials.gov/ct2/show/NCT02387099.

Topics: Adult; Aged; Aged, 80 and over; Breast Neoplasms; Everolimus; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Quality of Life; Receptor, ErbB-2; Sirolimus; Stomatitis

To determine whether treatment with tacrolimus plus sirolimus (Tac/Sir) as a prophylaxis for graft-versus-host disease worsens severe oral mucositis and delays healing compared to cyclosporine plus methotrexate (CsA/Mtx) following haematopoietic stem cell transplantation.. The study comprised 141 patients: 73 randomized to receive Tac/Sir and 68 to receive CsA/Mtx. The oral mucositis assessment scale and toxicity grading according to WHO were used to assess the severity, peak and duration of oral mucositis from the day -3 to day 24 post-transplant.. Eighty-seven patients developed oral mucositis in the first 24 days post-transplant. No significant difference in oral mucositis severity between the Tac/Sir and CsA/Mtx groups was observed. The peak oral mucositis score occurred on day 10 in both groups. Although oral mucositis scores had returned to baseline in the CsA/Mtx group on day 24 post-transplant, no significant difference compared with the Tac/Sir group was found.. The introduction of tacrolimus/sirolimus as a graft-versus-host disease prophylaxis in haematopoietic stem cell transplantation increased neither the incidence nor severity of oral mucositis compared with cyclosporine/methotrexate. Furthermore, oral mucositis healing was not prolonged and followed the same time pattern as cyclosporine/methotrexate.

Topics: Cyclosporine; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Methotrexate; Sirolimus; Stomatitis; Tacrolimus

Combining the mTOR inhibitor ridaforolimus and the anti-IGFR antibody dalotuzumab demonstrated antitumor activity, including partial responses, in estrogen receptor (ER)-positive advanced breast cancer, especially in high proliferation tumors (Ki67 > 15%).. This randomized, multicenter, international, phase II study enrolled postmenopausal women with advanced ER-positive breast cancer previously treated with a nonsteroidal aromatase inhibitor (NCT01234857). Patients were randomized to either oral ridaforolimus 30 mg daily for 5 of 7 days (once daily [qd] × 5 days/week) plus intravenous dalotuzumab 10 mg/kg/week or oral exemestane 25 mg/day, and stratified by Ki67 status. Due to a high incidence of stomatitis in the ridaforolimus-dalotuzumab group, two sequential, nonrandomized, reduced-dose cohorts were explored with ridaforolimus 20 and 10 mg qd × 5 days/week. The primary endpoint was progression-free survival (PFS).. Median PFS was 21.4 weeks for ridaforolimus 30 mg qd × 5 days/week plus dalotuzumab 10 mg/kg (n = 29) and 24.3 weeks for exemestane (n = 33; hazard ratio = 1.00; P = 0.5). Overall survival and objective response rates were similar between treatment arms. The incidence of drug-related, nonserious, and serious adverse events was higher with ridaforolimus/dalotuzumab (any ridaforolimus dose) than with exemestane. Lowering the ridaforolimus dose reduced the incidence of grade 3 stomatitis, but overall toxicity remained higher than acceptable at all doses without improved efficacy.. The combination of ridaforolimus plus dalotuzumab was no more effective than exemestane in patients with advanced ER-positive breast cancer, and the incidence of adverse events was higher. Therefore, the combination is not being further pursued.

Topics: Adult; Aged; Androstadienes; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Breast Neoplasms; Disease-Free Survival; Female; Humans; Middle Aged; Protein Kinase Inhibitors; Receptors, Estrogen; Sirolimus; Stomatitis

Lymphangioleiomyomatosis is a rare lung disease caused by proliferation of abnormal smooth muscle-like cells and typically occurs in premenopausal women. Sirolimus is now the first-line drug for the treatment of lymphangioleiomyomatosis. Sirolimus-induced stomatitis is the most frequent adverse event experienced during treatment. To identify risk factors, we investigated the association of stomatitis incidence with patient background data and treatment parameters, using data from the multicenter long-term sirolimus trial.. Subjects received sirolimus for 2 years at doses adjusted to maintain a trough blood level of 5 to 15 ng/mL. The incidence of stomatitis was correlated with baseline demographics, clinical characteristics, and changes in the longitudinal data. Risk factors at baseline were assessed by using univariate and multivariate analyses.. The most frequent adverse event was stomatitis, with the cumulative rate reaching 88.9% by 9 months, higher than that reported in postrenal transplant patients. The repetition, the duration, and the severity of stomatitis events were variable among patients. We found that patients with low hemoglobin (Hb) (<14.5 g/dL) showed significantly higher incidence than those with high Hb (≥14.5 g/dL, P < .01). The cumulative rate for stomatitis incidence was significantly associated with a decrease in the mean corpuscular volume, while the Hb level was constant; thus, red blood cell count in patients increased during the study.. Baseline Hb levels and a decrease in mean corpuscular volume during treatment were correlated with the incidence of stomatitis.

Topics: Adult; Antibiotics, Antineoplastic; Erythrocyte Indices; Female; Hemoglobins; Humans; Incidence; Japan; Lung Neoplasms; Lymphangioleiomyomatosis; Middle Aged; Multivariate Analysis; Prospective Studies; Risk Factors; Sirolimus; Stomatitis

Ridaforolimus is an investigational, potent, selective mTOR inhibitor. This study was conducted to determine the recommended phase 2 dose (RP2D), maximum tolerated dose, safety, pharmacokinetics, and antitumor activity of oral ridaforolimus in children with advanced solid tumors.. In this phase 1, multicenter, open-label study in children aged 6 to <18 years with advanced solid tumors, ridaforolimus was administered orally for 5 consecutive days/week in 28-day cycles until progression, unacceptable toxicity, or consent withdrawal. Dose started at 22 mg/m2 and increased to 28 mg/m2 and 33 mg/m2, followed by expansion at the RP2D.. Twenty patients were treated; 18 were evaluable for dose-limiting toxicities. One dose-limiting toxicity (grade 3 increased alanine aminotransferase) occurred in 1 patient at 33 mg/m2. Dose escalation concluded at 33 mg/m2; the maximum tolerated dose was not determined. The most common treatment-related adverse events (frequency ≥40%) were manageable grade 1-2 stomatitis, thrombocytopenia, hypertriglyceridemia, increased alanine aminotransferase, fatigue, hypercholesterolemia, anemia, and increased aspartate aminotransferase. Ridaforolimus exposure at 28 mg/m2 and 33 mg/m2 exceeded adult target levels. The RP2D for oral ridaforolimus in children was defined as 33 mg/m2. Four patients received at least 4 cycles; 2 with pineoblastoma and diffuse intrinsic pontine glioma had stable disease for 12 and 46 cycles, respectively.. Ridaforolimus is orally bioavailable and well tolerated in children with advanced solid tumors. The RP2D (33 mg/m2, 5 days/week) exceeds the adult RP2D. The favorable toxicity and pharmacokinetic profiles may allow for combination therapy, a promising therapeutic option in pediatric malignancies.

