***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: In the GRADE approach , r and omized trials start as high- quality evidence and observational studies as low- quality evidence , but both can be rated down if most of the relevant evidence comes from studies that suffer from a high risk of bias . Well-established limitations of r and omized trials include failure to conceal allocation , failure to blind , loss to follow-up , and failure to appropriately consider the intention-to-treat principle . More recently recognized limitations include stopping early for apparent benefit and selective reporting of outcomes according to the results . Key limitations of observational studies include use of inappropriate controls and failure to adequately adjust for prognostic imbalance . Risk of bias may vary across outcomes ( e.g. , loss to follow-up may be far less for all-cause mortality than for quality of life ) , a consideration that many systematic review s ignore . In deciding whether to rate down for risk of bias -- whether for r and omized trials or observational studies -- authors should not take an approach that averages across studies . Rather , for any individual outcome , when there are some studies with a high risk , and some with a low risk of bias , they should consider including only the studies with a lower risk of bias OBJECTIVES To analyze sources search ed in Cochrane review s , to determine the proportion of trials included in review s that are indexed in major data bases , and to compare the quality of these trials with those from other sources . METHODS All new systematic review s in the Cochrane Library , Issue1 2001 , that were restricted to r and omized controlled trials ( RCTs ) or quasi- RCTs were selected . The sources search ed in the review s were recorded , and the trials included were checked to see whether they were indexed in four major data bases . Trials not indexed were checked to determine how they could be identified . The quality of trials found in major data bases was compared with those found from other sources . RESULTS The range in the number of data bases search ed per review ranged between one and twenty-seven . The proportion of the trials in the four data bases were Cochrane Controlled Trials Register = 78.5 % , MEDLINE = 68.8 % , Embase = 65.0 % , and Science/Social Sciences Citation Index = 60.7 % . Search ing another twenty-six data bases after Cochrane Controlled Trials Register ( CCTR ) , MEDLINE , and Embase only found 2.4 % additional trials . There was no significant difference between trials found in the CCTR , MEDLINE , and Embase compared with other trials , with respect to adequate allocation concealment or sample size . CONCLUSIONS There was a large variation between review s in the exhaustiveness of the literature search es . CCTR was the single best source of RCTs . Additional data base search ing retrieved only a small percentage of extra trials . Contacting authors and manufacturers to find unpublished trials appeared to be a more effective method of obtaining the additional better quality trials PURPOSE To evaluate the efficacy and safety of high-dose , hypofractionated proton beam therapy for hepatocellular carcinoma ( HCC ) and intrahepatic cholangiocarcinoma ( ICC ) . MATERIAL S AND METHODS In this single-arm , phase II , multi-institutional study , 92 patients with biopsy-confirmed HCC or ICC , determined to be unresectable by multidisciplinary review , with a Child-Turcotte-Pugh score ( CTP ) of A or B , ECOG performance status of 0 to 2 , no extrahepatic disease , and no prior radiation received 15 fractions of proton therapy to a maximum total dose  of 67.5 Gy  equivalent . Sample size was calculated to demonstrate > 80 % local control ( LC ) defined by Response Evaluation Criteria in Solid Tumors ( RECIST ) 1.0 criteria at 2 years for HCC patients , with the parallel goal of obtaining acceptable precision for estimating outcomes for ICC . RESULTS Eighty-three patients were evaluable : 44 with HCC , 37 with ICC , and two with mixed HCC/ICC . The CTP score was A for 79.5 % of patients and B for 15.7 % ; 4.8 % of patients had no cirrhosis . Prior treatment had been given to 31.8 % of HCC patients and 61.5 % of ICC patients . The median maximum dimension was 5.0 cm ( range , 1.9 to 12.0 cm ) for HCC patients and 6.0 cm ( range , 2.2 to 10.9 cm ) for ICC patients . Multiple tumors were present in 27.3 % of HCC patients and in 12.8 % of ICC patients . Tumor vascular thrombosis was present in 29.5 % of HCC patients and in 28.2 % of ICC patients . The median dose delivered to both HCC and ICC patients was 58.0 Gy . With a median follow-up among survivors of 19.5 months , the LC rate at 2 years was 94.8 % for HCC and 94.1 % for ICC . The overall survival rate at 2 years was 63.2 % for HCC and 46.5 % ICC . CONCLUSION High-dose hypofractionated