***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: This report summarizes the U.S. Food and Drug Administration ( FDA ) 's approval of temsirolimus ( Torisel ) , on May 30 , 2007 , for the treatment of advanced renal cell carcinoma ( RCC ) . Information provided includes regulatory history , study design , study results , and literature review . A multicenter , three-arm , r and omized , open-label study was conducted in previously untreated patients with poor-prognosis , advanced RCC . The study objectives were to compare overall survival ( OS ) , progression-free survival ( PFS ) , objective response rate , and safety in patients receiving interferon (IFN)-alpha  versus those receiving temsirolimus alone or in combination with IFN-alpha . In the second planned interim analysis of the intent-to-treat population ( n = 626 ) , there was a statistically significant longer OS time in the temsirolimus ( 25 mg ) arm than in the IFN-alpha arm ( median , 10.9 months versus 7.3 months ; hazard ratio [ HR ] , 0.73 ; p = .0078 ) . The combination of temsirolimus ( 15 mg ) and IFN-alpha did not lead to a significant difference in OS compared with IFN-alpha alone . There was also a statistically significant longer PFS time for the temsirolimus ( 25 mg ) arm than for the IFN-alpha arm ( median , 5.5 months versus 3.1 months ; HR , 0.66 , p = .0001 ) . Common adverse reactions reported in patients receiving temsirolimus were rash , asthenia , and mucositis . Common laboratory abnormalities were anemia , hyperglycemia , hyperlipidemia , and hypertriglyceridemia . Serious but rare cases of interstitial lung disease , bowel perforation , and acute renal failure were observed . Temsirolimus has demonstrated superiority in terms of OS and PFS over IFN-alpha and provides an additional treatment option for patients with advanced RCC Pre clinical studies indicate autophagy inhibition with hydroxychloroquine ( HCQ ) can augment the efficacy of DNA-damaging therapy . The primary objective of this trial was to determine the maximum tolerated dose ( MTD ) and efficacy of HCQ in combination with radiation therapy ( RT ) and temozolomide ( TMZ ) for newly diagnosed glioblastoma ( GB ) . A 3 + 3 phase I trial design followed by a noncomparative phase II study was conducted in GB patients after initial resection . Patients received HCQ ( 200 to 800 mg oral daily ) with RT and concurrent and adjuvant TMZ . Quantitative electron microscopy and immunoblotting were used to assess changes in autophagic vacuoles ( AVs ) in peripheral blood mononuclear cells ( P BMC ) . Population pharmacokinetic ( PK ) modeling enabled PK-pharmacodynamic correlations . Sixteen phase I subjects were evaluable for dose-limiting toxicities . At 800 mg HCQ/d , 3/3 subjects experienced Grade 3 and 4 neutropenia and thrombocytopenia , 1 with sepsis .  HCQ 600 mg/d was found to be the MTD in this combination . The phase II cohort ( n = 76 ) had a median survival of 15.6 mos with survival rates at 12 , 18 , and 24 mo of 70 % , 36 % , and 25 % . PK analysis indicated dose-proportional exposure for HCQ . Significant therapy-associated increases in AV and LC3-II were observed in P BMC and correlated with higher HCQ exposure . These data establish that autophagy inhibition is achievable with HCQ , but dose-limiting toxicity prevented escalation to higher doses of HCQ . At HCQ 600 mg/d , autophagy inhibition was not consistently achieved in patients treated with this regimen , and no significant improvement in overall survival was observed . Therefore , a definitive test of the role of autophagy inhibition in the adjuvant setting for glioma patients awaits the development of lower-toxicity compounds that can achieve more consistent inhibition of autophagy than HCQ Context The median survival for patients with glioblastoma multiforme is 1 year despite aggressive treatment . Chloroquine interferes with cellular mechanisms that might cause treatment resistance . Content In this single-center , r and omized , double-blind , placebo-controlled trial , 30 patients receiving surgery , chemotherapy , and radiotherapy for glioblastoma multiforme were r and omly assigned to receive chloroquine or placebo for 12 months . Median survival was 24 months for patients who received chloroquine and 11 months for patients who received placebo . No patient stopped therapy because of toxicity . Limitations The number of patients was small , and the difference in survival was not statistically significant ( P= 0.139 ) . Implication s Chloroquine , in