Topics: Administration, Oral; Adolescent; Adult; Antineoplastic Agents; Child; Combined Modality Therapy; Drug Dosage Calculations; Female; Humans; Male; Neoplasm Staging; Neoplasms; Sirolimus; Stomatitis; TOR Serine-Threonine Kinases

Human epidermal growth factor (HER) -mediated signaling is critical in many cancers, including subsets of breast and lung cancer. HER family members signal via the phosphatidylinositide 3-kinase (PI3K) -AKT/protein kinase B-mammalian target of rapamycin (mTOR) cascade; mTOR activation is critical for the expression of multiple contributors to tumor growth and invasion. On the basis of preclinical data suggesting synergy of HER2 inhibition and mTOR inhibition in breast and lung cancer models, we conducted a phase I combination study of neratinib, a small-molecule irreversible pan-HER tyrosine kinase inhibitor, and temsirolimus, an mTOR inhibitor, in patients with advanced solid tumors.. This study enrolled patients to dosing combinations of neratinib and temsirolimus. The primary objective was to estimate the toxicity contour of the combination and establish recommended phase II doses.. Sixty patients were treated on 12 of 16 possible dosing combinations. Diarrhea was the most common drug-related (93%) and dose-limiting toxicity (DLT), constituting four of 10 DLTs. Dose-limiting grade 3 metabolic abnormalities were also observed. Other frequent drug-related toxicities included nausea, stomatitis (both 53%), and anemia (48%). Two maximum-tolerated dose combinations were identified: 200 mg of neratinib/25 mg of temsirolimus and 160 mg of neratinib/50 mg of temsirolimus. Responses were noted in patients with HER2-amplified breast cancer resistant to trastuzumab, HER2-mutant non-small-cell lung cancer, and tumor types without identified mutations in the HER-PI3K-mTOR pathway.. The combination of neratinib and temsirolimus was tolerable and demonstrated antitumor activity in multiple tumor types, warranting further evaluation.

Topics: Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Breast Neoplasms; Diarrhea; Dose-Response Relationship, Drug; Female; Gene Amplification; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Nausea; Neoplasms; Phosphatidylinositol 3-Kinases; Quinolines; Receptor, ErbB-2; Signal Transduction; Sirolimus; Stomatitis; TOR Serine-Threonine Kinases; Treatment Outcome

Everolimus is an oral raptor mTOR inhibitor and has shown activity in patients with Waldenstrom's macroglobulinemia (WM). This study examines a large cohort of patients with relapsed/refractory WM with long-term follow up for survival. Patients were eligible if they had measurable disease, a platelet count >75,000 x 10(6)/L, an absolute neutrophil count >1,000 x 10(6)/L. Patients received everolimus 10 mg PO daily and were evaluated monthly. A success was defined as a complete or partial response (PR); minor responses (MR) were recorded and considered to be of clinical benefit. Sixty patients were enrolled and treated. The overall response rate (ORR) was 50% (all PR); the clinical benefit rate including MR or better was 73% (95% CI: 60-84%) with 23% MR. The median time to response for patients who achieved PR was 2 months (range, 1-26). The median duration of response has not been reached and median progression-free survival (PFS) was 21 months. Grade 3 or higher toxicities (at least possibly related to everolimus) were observed in 67% of patients. The most common grade 3 or 4 toxicities were anemia (27%), leukopenia (22%), and thrombocytopenia (20%). Other nonhematological toxicities were diarrhea (5%), fatigue (8%), stomatitis (8%) and pulmonary toxicity (5%). Everolimus has a high single-agent activity of 73% including MR, with a progression free survival of 21 months, indicating that this agent is active in relapsed/refractory WM.

Topics: Adult; Aged; Aged, 80 and over; Alkylating Agents; Angiogenesis Inhibitors; Antibodies, Monoclonal, Murine-Derived; Antimetabolites; Bone Marrow; Diarrhea; Disease-Free Survival; Drug Resistance; Everolimus; Fatigue; Female; Hematologic Diseases; Humans; Immunoglobulin M; Kaplan-Meier Estimate; Male; Middle Aged; Pain; Paraproteins; Recurrence; Rituximab; Sirolimus; Stomatitis; TOR Serine-Threonine Kinases; Treatment Outcome; Waldenstrom Macroglobulinemia

Grades 2-4 acute graft-versus-host disease (GVHD) occurs in approximately 35% of matched, related donor (MRD) allogeneic hematopoietic cell transplantation (HCT) recipients. We sought to determine if the combination of tacrolimus and sirolimus (Tac/Sir) was more effective than tacrolimus and methotrexate (Tac/Mtx) in preventing acute GVHD and early mortality after allogeneic MRD HCT in a phase 3, multicenter trial. The primary end point of the trial was to compare 114-day grades 2-4 acute GVHD-free survival using an intention-to-treat analysis of 304 randomized subjects. There was no difference in the probability of day 114 grades 2-4 acute GVHD-free survival (67% vs 62%, P = .38). Grades 2-4 GVHD was similar in the Tac/Sir and Tac/Mtx arms (26% vs 34%, P = .48). Neutrophil and platelet engraftment were more rapid in the Tac/Sir arm (14 vs 16 days, P < .001; 16 vs 19 days, P = .03). Oropharyngeal mucositis was less severe in the Tac/Sir arm (peak Oral Mucositis Assessment Scale score 0.70 vs 0.96, P < .001), but otherwise toxicity was similar. Chronic GVHD, relapse-free survival, and overall survival at 2 years were no different between study arms (53% vs 45%, P = .06; 53% vs 54%, P = .77; and 59% vs 63%, P = .36). Based on similar long-term outcomes, more rapid engraftment, and less oropharyngeal mucositis, the combination of Tac/Sir is an acceptable alternative to Tac/Mtx after MRD HCT. This study was funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute; and the trial was registered at www.clinicaltrials.gov as #NCT00406393.

