***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: PURPOSE The oral mammalian target of rapamycin inhibitor everolimus demonstrated promising efficacy in a phase II study of pretreated advanced gastric cancer . This international , double-blind , phase III study compared everolimus efficacy and safety with that of best supportive care ( BSC ) in previously treated advanced gastric cancer . PATIENTS AND METHODS Patients with advanced gastric cancer that progressed after one or two lines of systemic chemotherapy were r and omly assigned to everolimus 10 mg/d ( assignment schedule : 2:1 ) or matching placebo , both given with BSC . R and omization was stratified by previous chemotherapy lines ( one v two ) and region ( Asia v rest of the world [ ROW ] ) . Treatment continued until disease progression or intolerable toxicity . Primary end point was overall survival ( OS ) . Secondary end points included progression-free survival ( PFS ) , overall response rate , and safety . RESULTS Six hundred fifty-six patients ( median age , 62.0 years ; 73.6 % male ) were enrolled .  Median OS was 5.4 months with everolimus and 4.3 months with placebo ( hazard ratio , 0.90 ; 95 % CI , 0.75 to 1.08 ; P = .124 ) . Median PFS was 1.7 months and 1.4 months in the everolimus and placebo arms , respectively ( hazard ratio , 0.66 ; 95 % CI , 0.56 to 0.78 ) . Common grade 3/4 adverse events included anemia , decreased appetite , and fatigue . The safety profile was similar in patients enrolled in Asia versus ROW . CONCLUSION Compared with BSC , everolimus did not significantly improve overall survival for advanced gastric cancer that progressed after one or two lines of previous systemic chemotherapy . The safety profile observed for everolimus was consistent with that observed for everolimus in other cancers OBJECTIVE We report the clinical features and management outcomes in 7 patients with everolimus-related stomatitis . STUDY DESIGN Fifteen women with hormone-receptor-positive advanced breast cancer receiving everolimus combined with exemestane  were prospect ively evaluated to assess the development of stomatitis . Oral ulcers were diagnosed based on established criteria . RESULTS 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 . CONCLUSIONS 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 BACKGROUND We tested the oral mammalian target of rapamycin ( mTOR ) inhibitor everolimus in addition to paclitaxel in patients with HER2-negative tumours not responding to initial neoadjuvant cytotoxic and anti-angiogenic treatment . METHODS Patients with primary HER2-negative tumours received four neoadjuvant cycles of epirubicin/cyclophosphamide ( EC ) with or without bevacizumab .  Patients without clinical response were r and omised to receive weekly paclitaxel ( 80 mg/m(2 ) ) with or without everolimus ( 5 mg p.o . daily , after a step-wise dose-escalation starting from 2.5 mg bid ) for 12 weeks before surgery . To detect an increase in pathological complete response ( pCR ; ypT0 ypN0 ) from 5 % to 12.1 % ( odds ratio 2.62 ) 566 patients had to be recruited . The trial was stopped prematurely due to completion of accrual in the main study . FINDINGS Of 1948 patients initially starting neoadjuvant treatment 403 were r and omised . A total of 18 ( 4.6 % ) patients , 7 ( 3.6 % ) treated with paclitaxel and everolimus and 11 ( 5.6 % ) treated with paclitaxel alone had a pCR ( odds ratio 0.36 ( OR ) ( 95 % confidence interval ( CI ) , 0.24 - 1.6 ) p=0.34 ) . Overall response rate in breast and lymph nodes at surgery was 52.2 % after paclitaxel plus everolimus and 61.7 % after paclitaxel alone ( p=0.063 ) . Breast conserving treatment was performed in 54.4 % of patients with the combination treatment and 61.9 % with paclitaxel alone ( p=0.20 ) . Mucosal inflammation , thrombocytopenia , neutropenia , infection , and skin rash were more frequent when everolimus was added to paclitaxel . INTERPRETATION Neoadjuvant therapy with everolimus and paclitaxel for patients with HER2-negative disease unresponsive to EC with or without bevacizumab did not improve the pCR rate . Long-term outcome is awaited . FUNDING Novartis , Roche , and Sanofi-Aventis 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 protocol s 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 grade s 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 c and idiasis ( 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 . Prospect i ve studies are necessary to evaluate the effectiveness of treatment and prevention strategies with the ultimate goal of improving overall cancer treatment outcomes PURPOSE Cross-talk between the estrogen receptor ( ER ) and the phosphoinositide-3-kinase (PI3K)/Akt/mammalian target of rapamycin ( mTOR ) pathways is a mechanism of resistance to endocrine therapy , and blockade of both pathways enhances antitumor activity in pre clinical models . This study explored whether sensitivity to letrozole was enhanced with the oral mTOR inhibitor , everolimus ( RAD001 ) . PATIENTS AND METHODS Two hundred seventy postmenopausal women with operable ER-positive breast cancer were r and omly assigned to receive 4 months of neoadjuvant treatment with letrozole ( 2.5 mg/day ) and either everolimus ( 10 mg/day ) or placebo . The primary end