conjunction with other treatments , may prolong survival in patients with glioblastoma multiforme . Larger clinical trials are needed . The Editors Despite numerous advances in the diagnosis of glioblastoma multiforme , there have been relatively few advances in therapy , and the prognosis of patients with this disorder has not changed considerably during the past decades . Recent studies have shown that median survival after aggressive treatment combining surgery , radiotherapy , and chemotherapy is approximately 1 year ( 1 - 4 ) . Even the most sophisticated approaches , such as stereotactic radiosurgery , have failed to improve survival or quality of life ( 5 ) . There are 2 main reasons that explain the high rate of therapeutic failure : the infiltrative nature of glioblastoma multiforme and the presence of cancer cells resistant to radiotherapy and chemotherapy . The latter might be due to the unrestricted growth of resistant cell clones within the original tumor , which replace those cells initially susceptible , or to the emergence of new mutant cell clones resistant to the treatment . This phenomenon could be prompted by the high rate of mutagenesis of malignant glial cells , which is increased by both ionizing radiation and antineoplastic drugs ( 1 , 2 , 4 , 6 ) . Antimalarial drugs , particularly chloroquine and quinacrine , are strong DNA-intercalating agents and are lysosomotropic ; both actions in eukaryotic cells modify several cell functions . In cells with a high mitotic rate , such as cancer cells , chloroquine and quinacrine are antimutagenic ( 7 , 8) ; however , they are not cytotoxic or antimitotic and do not exhibit a substantial antineoplastic effect ( 9 ) . In cultured glioma cells and in malignant glioma in rats , we have shown that these substances have a strong potentiating effect on the antineoplastic action of carmustine and maintain the long-term susceptibility of malignant glioma cells to chemotherapy ( 10 ) . On the basis of these experimental findings , we conducted a preliminary , open-label trial on patients with glioblastoma multiforme by administering chloroquine in addition to surgery and to the st and ard courses of radiotherapy and chemotherapy ; when compared with concurrent controls , survival was statistically significantly longer in chloroquine-treated patients ( 6 ) . After that initial experience , we conducted the present double-blind , placebo-controlled study of chloroquine as adjuvant therapy for patients with glioblastoma multiforme . Methods Patient Recruitment , Enrollment , and Follow-up During a 40-month period ( October 2000 to January 2004 ) , 120 patients with clinical suspicion of a malignant brain tumor were screened at the National Institute of Neurology and Neurosurgery of Mexico . Of these patients , 30 participated in the present study . All patients fulfilled the following inclusion criteria : glioblastoma multiforme , which was confirmed by 2 independent pathologists on the histologic specimen obtained at surgery ; fair clinical neurologic status with a Karnofsky performance score of 70 or higher at the time of diagnosis ; absence of associated severe disorders , such as diabetes and hypertension ; evidence on magnetic resonance imaging ( MRI ) scans that the tumor was restricted to 1 hemisphere of the brain ; and age younger than 60 years . Intervention All patients participating in the study received the same conventional scheme of chemotherapy and radiotherapy : extensive tumor ablation by surgery ; 4 courses of carmustine at 200 mg/m2 , one given every 5 weeks and the first given 8 weeks after surgery ; and radiotherapy that began 3 weeks after surgery , for a total radiation dose of 60 Gy ( 6000 rads ) separated in 30 to 32 courses with daily fractionated doses . All patients and their legal guardians signed the informed consent document , clearly stating their willingness to participate in a r and omized , double-blind , placebo-controlled trial . Chloroquine tablets ( Aralen , Sanofi-Synthelabo , Mexico City , Mexico ) , 150 mg , were commercially purchased , and identical placebo tablets were formulated ; treatments were r and omly distributed into 15 chloroquine and 15 placebo sets ( each set was design ed for 1-year treatment ) and were coded at the laboratory of an independent investigator at another institution . We received the 30 sets coded and numbered , and they were administered in sequential order as the patients entered the trial . The study monitor sealed and kept the code until the