Topics: Adolescent; Adult; Allografts; Disease-Free Survival; Female; Follow-Up Studies; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Methotrexate; Middle Aged; Sirolimus; Stomatitis; Survival Rate; Tacrolimus; Time Factors

Tuberous sclerosis complex is a genetic disorder leading to constitutive activation of mammalian target of rapamycin (mTOR) and growth of benign tumours in several organs. In the brain, growth of subependymal giant cell astrocytomas can cause life-threatening symptoms--eg, hydrocephalus, requiring surgery. In an open-label, phase 1/2 study, the mTOR inhibitor everolimus substantially and significantly reduced the volume of subependymal giant cell astrocytomas. We assessed the efficacy and safety of everolimus in patients with subependymal giant cell astrocytomas associated with tuberous sclerosis complex.. In this double-blind, placebo-controlled, phase 3 trial, patients (aged 0-65 years) in 24 centres in Australia, Belgium, Canada, Germany, the UK, Italy, the Netherlands, Poland, Russian Federation, and the USA were randomly assigned, with an interactive internet-response system, in a 2:1 ratio to oral everolimus 4·5 mg/m(2) per day (titrated to achieve blood trough concentrations of 5-15 ng/mL) or placebo. Eligible patients had a definite diagnosis of tuberous sclerosis complex and at least one lesion with a diameter of 1 cm or greater, and either serial growth of a subependymal giant cell astrocytoma, a new lesion of 1 cm or greater, or new or worsening hydrocephalus. The primary endpoint was the proportion of patients with confirmed response--ie, reduction in target volume of 50% or greater relative to baseline in subependymal giant cell astrocytomas. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00789828.. 117 patients were randomly assigned to everolimus (n=78) or placebo (n=39). 27 (35%) patients in the everolimus group had at least 50% reduction in the volume of subependymal giant cell astrocytomas versus none in the placebo group (difference 35%, 95% CI 15-52; one-sided exact Cochran-Mantel-Haenszel test, p<0·0001). Adverse events were mostly grade 1 or 2; no patients discontinued treatment because of adverse events. The most common adverse events were mouth ulceration (25 [32%] in the everolimus group vs two [5%] in the placebo group), stomatitis (24 [31%] vs eight [21%]), convulsion (18 [23%] vs ten [26%]), and pyrexia (17 [22%] vs six [15%]).. These results support the use of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis. Additionally, everolimus might represent a disease-modifying treatment for other aspects of tuberous sclerosis.. Novartis Pharmaceuticals.

Topics: Adolescent; Adult; Astrocytoma; Child; Child, Preschool; Double-Blind Method; Everolimus; Female; Fever; Humans; Infant; Male; Oral Ulcer; Seizures; Sirolimus; Stomatitis; Treatment Outcome; Tuberous Sclerosis; Young Adult

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

To determine sirolimus steady-state pharmacokinetics, and to assess the relationship between time-normalized trough sirolimus concentration (C(min,TN)) and evidence of efficacy (rejection and death) and adverse reactions (stomatitis and pneumonia) in liver allograft patients.. Dense sampling of sirolimus was performed over a single daily-dosing interval in 11 hepatic allograft recipients on day 28 and at 3 months after start of treatment. Serial trough concentration sampling was performed in 380 hepatic allograft recipients on days 1, 7, 14, 28, 42, 60, 90, 180, 270 and 360 after start of treatment. Occurrence of stomatitis, pneumonia, rejection, and death were collected for 360 days after start of treatment. Noncompartmental pharmacokinetic parameters were analyzed in the 11 densely sampled patients; C(min,TN) was determined in the 380 patients.. Mean maximum concentration (C(max)), time to C(max) (t(max)), area under the curve for the given dose interval (AUC(tau)), and whole blood oral clearance at 3 months were 20.8 ± 7.6 ng/mL, 3 ± 1 h, 338 ± 144 ng·h/mL, and 10.0 ± 5.6 L/hr, respectively. In the 11 densely sampled patients, linear regression showed that C(min,TN) was highly predictive of AUC(tau) (r² = 0.77, P < 0.0001) at each analysis time point. Logistic regression showed a relationship between C(min,TN) in the 380 patients and pneumonia occurrence, but not between C(min,TN) and stomatitis, rejection, or death.. In this study, the pharmacokinetic profile of sirolimus in hepatic allograft patients was consistent with that of renal transplantation recipients. With the exception of pneumonia, no correlation was observed between C(min,TN) and the occurrence of adverse events of interest.

Topics: Adult; Female; Graft Rejection; Hepatic Insufficiency; Humans; Immunosuppressive Agents; Incidence; Liver; Liver Transplantation; Male; Metabolic Clearance Rate; Middle Aged; Pneumonia; Risk; Severity of Illness Index; Sirolimus; Stomatitis; Transplantation, Homologous

Resistance to endocrine therapy in breast cancer is associated with activation of the mammalian target of rapamycin (mTOR) intracellular signaling pathway. In early studies, the mTOR inhibitor everolimus added to endocrine therapy showed antitumor activity.. In this phase 3, randomized trial, we compared everolimus and exemestane versus exemestane and placebo (randomly assigned in a 2:1 ratio) in 724 patients with hormone-receptor-positive advanced breast cancer who had recurrence or progression while receiving previous therapy with a nonsteroidal aromatase inhibitor in the adjuvant setting or to treat advanced disease (or both). The primary end point was progression-free survival. Secondary end points included survival, response rate, and safety. A preplanned interim analysis was performed by an independent data and safety monitoring committee after 359 progression-free survival events were observed.. Baseline characteristics were well balanced between the two study groups. The median age was 62 years, 56% had visceral involvement, and 84% had hormone-sensitive disease. Previous therapy included letrozole or anastrozole (100%), tamoxifen (48%), fulvestrant (16%), and chemotherapy (68%). The most common grade 3 or 4 adverse events were stomatitis (8% in the everolimus-plus-exemestane group vs. 1% in the placebo-plus-exemestane group), anemia (6% vs. <1%), dyspnea (4% vs. 1%), hyperglycemia (4% vs. <1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%). At the interim analysis, median progression-free survival was 6.9 months with everolimus plus exemestane and 2.8 months with placebo plus exemestane, according to assessments by local investigators (hazard ratio for progression or death, 0.43; 95% confidence interval [CI], 0.35 to 0.54; P<0.001). Median progression-free survival was 10.6 months and 4.1 months, respectively, according to central assessment (hazard ratio, 0.36; 95% CI, 0.27 to 0.47; P<0.001).. Everolimus combined with an aromatase inhibitor improved progression-free survival in patients with hormone-receptor-positive advanced breast cancer previously treated with nonsteroidal aromatase inhibitors. (Funded by Novartis; BOLERO-2 ClinicalTrials.gov number, NCT00863655.).