proton therapy demonstrated high LC rates for HCC and ICC safely , supporting ongoing phase III trials of radiation in HCC and ICC Methods for combining data from several studies exist and appear to be quite useful . None satisfactorily addresses the question of what studies should be combined . This issue is the most serious method ological limitation . Even studies with statistically significant interaction might still be combined if the effect were in the same direction . Thus , substantial scientific input is required as to what criteria must be met by each potential study . Much can be learned from combining or pooling data but it must be done cautiously . Pooling exercises do not replace well design ed prospect i ve clinical trials . Efforts for establishing basic design criteria to allow for multicentre and multicountry trials to be more easily combined might be useful . PURPOSE To describe results of a planned interim analysis of a prospect i ve , r and omized clinical trial developed to compare treatment outcomes among patients with newly diagnosed hepatocellular carcinoma ( HCC ) . METHODS AND MATERIAL S Eligible subjects had either clinical or pathologic diagnosis of HCC and met either Milan or San Francisco transplant criteria . Patients were r and omly assigned to  transarterial chemoembolization ( TACE ) or to proton beam radiation therapy .  Patients r and omized to  TACE received at least 1 TACE with additional TACE for persistent disease . Proton beam radiation therapy was delivered to all areas of gross disease to a total dose of 70.2 Gy in 15 daily fractions over 3 weeks . The primary endpoint was progression-free survival , with secondary endpoints of overall survival , local tumor control , and treatment-related toxicities as represented by posttreatment days of hospitalization . RESULTS At the time of this analysis 69 subjects were available for analysis . Of these , 36 were r and omized to TACE and 33 to proton .  Total days of hospitalization within 30 days of TACE/proton was 166 and 24 days , respectively ( P<.001 ) . Ten TACE and 12 proton patients underwent liver transplantation after treatment . Viable tumor identified in the explanted livers after TACE/proton averaged 2.4 and 0.9 cm , respectively . Pathologic complete response after TACE/proton was 10%/25 % ( P=.38 ) . The 2-year overall survival for all patients was 59 % , with no difference between treatment groups . Median survival time was 30 months ( 95 % confidence interval 20.7 - 39.3 months ) . There was a trend toward improved 2-year local tumor control ( 88 % vs 45 % , P=.06 ) and progression-free survival ( 48 % vs 31 % , P=.06 ) favoring the proton beam treatment group . CONCLUSIONS This interim analysis indicates similar overall survival rates for proton beam radiation therapy and TACE . There is a trend toward improved local tumor control and progression-free survival with proton beam . There are significantly fewer hospitalization days after proton treatment , which may indicate reduced toxicity with proton beam therapy 4024 Background : Proton beam radiotherapy ( PRT ) has an excellent depth-dose profile that can deliver high dose to the liver tumor without debilitating liver function compared to photon beam radiotherapy . It is reasonable to evaluate the safety and efficacy of PRT prospect ively for hepatocellular carcinoma ( HCC ) . METHODS Eligibility criteria for this study were : solitary HCC ; neither surgery nor local ablation therapy were indicated ; no ascites ; age ≥20 years ; Zubord performance status is 0∼2 ; no serious co-morbidities other than liver cirrhosis ; written informed consent . Tumor close to the stomach or intestinal loop was not considered as a subject for this study . Clinical target volume ( CTV ) was defined as gross tumor volume plus 5 mm of lateral and cranio-caudal margin . PRT administering 76 GyE/20 fractions/5 weeks to the CTV was done using respiration-gated irradiation system ( ReGIS ) with 150∼190 MeV proton beam . Relative biological effectiveness of our proton beam was defined as 1.1 . No patients received transarterial chemoembolization or local ablation in combination with PRT . RESULTS Thirty patients were enrolled between May 1999 and Feb. 2003 . There were 20 male and 10 female with a median age of 70 years ( range : 48∼87 years ) . Maximum tumor diameter ranged from 25 ∼ 82 mm ( median 45 mm ) . All patients had liver cirrhosis of which the degree was Child class A in 9 , B in 19 , and C in 2 . Acute reactions of PRT were well tolerated , and PRT were completed as planned in all patients . After a median follow-up period of 31 months ( 14∼54 months ) , only 1 patient experienced tumor recurrence within the CTV and 2-year actuarial local control rate was as 96 % ( 95 % confidence interval : 88%∼100 % ) . Actuarial overall survival rate at 2 years was 64 % ( 46∼83 % ) . Pretreatment liver function that was evaluated with indocyanin green clearance at 15 minutes ( ICG 15 ) , and liver volume that received 30 GyE or more ( V30 ) significantly correlated with overall survival . CONCLUSIONS Since PRT showed minimal acute toxicity and excellent tumor control within CTV , it is expected as one of the convincing non-surgical treatment options for HCC . ICG 15 and V30 were considered as useful indicators of patient prognosis . No significant financial relationships to disclose This article introduces the approach of GRADE to rating  quality of evidence .  