end of the study . Therefore , the participants , those administering the treatment , and those assessing the outcomes were blinded to group assignment . Chloroquine was administered at 150 mg/d , starting on day 5 after surgery , and was continued for 12 months ; in a nontrial setting , chemotherapy and radiotherapy would have been completed before 12 months had passed . The dose of chloroquine used in this study was selected on the basis of several pharmacologic studies on toxicity , long-term administration , and antimalarial effectiveness ( 6 , 7 ) ; it is also identical to the dose used in our preliminary study ( 6 ) . The assignment of treatments was decodified in January 2005 , when all patients had had surgery at least 1 year previously , and the follow-up continued until October 2005 . Our institutional review board of research and the institutional board of ethics both approved the study . This study complied with the Consoli date d St and ards for Reporting Trials ( CONSORT ) items for a r and omized trial ( 11 ) . Primary and Secondary Outcomes Clinical evaluation after hospital discharge was done every 2 weeks , and MRI studies were done every 2 months . Tumor size was measured on the MRI scan taken before surgery ; the largest diameter of the tumor on the axial planes was considered as a single value . Primary outcome was survival after surgery . Karnofsky score was determined at the time of diagnosis , 1 month after surgery , and 5 months after surgery . Signs of systemic toxicity induced by the therapy were studied monthly by routine analysis of peripheral blood , which included hematic biometry , blood chemistry , and hepatic tests . In addition , potential signs of drug toxicity in the retina as a result of chloroquine treatment were monitored monthly by ophthalmoscopic evaluation in all patients . Statistical Analysis KaplanMeier survival curves were plotted . Survival times in the 2 groups were compared by using the hazard ratio and 95 % CI from a bivariate Cox regression . Statistical significance was assessed with the log-rank test . Other statistical comparisons were made by using the unpaired t-test and the Fisher exact test ( SPSS , version 10.0 , SPSS Inc. , Chicago , Illinois ) . Role of the Funding Source This work was conducted at the National Institute of Neurology and Neurosurgery of Mexico , which is a public institution without any commercial interests . Partial support was obtained by a grant from Consejo Nacional de Ciencia y Tecnologa ( CONACyT ) , which is the federal agency for support of scientific research in Mexico . The agency did not participate in the design , conduct , analysis , or reporting of this study . No pharmaceutical companies participated in any part of the study . Results Patient Characteristics and Follow-up In the chloroquine group , the duration of symptoms and the diameter of the tumor were greater but the average age of the patients was slightly lower than in the placebo group ; otherwise , the characteristics of patients were similar in the 2 groups ( Table ) . Maximum , minimum , and median follow-ups were 59 , 5 , and 15 months , respectively . Radiotherapy or chemotherapy was not stopped in any surviving patient during the study period . Table . Characteristics of Patients with Glioblastoma Multiforme Survival  Median survival over the entire study period was 24 months for the patients in the chloroquine-treated group and 11 months for controls . At the end of the observation period , 6 patients ( 40 % ) from the chloroquine-treated group and 3 patients from the control group ( 20 % ) were still alive ( Figure 1 ) . Figure 1 . KaplanMeier estimates of survival in 30 patients with glioblastoma multiforme who received chloroquine ( n = 15 ) or placebo ( n = 15 ) in addition to conventional therapy . Secondary Outcomes In October 2005 , 6 patients from the chloroquine-treated group were alive . Of these , 1 had survived 59 months after surgery ( Figure 2 ) ; 1 patient each had survived 45 , 30 , and 20 months , respectively , and 2 additional patients had survived 27 months . The patients from the control group had survived 32 , 25 , and 22 months , respectively . Although not statistically significantly different , the rate of death over time was approximately half as large in patients receiving chloroquine as in patients receiving placebo ( 
    Output:
    
Autophagy overactivation would cause cell death through lysosomal overactivation , thus introducing another cell death pathway in addition to apoptosis .