Topics: Adult; Aged; Aged, 80 and over; Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Bone Neoplasms; Breast Neoplasms; Disease-Free Survival; ErbB Receptors; Everolimus; Female; Humans; Kaplan-Meier Estimate; Middle Aged; Postmenopause; Recurrence; Sirolimus; Stomatitis; TOR Serine-Threonine Kinases

Ridaforolimus, a potent inhibitor of the mammalian target of rapamycin (mTOR), is under development for the treatment for solid tumors. This open-label, randomized, 3-period crossover study investigated the effect of food on the pharmacokinetics of ridaforolimus 40 mg as well as safety and tolerability of the study medication.. Ridaforolimus was administered to 18 healthy, male subjects (mean age 36.4 years) in the fasted state, following ingestion of a light breakfast, and following a high-fat breakfast. Whole blood samples were collected from each subject pre-dose and 1, 2, 3, 4, 6, 8, 24, 48, 72, 96, and 168 h post-dose.. The geometric mean (95 % confidence interval, CI) fasted blood area under the curve (AUC(0-∞)) and maximum concentration (C(max)) were 1940 (1510, 2500) ng h/mL and 116 (87, 156) ng/mL, respectively, and median time to C(max) (T(max)) and average apparent terminal half-life (t(1/2)) were 6.0 and 64.5 h, respectively. Both T(max) and t(1/2) were similar in the fasted and fed states. With a light breakfast, the geometric mean intra-individual ratios (GMRs) for AUC(0-∞) and C(max) (fed/fasted) and 90 % CIs were 1.06 (0.85, 1.32) and 1.15 (0.83, 1.60); following a high-fat breakfast, the AUC(0-∞) and C(max) GMRs (90 % CI) were 1.46 (1.18, 1.81) and 1.12 (0.81, 1.53), respectively.. Increases in ridaforolimus exposure following both the light and high-fat breakfasts were not considered to be clinically meaningful. Ridaforolimus was generally well tolerated, and there were no discontinuations due to drug-related AEs. Ridaforolimus should be given without regard to food.

Topics: Adult; Area Under Curve; Biological Availability; Cross-Over Studies; Dietary Fats; Fasting; Food-Drug Interactions; Humans; Male; Metabolic Clearance Rate; Sirolimus; Stomatitis; Time Factors; Tonsillitis; Young Adult

Temsirolimus, an inhibitor of the mammalian target of rapamycin, is approved for treatment of patients with advanced renal cell carcinoma in the USA and Europe. Temsirolimus was not yet evaluated in East Asian patients.. This non-randomized Phase II study enrolled 82 patients with advanced renal cell carcinoma [20 (24%) Japanese, 30 (37%) Korean and 32 (39%) Chinese patients; median age (range): 55 (26-83) years]. Most (71%) received prior systemic therapy for metastatic disease; two-thirds were intermediate risk. Six Japanese patients received intravenous temsirolimus 20 mg/m(2) weekly for tolerability assessment (Group A); the remaining 76 received a 25 mg flat dose weekly (Group B). Temsirolimus was dosed once weekly. Primary efficacy end point was the Response Evaluation Criteria in Solid Tumors-defined clinical benefit rate in the intent-to-treat population.. In the entire population, regardless of treatment group, the clinical benefit rate was 48% (95% confidence interval: 36, 59). Objective response rate was 11% (95% confidence interval: 5, 20), median progression-free survival was 7.3 months (95% confidence interval: 4.0, 9.2) and median time to treatment failure was 5.4 months (95% confidence interval: 3.5, 7.4). No patient in Group A demonstrated dose-limiting toxicity. The most frequent Grade 3 or 4 drug-related adverse events were anemia, hyperglycemia, hypophosphatemia and stomatitis (5% each). Serious adverse events reported in ≥ 5% of patients were pneumonia (9%) and interstitial lung disease (7%). Temsirolimus and its major metabolite, sirolimus, were long-lived throughout the dosage interval, with no evidence of accumulation.. Temsirolimus was well tolerated and showed promising activity in Japanese, Korean and Chinese patients with advanced renal cell carcinoma.

Topics: Adult; Aged; Anemia; Antineoplastic Agents; Asian People; Carcinoma, Renal Cell; Disease-Free Survival; Drug Administration Schedule; Female; Humans; Hyperglycemia; Hypophosphatemia; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Outpatients; Protein Kinase Inhibitors; Sirolimus; Stomatitis; 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

Temsirolimus (CCI-779) is a novel inhibitor of the mammalian target of rapamycin. This Phase 1 study was aimed at investigating the maximum-tolerated dose, toxicity, pharmacokinetics and antitumor activity in Japanese patients with advanced solid tumors.. Temsirolimus was given as a 30 min intravenous infusion once a week. Patients with solid tumors not amenable to standard forms of treatment were eligible. Dose escalation of temsirolimus was planned from 15, 45, 80 to 165 mg/m(2). The pharmacokinetics of temsirolimus and sirolimus in whole blood were examined for cycles 1, 2, 4 and 5 of treatment.. Ten patients (median age 60.5 years; range 41-69 years) with advanced solid tumors were enrolled. Their primary cancers were renal cell carcinoma (five patients), lung cancer (three patients) and colorectal cancer (two patients). The major toxicities were hypophosphatemia diarrhea, hyperglycemia, stomatitis, pyrexia, elevated aspartate aminotransferase, rash, reduced neutrophil count, elevated alanine aminotransferase, anorexia, hypertriglyceridemia and somnolence. Two of three patients who received temsirolimus 45 mg/m(2) developed dose-limiting toxicities of Grade 3 stomatitis (one patient) and Grade 3 diarrhea (two patients). The maximum-tolerated dose was 15 mg/m(2). The peak blood concentrations of temsirolimus and sirolimus, a major active metabolite, increased in a dose-dependent manner. The area under the concentration-versus-time curve of sirolimus, but not temsirolimus, increased in a dose-dependent manner.. The recommended dose for Phase 2 clinical studies of temsirolimus in Japanese patients with advanced solid tumors is 15 mg/m(2) intravenously once a week.