GRADE specifies four categories-high , moderate , low , and very low-that are applied to a body of evidence , not to individual studies . In the context of a systematic review , quality reflects our confidence that the estimates of the effect are correct . In the context of recommendations , quality reflects our confidence that the effect estimates are adequate to support a particular recommendation . R and omized trials begin as high- quality evidence , observational studies as low quality . " Quality " as used in GRADE means more than risk of bias and so may also be compromised by imprecision , inconsistency , indirectness of study results , and publication bias . In addition , several factors can increase our confidence in an estimate of effect . GRADE provides a systematic approach for considering and reporting each of these factors . GRADE separates the process of assessing quality of evidence from the process of making recommendations . Judgments about the strength of a recommendation depend on more than just the quality of evidence The purpose of this study was to evaluate the clinical efficacy , toxicity and adverse effects of stereotactic body radiotherapy ( SBRT ) combined with transarterial chemoembolization ( TACE ) in patients with advanced hepatocellular carcinoma ( HCC ) with portal vein tumor thrombosis ( PVTT ) . A total of 101 patients diagnosed with primary HCC with PVTT were enrolled in this study and were r and omly divided into three groups as follows : group A , 34 patients treated with γ-SBRT followed by TACE ; group B , 37 patients treated with TACE followed by γ-SBRT ; and group C , 30 patients treated with γ-SBRT alone .  The effective response rate for the entire patient sample was 87.1 % ( 88/101 ) following a 3-month treatment . The differences in the response rate , survival rate , α-fetoprotein level restoration rate and rate of improvement of abdominal distention and discomfort between groups A and B were not statistically significant ( P>0.05 ) . However , the rates of groups A and B were higher compared to those of group C ( P<0.05 ) . The exacerbation rate of liver function in group A was lower compared to that in group B ( P<0.05 ) , although it exhibited no statistically significant difference from that in group C ( P>0.05 ) . No severe radiation-related complications were reported during the follow-up period . The combination of γ-SBRT and TACE was shown to be a relatively effective local treatment for primary HCC patients with PVTT . Compared to γ-SBRT followed by TACE and γ-SBRT alone , TACE followed by γ-SBRT may exert a negative effect on liver function . These results suggested that the combination of TACE and γ-SBRT may be considered a relatively effective , safe and feasible treatment method for primary HCC patients with PVTT , although TACE followed by γ-SBRT may negatively affect liver function Proton beam therapy ( PBT ) may provide useful local‐regional treatment for hepatocellular carcinoma ( HCC ) . The purpose of this study was to evaluate the safety and efficacy of PBT for HCC In the GRADE approach , r and omized trials 
    Output:
    
For the comparison of radiotherapy plus chemoembolisation versus chemoembolisation alone , the risk ratio for one-year all-cause mortality was 0.51 ( 95 % confidence interval ( CI ) 0.41 to 0.62 ; P < 0.001 ; 9 trials ; low- quality evidence ) ; for complete response rate was 2.14 ( 95 % CI 1.47 to 3.13 ; P < 0.001 ; 7 trials ; low- quality evidence ) ; and for overall response rate defined as complete response plus partial response was 1.58 ( 95 % CI 1.40 to 1.78 ; P < 0.001 ; 7 trials ; low- quality evidence ) , all in favour of combined treatment with external beam radiotherapy plus transarterial chemoembolisation and seemingly supported by our Trial Sequential Analysis .
Additionally , the combined treatment was associated with a higher risk of elevated total bilirubin and elevated alanine aminotransferase .
AUTHORS ' CONCLUSIONS We found very low- and low- quality evidence suggesting that combined external beam radiotherapy and chemoembolisation may be associated with lower mortality and increased complete and overall response rates , despite an increased toxicity as expressed by a higher rise of bilirubin and alanine aminotransferase .