point was clinical response by palpation . M and atory biopsies were obtained at baseline and after 2 weeks of treatment ( ie , day 15 ) . Sample s were assessed for PI3 K mutation status ( PIK3CA ) and for pharmacodynamic changes of Ki67 , phospho-S6 , cyclin D1 , and progesterone receptor ( PgR ) by immunohistochemistry . RESULTS Response rate by clinical palpation in the everolimus arm was higher than that with letrozole alone ( ie , placebo ; 68.1 % v 59.1 % ) , which was statistically significant at the preplanned , one-sided , alpha = 0.1 level ( P = .062 ) . Marked reductions in progesterone receptor and cyclin D1 expression occurred in both treatment arms , and dramatic downregulation of phospho-S6 occurred only in the everolimus arm . An antiproliferative response , as defined by a reduction in Ki67 expression to natural logarithm of percentage positive Ki67 of less than 1 at day 15 , occurred in 52 ( 57 % ) of 91 patients in the everolimus arm and in 25 ( 30 % ) of 82 patients in the placebo arm ( P < .01 ) . The safety profile was consistent with historical results of everolimus monotherapy ; grade s 3 to 4 adverse events occurred in 22.6 % of patients who received everolimus and in 3.8 % of patients who received placebo . CONCLUSION Everolimus significantly increased letrozole efficacy in neoadjuvant therapy of patients with ER-positive breast cancer BACKGROUND Interferon alfa is widely used for metastatic renal-cell carcinoma but has limited efficacy and tolerability .  Temsirolimus , a specific inhibitor of the mammalian target of rapamycin kinase , may benefit patients with this disease . METHODS In this multicenter , phase 3 trial , we r and omly assigned 626 patients with previously untreated , poor-prognosis metastatic renal-cell carcinoma to receive 25 mg of intravenous temsirolimus weekly , 3 million U of interferon alfa ( with an increase to 18 million U ) subcutaneously three times weekly , or combination therapy with 15 mg of temsirolimus weekly plus 6 million U of interferon alfa three times weekly . The primary end point was overall survival in comparisons of the temsirolimus group and the combination-therapy group with the interferon group . RESULTS Patients who received temsirolimus alone had longer overall survival ( hazard ratio for death , 0.73 ; 95 % confidence interval [ CI ] , 0.58 to 0.92 ; P=0.008 ) and progression-free survival ( P<0.001 ) than did patients who received interferon alone . Overall survival in the combination-therapy group did not differ significantly from that in the interferon group ( hazard ratio , 0.96 ; 95 % CI , 0.76 to 1.20 ; P=0.70 ) . Median overall survival times in the interferon group , the temsirolimus group , and the combination-therapy group were 7.3 , 10.9 , and 8.4 months , respectively . Rash , peripheral edema , hyperglycemia , and hyperlipidemia were more common in the temsirolimus group , whereas asthenia was more common in the interferon group . There were fewer patients with serious adverse events in the temsirolimus group than in the interferon group ( P=0.02 ) . CONCLUSIONS As compared with interferon alfa , temsirolimus improved overall survival among patients with metastatic renal-cell carcinoma and a poor prognosis . The addition of temsirolimus to interferon did not improve survival . ( Clinical Trials.gov number , NCT00065468 [ Clinical Trials.gov ] . ) BACKGROUND Oral ulcers is a well-recognised adverse event ( AE ) of mTOR inhibitors . Paradoxically , little is known about its natural history , risk factors , and basic management . PATIENTS AND METHODS AEs of 79 patients prospect ively enrolled in 6 phase I-II studies testing everolimus  were review ed . The following parameters were analysed : incidence , severity , duration and associated AE . The association between OU and everolimus dose , pharmacokinetics and the effectiveness of empiric treatments were explored . RESULTS OU , grade 3 - 4 OU , prolonged time under OU and RCOU ( recurrent and chronic oral ulcer ) were observed in 72 % 11 % , 30 % and 25 % patients , respectively . Patients with antecedent of prior chemotherapy , with PS 1 , or receiving everolimus in combination tended to present higher rates of prolonged time under OU and of grade 3 - 4 OU . As everolimus daily dose increased , the median time to OU was shorter , the median duration was longer and OU incidence tended to increase . Simultaneously , OU tended to be associated with higher everolimus exposure . None of the empiric treatments appeared effective against OU ( preventive or curative intent ) . CONCLUSION Everolimus-induced  OU is a frequent , recurrent and sometimes harmful complication . A dose effect relationship is displayed . Its daily management remains challenging . OU represents a key issue in the compliance of mTOR inhibitors BACKGROUND Disease progression in patients with HER2-positive breast cancer receiving trastuzumab might be associated with activation of the PI3K/Akt/mTOR intracellular signalling pathway . We 
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On subgroup analysis , there was no statistically significant difference between everolimus and temsirolimus in the risk of relevant adverse events .
CONCLUSIONS 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 .