Topics: Adult; Aged; Anti-Allergic Agents; Antineoplastic Agents; Area Under Curve; Carcinoma, Renal Cell; Colorectal Neoplasms; Diarrhea; Diphenhydramine; Disorders of Excessive Somnolence; Drug Administration Schedule; Drug Eruptions; Fever; Humans; Hyperglycemia; Hypertriglyceridemia; Hypophosphatemia; Infusions, Intravenous; Intestinal Perforation; Kidney Neoplasms; Lung Neoplasms; Maximum Tolerated Dose; Middle Aged; Neoplasms; Neutropenia; Premedication; Sirolimus; Stomatitis; Treatment Outcome

Concurrent inhibition of multiple oncogenic signaling pathways might improve the efficacy of anticancer agents and abrogate resistance mechanisms. This phase I study evaluated temsirolimus in combination with sunitinib in patients with advanced RCC.. Eligibility included advanced RCC and or= 7 days) were observed in 2 of 3 patients. One patient experienced grade 3 rash during week 3, which led to treatment discontinuation. A second patient had grade 3 thrombocytopenia (platelet count, 48,000/microL), cellulitis, and gout during week 3 and was hospitalized; platelets recovered to 109,000/microL 4 days after discontinuation of protocol therapy. A third patient experienced rash, asthenia, diarrhea, stomatitis, constipation, fever, and rectal hemorrhage, all of which were mild in severity. The study was terminated because of dose-limiting toxicity observed at low starting doses of both agents.. Concomitant use of I.V. temsirolimus 15 mg weekly and oral sunitinib 25 mg daily (4 weeks on, 2 weeks off) is not recommended.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Cellulitis; Diarrhea; Drug Eruptions; Female; Humans; Indoles; Infusions, Intravenous; Kidney Neoplasms; Male; Middle Aged; Pyrroles; Sirolimus; Stomatitis; Sunitinib; Thrombocytopenia; Treatment Outcome

We report the 48-month results of a trial testing whether withdrawal of cyclosporine (CsA) from a sirolimus (SRL)-CsA-steroid (ST) regimen would impact renal allograft survival. Eligible patients receiving SRL-CsA-ST from transplantation were randomly assigned at 3 months to remain on triple therapy (SRL-CsA-ST, n = 215) or to have CsA withdrawn and SRL trough concentrations increased (SRL-ST, n = 215). SRL-ST therapy resulted in significantly better graft survival, either when including death with a functioning graft as an event (84.2% vs. 91.5%, P = 0.024) or when censoring it (90.6% vs. 96.1%, P = 0.026). Calculated glomerular filtration rate (43.8 vs. 58.3 ml/min, P < 0.001) and mean arterial blood pressure (101.3 vs. 97.1 mmHg, P = 0.047) were also improved with SRL-ST. Differences in the incidences of biopsy-proven acute rejection after randomization (6.5% vs. 10.2%, SRL-CsA-ST versus SRL-ST, respectively) and mortality (7.9% vs. 4.7%) were not significant. SRL-CsA-ST-treated patients had significantly higher incidences of adverse events generally associated with CsA, whereas those in the SRL-ST group experienced greater frequencies of events commonly related to higher trough levels of SRL. In conclusion, early withdrawal of CsA from a SRL-CsA-ST regimen rapidly improves renal function and ultimately results in better graft survival.

Topics: Adrenal Cortex Hormones; Cyclosporine; Drug Therapy, Combination; Follow-Up Studies; Glomerular Filtration Rate; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Patient Compliance; Sirolimus; Stomatitis; Survival Analysis; Time Factors

The aim of this study was to evaluate the association between axitinib, sunitinib and temsirolimus toxicities and patient survival in metastatic renal cell cancer patients. Overall survival (OS) and progression-free survival (PFS) of metastatic renal cell cancer patients from the prospective multicenter STAR-TOR study were assessed using multivariable Cox models. A total of 1195 patients were included (n = 149 axitinib; n = 546 sunitinib; n = 500 temsirolimus). The following toxicities significantly predicted outcomes: hand-foot skin reaction (hazard ratio [HR] = 0.29) for PFS with axitinib; stomatitis (HR = 0.62) and pneumonitis (HR = 0.23) for PFS with temsirolimus; stomatitis (HR = 0.52) and thrombocytopenia (HR = 0.6) for OS with temsirolimus; fatigue (HR = 0.71) for PFS with sunitinib; hand-foot skin reaction (HR = 0.56) and fatigue (HR = 0.58) for OS with sunitinib. In conclusion, in metastatic renal cell cancer, axitinib, sunitinib and temsirolimus demonstrate specific toxicities that are protective OS/PFS predictors.

Topics: Aged; Axitinib; Carcinoma, Renal Cell; Chemotherapy, Adjuvant; Disease Progression; Fatigue; Female; Hand-Foot Syndrome; Humans; Incidence; Kidney Neoplasms; Male; Middle Aged; Nephrectomy; Pneumonia; Prognosis; Progression-Free Survival; Prospective Studies; Protective Factors; Risk Assessment; Sirolimus; Stomatitis; Sunitinib; Thrombocytopenia

Background Signal transduction inhibitors (STIs) have considerably improved treatment of advanced/metastasized renal cell carcinoma (mRCC). Most safety data for these drugs are derived from clinical trials. The purpose of this study was to evaluate which adverse drug reactions are documented during first-line treatments in routine clinical practice. Patients and methods The ongoing prospective German mRCC clinical registry is recruiting patients in 110 oncology and urology outpatient centers. Data from the first 250 patients who had completed first-line treatment were analyzed regarding adverse drug reactions (ADRs) documented in patients' medical records. Results Patients were older than in clinical trials and had comorbidities. Patients were treated with the STIs sunitinib (61%), temsirolimus (14%), sorafenib (10%), or bevacizumab combined with interferon (6%). About 520 ADRs were documented, of which 29% resulted in treatment modifications. The most frequently affected organ system was the gastrointestinal system. The most frequently documented ADRs were mucositis/stomatitis (14%), fatigue (14%), diarrhea (12%), and nausea (12%). Conclusions In routine practice, mRCC first-line treatments using STIs frequently lead to ADRs partly necessitating treatment modifications. The pattern of reported ADRs is similar to that reported in clinical trials, but frequencies of events differ, especially for symptoms of multifactorial origin that are not immediately associated with the treatment. These results indicate that perception and documentation of adverse reactions is different between clinical trials and routine practice, and that reviews of patients' medical records might not be the best method to assess safety in routine practice.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Renal Cell; Diarrhea; Documentation; Fatigue; Female; Germany; Humans; Indoles; Interferons; Kidney Neoplasms; Male; Medical Oncology; Middle Aged; Nausea; Niacinamide; Phenylurea Compounds; Prospective Studies; Pyrroles; Registries; Sirolimus; Sorafenib; Stomatitis; Sunitinib

Mammalian targets of rapamycin inhibitors (mTOR inhibitors, mTORI) are indicated for the management of several cancer types, including hormone receptor--positive or HER2-negative breast cancer, advanced renal cell carcinoma, advanced neuroendocrine tumors of pancreatic origin, and tuberous sclerosis complex-related tumors. Among the most common adverse events of mTORI medication are discrete, large, solitary or multiple, superficial ulcers, almost exclusively situated on nonkeratinized oral mucosa, described as mTORI-associated stomatitis (mIAS). We describe the clinical presentation, course, and management of mIAS in three patients receiving the mTORI everolimus (Afinitor, Novartis, East Hanover, NJ). In two patients, mIAS manifested 9 and 30 days after first using everolimus, respectively, whereas in the third patient, it recurred 3 months after re-introduction of everolimus. Oral rinses with a "magic mouthwash" solution (dexamethasone oral drops solution 2 mg/mL × 10 mL, lidocaine gel 2% × 30 g, doxycycline suspension 50 mg/5 mL × 60 mL, and sucralfate oral suspension 1000 mg/5 mL × 150 mL, dissolved in sodium chloride 0.9% × 2000 mL) four times daily proved helpful in alleviating the symptoms, and the ulcers healed in 4 to 15 days. No side effects were recorded, and dose reduction or discontinuation of everolimus was not necessitated in two cases.

Topics: Aged; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Renal Cell; Everolimus; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Sirolimus; Stomatitis

The mammalian target of rapamycin (mTOR) inhibitor sirolimus is effective in reducing incidence of graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Agents that inhibit the mTOR pathway are known to be associated with significant and potentially dose-limiting toxicities, including stomatitis. The objective of this study was to report the clinical features and management outcomes of sirolimus-associated oral ulcers in the context of post-HSCT prophylaxis of GVHD. Seventeen patients, from a study cohort of 967, who were treated with sirolimus as prophylaxis for GVHD after allogeneic HSCT at the Dana-Farber/Brigham and Women's Cancer Center developed oral ulcers and were referred to the oral medicine clinic for evaluation and treatment over a period of 6 years. Clinical characteristics (appearance, anatomic site, size) and therapeutic outcomes (time to complete resolution) were documented. Median time to onset of oral ulceration was 55 days after allogeneic HSCT (range, 6 to 387 days); 92.9% of ulcers were located on nonkeratinized mucosa, with the ventrolateral tongue the most common site of involvement. Thirteen patients were treated with topical corticosteroid therapy; 12 of these patients also required intralesional corticosteroid injections. Clinical improvement (resolution of the lesions and improvement of symptoms) was noted in all cases, with no reported adverse events. Median time to complete resolution after onset of therapy was 14 days (range, 2 to 70 days). Patients receiving sirolimus for GVHD prophylaxis may develop painful oral ulcerations, which can be effectively managed with topical steroid treatment. Further prospective studies are needed to better elucidate the incidence of this complication, identify risk factors, and evaluate the effectiveness of interventions.

Topics: Adult; Aged; Allografts; Female; Graft vs Host Disease; Hematopoietic Stem Cells; Humans; Immunosuppressive Agents; Male; Middle Aged; Retrospective Studies; Sirolimus; Stomatitis; Time Factors; TOR Serine-Threonine Kinases

Oral mucositis (OM) is a side effect of intensive chemotherapy and radiation and has been reported to affect 75-100% of hematopoietic stem cell transplantation (HSCT) recipients. The purpose of this study was to compare the incidence of OM in patients conditioned with myeloablative conditioning (MAC) to reduced-intensity conditioning (RIC) and to determine the effect of a new oral care protocol.. The study involved 171 HSCT recipients, with hematological malignancies transplanted between 2007 and 2011. Median age of the patients was 50 years (range 12-71). Ninety-nine (58%) received RIC and 72 received MAC. Clinical features of OM were recorded from day -3 before to day +25 after HSCT using the World Health Organization (WHO) scoring system and the oral mucositis assessment score (OMAS).. Overall, 87% of the patients developed OM of any severity, which peaked on days 10-11. The mean WHO score was 1.7. In multivariate analysis, the severity of OM was associated with MAC (relative hazard (RH) 1.57, 95% confidence interval (CI) 1.37-1.80, p < 0.001), all donor-recipient gender combinations except female-to-male (RH = 1.26, 95% CI 1.10-1.4, p = 0.001), and early year of HSCT (RH = 0.84, 95%CI 0.7-0.96, p = 0.013). There was a correlation between long hospitalization and OM (day 15, r = 0.31, p < 0.001). There was a good correlation between the WHO and OMAS scoring systems for OM (r = 0.74, p < 0.001).. Oral mucositis was reduced in patients treated with RIC and in patients treated during recent years, when oral care was intensified. Increased scores of OM prolonged hospitalization.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child; Cyclophosphamide; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Multivariate Analysis; Oral Hygiene; Prednisone; Sirolimus; Stomatitis; Transplantation Conditioning; Vidarabine; Whole-Body Irradiation; Young Adult

Everolimus is indicated for the therapy of adults with advanced renal cell carcinoma after failure of treatment with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI). The aim of the study was a multicenter evaluation of efficiency and toxicity of everolimus in patients with metastatic renal carcinoma who received one line of VEGFR-TKI therapy. Data of one hundred and one patients were analyzed retrospectively. Patients received everolimus therapy between January 2010 and July 2013. Data were collected in 7 different oncology institutes in Hungary. Starting daily dose of everolimus was 10 mg in 28-day cycles. Physical and laboratory examinations were done monthly. Imaging tests were performed every 3 months. Tumor response and toxicity were evaluated according to RECIST 1.0 and NCI CTCAE 3.0, respectively. Statistical analysis was performed with SPPS version 20.0 for Windows. Currently 26 (27%) patients are being treated, 52 (54.1%) patients are alive. Median progression-free survival (PFS) was 5.7 months (95% CI 4.07-7.33). Partial remission, stable disease and progression occurred in 6 (6%), 71 (74%) and 19 (20%) patients, respectively. Median overall survival (OS) was 14.3 months (95% CI 6.99-19.81). PFS and OS results were more favorable in patients with ECOG 0-1. Survival was poorer in case of anemia, while better if PFS was longer than 12 months. In anemic patients with ECOG 0-1 and ECOG 2-3 OS was 30.9 and 7.7 months, respectively (p=0.031). Dose reduction and treatment delay happened in 8 (7.9%) and 12 (11.9%) cases, respectively. The most common side effects were the following: exanthema, edema, stomatitis, pneumonitis, anemia and abnormal kidney-, liver functions, blood sugar and cholesterol levels. According to the Hungarian experience, everolimus can safely be administered. PFS and OS results representing the centers' everyday practice, are similar to the results of the respective subgroups in the registration study.. Az everolimus elõrehaladott vesesejtes carcinoma kezelésére javallt, vascularis endothelialis növekedési faktor receptor (VEGFR) tirozinkináz-gátló (TKI) kezelést követõen. A vizsgálat célja metasztatikus veserákban szenvedõ betegeknél egy vonalban alkalmazott VEGFR-TKI kezelés utáni everolimusterápia hatékonyságának és toxicitási profiljának multicentrikus értékelése volt. 2010. 01.–2013. 07. között hazánk 7 onkológiai intézményében 101 betegnél indult everolimusterápia retrospektív elemzése. Az induló dózis 10 mg volt naponta, 28 napos ciklusokban. Fizikális és laborvizsgálat havonta, képalkotó kontroll 3 havonta történt. A tumorválaszt RECIST 1.0, a toxicitást NCI CTCAE 3.0 szerint értékeltük. Jelenleg 26 (27%) beteg kezelése zajlik, 52 beteg (54,1%) él. A medián progressziómentes túlélés (PFS) 5,7 hónap. Részleges remisszió 6 (6%), stabil betegség 71 (74%), progresszió 19 (20%). A medián teljes túlélés (OS) 14,3 hónap. A jobb általános állapotú (ECOG 0-1) betegek PFS és OS eredménye kedvezõbb volt. A túlélést csökkentette a fellépõ anémia (p=0,037), viszont javította a 12 hónapon túli PFS (p=0,001). A OS ECOG 0-1 és nem anémiás betegeknél 30,9, míg ECOG 2-3 és anémia esetén 7,7 hónap (p=0,031) volt. Dózisredukció 8 (7,9%), terápiahalasztás 12 (11,9%) esetben történt. Leggyakoribb mellékhatások: bõrkiütés, ödéma, stomatitis, pneumonitis, anémia, valamint vesefunkció-, májfunkció-, vércukor- és koleszterinszint-emelkedés. A hazai gyakorlatban szerzett tapasztalatok alapján az everolimus biztonsággal alkalmazható mTOR-gátló szer. A centrumok napi gyakorlata során elért PFS és OS hasonló a törzskönyvezõ vizsgálat megfelelõ alcsoportjainak eredményeihez.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Drug Administration Schedule; Drug Eruptions; Edema; Everolimus; Female; Humans; Hungary; Kidney Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Retrospective Studies; Sirolimus; Stomatitis; Treatment Failure; Treatment Outcome

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

Everolimus (EVE; an inhibitor of mammalian target of rapamycin [mTOR]) enhances treatment options for postmenopausal women with hormone-receptor-positive (HR(+)), human epidermal growth factor receptor-2-negative (HER2(-)) advanced breast cancer (ABC) who progress on a non-steroidal aromatase inhibitor (NSAI). This is especially true for patients with visceral disease, which is associated with poor prognosis. The BOLERO-2 (Breast cancer trial of OraLEveROlimus-2) trial showed that combination treatment with EVE and exemestane (EXE) versus placebo (PBO)+EXE prolonged progression-free survival (PFS) by both investigator (7.8 versus 3.2 months, respectively) and independent (11.0 versus 4.1 months, respectively) central assessment in postmenopausal women with HR(+), HER2(-) ABC recurring/progressing during/after NSAI therapy. The BOLERO-2 trial included a substantial proportion of patients with visceral metastases (56%).. Prespecified exploratory subgroup analysis conducted to evaluate the efficacy and safety of EVE+EXE versus PBO+EXE in a prospectively defined subgroup of patients with visceral metastases.. At a median follow-up of 18 months, EVE+EXE significantly prolonged median PFS compared with PBO+EXE both in patients with visceral metastases (N=406; 6.8 versus 2.8 months) and in those without visceral metastases (N=318; 9.9 versus 4.2 months). Improvements in PFS with EVE+EXE versus PBO+EXE were also observed in patients with visceral metastases regardless of Eastern Cooperative Oncology Group performance status (ECOG PS). Patients with visceral metastases and ECOG PS 0 had a median PFS of 6.8 months with EVE+EXE versus 2.8 months with PBO+EXE. Among patients with visceral metastases and ECOG PS ≥1, EVE+EXE treatment more than tripled median PFS compared with PBO+EXE (6.8 versus 1.5 months).. Adding EVE to EXE markedly extended PFS by ≥4 months among patients with HR(+) HER2(-) ABC regardless of the presence of visceral metastases.

Topics: Aged; Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials, Phase III as Topic; Everolimus; Exanthema; Fatigue; Female; Follow-Up Studies; Humans; Kaplan-Meier Estimate; Middle Aged; Multicenter Studies as Topic; Neoplasm Metastasis; Placebos; Postmenopause; Prognosis; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Receptors, Steroid; Sirolimus; Stomatitis; Treatment Outcome; Viscera

The aim of the study was to assess the safety and efficacy of everolimus therapy for advanced renal cell carcinoma in Japanese patients receiving real-world care.. Patients who had been treated with everolimus for advanced renal cell carcinoma at 39 Japanese medical centers between January 2010 and November 2011 were retrospectively investigated to assess adverse events and the time to treatment failure.. A total of 180 patients were identified. Their median age was 65 years (range 23-93). The median time to treatment failure was 2.9 months (95% confidence interval 2.4-3.4). The median time to treatment failure was significantly longer in patients with dose modification (4.2 months; 95% confidence interval 3.4-5.0) than in patients without dose modification (1.7 months; 95% confidence interval 1.0-2.3; P < 0.01) after experiencing adverse events. Stomatitis (44%) was the most frequent adverse event, followed by thrombocytopenia (31%), anemia (22%), interstitial pneumonia (22%) and hyperglycemia (17%). Interstitial pneumonia was the most frequent cause of discontinuation in patients who discontinued everolimus due to intolerability regardless of the dose modification status. None of the patients with dose modification of everolimus discontinued everolimus due to thrombocytopenia or leukopenia.. The adverse event profile of everolimus may differ between Japanese and Caucasian patients. Dose modification of everolimus might be associated with longer treatment duration in patients with advanced renal cell carcinoma. Further studies are required to clarify this association. Interstitial pneumonia may be difficult to overcome by dose modification.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Drug Administration Schedule; Everolimus; Female; Humans; Hyperglycemia; Japan; Kaplan-Meier Estimate; Kidney Neoplasms; Lung Diseases, Interstitial; Male; Middle Aged; Retrospective Studies; Sirolimus; Stomatitis; Thrombocytopenia; Treatment Outcome

Anti-cancer agents that inhibit the mTOR pathway are associated with a number of unique toxicities, with one of the most significant and potentially dose-limiting being stomatitis. The objective of this study was to report the clinical features and management outcomes of a series of cancer patients who developed painful mTOR inhibitor-associated stomatitis (mIAS). Seventeen cancer patients developed mIAS while being treated with everolimus- or ridaforolimus-containing protocols at the Dana-Farber Cancer Institute and were referred to the oral medicine clinic for evaluation and management. Clinical characteristics, toxicity management, and outcomes were summarized. In addition, the frequency and rationale for dose reductions and therapy discontinuation were assessed. The median duration of mTOR inhibitor therapy was 80 days (range 9-187 days). The median time to development of mouth ulcers was 10 days (range 4-25 days). Five patients required protocol-directed dose reductions due to grades 2 and 3 stomatitis and one patient discontinued cancer treatment due to mouth ulcers. Clinical improvement and pain relief was reported in 86.6% of patients following topical, intralesional, or systemic corticosteroid therapy, with side effects limited to secondary candidiasis (n=2). Mouth ulcers are a common and potentially dose limiting toxicity associated with the use of mTOR inhibitors in cancer treatment. This case series demonstrates that local and systemic corticosteroid therapy is an effective approach to managing patients with symptomatic mIAS. Prospective studies are necessary to evaluate the effectiveness of treatment and prevention strategies with the ultimate goal of improving overall cancer treatment outcomes.

Topics: Adrenal Cortex Hormones; Adult; Aged; Everolimus; Female; Humans; Male; Middle Aged; Neoplasms; Retrospective Studies; Sirolimus; Stomatitis; TOR Serine-Threonine Kinases; Treatment Outcome

Mammalian target of rapamycin (mTOR) inhibitors may have efficacy as an intervention for advanced malignancies. Oral ulceration (OU), reported as mucositis, has been a dose-limiting toxicity for this new class of agents. An analysis of the appearance, course, and toxicity associations of mTOR inhibitor-associated stomatitis (mIAS) demonstrated that the condition is distinct from conventional mucositis (CM) and more closely resembles aphthous stomatitis.. Safety data from 78 solid tumor patients enrolled in 2 Phase 1, multicenter trials of the mTOR inhibitor deforolimus (AP23573, MK-8669) were evaluated. Adverse events (AEs) based on National Cancer Institute Common Toxicity Criteria for National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0) criteria were coded, consolidated, and stratified according to the presence or absence and duration of concordant OU. The relation between OU and other AEs was analyzed.. Treatment-emergent AEs were reported in 91% of 78 study participants. OUs were reported in 66%, appeared within 5 days of deforolimus administration, and were discrete, ovoid, superficial, well demarcated, and surrounded by an erythematous halo. Their clinical appearance and distribution were similar to that of aphthous stomatitis but inconsistent with CM. Patients with OU were more likely to have nonspecific rashes and acneiform dermatitis but not gastrointestinal AEs.. OU associated with mTOR inhibitor therapy differed from CM. Lesions more closely resembled those of aphthous stomatitis. The lack of other gastrointestinal involvement but the presence of a higher incidence of concomitant cutaneous AEs provided additional evidence to suggest a distinction between mIAS and CM. Treatment strategies for aphthous stomatitis may be a rational approach for the prevention and control of mIAS.

Topics: Adult; Aged; Antineoplastic Agents; Clinical Trials, Phase I as Topic; Female; Humans; Intracellular Signaling Peptides and Proteins; Male; Middle Aged; Mucositis; Neoplasms; Protein Serine-Threonine Kinases; Sirolimus; Stomatitis; TOR Serine-Threonine Kinases

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

Oral mucositis occurs in up to 75% of recipients of high-dose chemoradiotherapy conditioning regimens used for allogeneic hematopoietic stem cell transplantation (HSCT). As a result of mucositis, narcotic analgesia and total parenteral nutrition (TPN) are commonly required after HSCT. Methotrexate, an antiproliferative graft-versus-host disease (GVHD) prophylaxis agent, impairs mucosal regeneration and worsens and prolongs mucositis. We assessed the effect of substituting sirolimus for methotrexate as GVHD prophylaxis on outcomes associated with mucositis. Two patient cohorts undergoing allogeneic HLA-matched related donor peripheral blood stem cell transplantation with cyclophosphamide/total body irradiation conditioning were prospectively analyzed for mucositis severity and retrospectively reviewed for correlative outcomes. GVHD prophylaxis consisted of sirolimus/tacrolimus (ST) in the study group and tacrolimus/methotrexate (TM) in the control group. Thirty patients received ST and 24 patients received TM as GVHD prophylaxis between October 2000 and May 2003. Mild, moderate, and severe mucositis was noted in 37%, 57%, and 7% of the ST group and 8%, 42%, and 50% of the TM group (P = .0002). Less TPN was used in the ST group than the TM group (17% versus 43% of posttransplantation hospital days; P = .02). The total number of narcotic days was lower in the ST group in comparison with the TM group (median, 13.5 versus 17 days; P = .08). The time to first hospital discharge was shorter in the ST group compared with the TM group (median, 18 versus 22 days; P = .07). The substitution of sirolimus for methotrexate as GVHD prophylaxis is associated with a reduction in mucositis severity. As a result, TPN and narcotic use are reduced, and hospitalization duration is shortened. Less toxic GVHD prophylaxis regimens without methotrexate may have a significant effect on patient quality of life, patient outcomes, and economic outcomes associated with allogeneic stem cell transplantation.

Topics: Adult; Cohort Studies; Drug Evaluation; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Length of Stay; Male; Methotrexate; Middle Aged; Mouth Mucosa; Premedication; Retrospective Studies; Sirolimus; Stomatitis; Tacrolimus; Transplantation, Homologous; Treatment Outcome