***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: Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more e18015 Background : Significant advances in the systemic management of metastatic non-small cell lung cancer ( NSCLC ) have occurred over the past decade , with options now including multiple lines of chemotherapy , EGFR inhibitors , and anti-angiogenic agents . Improvements in overall survival have been demonstrated in r and omized controlled trials comparing these newer agents to best supportive care ( BSC ) or st and ard therapy . This study examined uptake of these therapies in general practice and their impact on survival . METHODS This retrospective cohort study compared demographic , treatment and survival data among 987 patients diagnosed with stage IV NSCLC at two institutions in 1998 , 2003 , and 2008 . Cohorts were selected based on intervals when doublet chemotherapy , second line chemotherapy , and targeted agents were incorporated into the st and ard treatment regimen . RESULTS The proportion of patients receiving systemic therapy increased over time ( 20 % in 1998 , 42 % in 2008 ) . Treated patients diagnosed in 2008 were more likely to receive ≥2 lines of systemic therapy ( 60 % vs. 7 % in 1998 ) . Overall survival improved significantly across cohorts ( P < 0.001 ) , with 2 year survival rates of 0.3 % in 1998 , 4 % in 2003 , and 15 % in 2008 . After controlling for other variables , risk of death was diminished by 55 % in patients receiving 1 line of systemic therapy and 72 % in those receiving ≥2 lines , compared with BSC alone . Elderly patients ( age ≥70 years ) were also more likely to receive systemic therapy over time , with improved overall survival ( P < 0.001 ) . CONCLUSIONS Over the past decade , there has been increased use of systemic therapy in stage IV NSCLC patients , including the elderly . This has been associated with significantly improved overall survival Bisphophonates are the treatment of choice to prevent skeletal events in patients with multiple myeloma . Some pre clinical studies suggested that bisphophonates can be useful as antitumor drugs in some malignancies . We conducted a controlled clinical trial to assess if zoledronic acid can have this clinical activity . Ninetyfour patients with previously untreated multiple myeloma were treated with a conventional chemotherapy program : cyclophosphamide , vincristine , melphalan , and prednisone ( CVMP ) and were r and omized to received either zoledronic acid ( 4 mg , iv , every 28 d ) or not ( control group ) . The end-point of the present study was to assess improvement in outcome , measured by event-free survival ( EFS ) and overall survival ( OS ) , and the second-end point was to confirm the efficacy in preventing skeletal events . In an intent-to-treat analysis , all patients were available for efficacy and toxicity . Median follow up was 49.6 mo ( range : 34–72 mo ) . Five year actuarial curves showed that EFS was 80 % in the zoledronic acid group , which was statistically different from 52 % in the control group ( p < 0.01 ) . Actuarial 5 yr OS was 80 % in the zoledronic acid arm , and 46 % in the control group ( p < 0.01 ) . Sketeletal events were more frequent in the control group when compared to zoledronic acid . Toxicity was mild . We confirm the efficacy of zoledronic acid to prevent skeletal events , but we felt that we can demonstrate that zoledronic acid has a clinical antitumor effect measured from a increase in complete response rate and EFS and OS that were better when compared with the control group . We began a controlled clinical trial with modern treatment ( including transplant procedures ) in combination with zoledronic acid to define the role of zoledonic acid in this setting of patients Summary Background Bisphosphonates reduce the risk of skeletal events in patients with malignant bone disease , and zoledronic acid has shown potential anticancer effects in pre clinical and clinical studies . We aim ed to establish whether bisphosphonates can affect clinical outcomes in patients with multiple myeloma . Methods Patients of age 18 years or older with newly diagnosed multiple myeloma were enrolled from 120 centres in the UK . Computer-generated r and omisation sequence was used to allocate patients equally , via an automated telephone service , to receive 4 mg zoledronic acid as an infusion every 3–4 weeks or 1600 mg oral clodronic acid daily . Patients also received intensive or non-intensive induction chemotherapy . No investigators , staff , or patients were masked to treatment allocation , and bisphosphonate and maintenance therapy continued at least until disease progression . The primary endpoints were overall survival , progression-free survival , and overall response rate . We assessed between-group differences with Cox proportional hazards models for progression-free survival and overall survival , and with logistic regression models for overall response rate . Analysis was by intention to treat . This trial is registered , number IS RCT N68454111 . Findings 1970 patients were enrolled between May , 2003 , and November , 2007 , of whom 1960 were eligible for intention-to-treat analysis : 981 in the zoledronic acid group ( 555 on intensive chemotherapy  , 426 on non-intensive chemotherapy ) ; and 979 on clodronic acid  ( 556 on  intensive chemotherapy , 423 on  non-intensive chemotherapy ) . The treatment cutoff was Oct 5 , 2009 , with patients receiving bisphosphonates for a median of 350 days ( IQR 137–632 ) before disease progression , with a median of 3·7 years ' follow-up ( IQR 2·9–4·7 ) . Zoledronic acid  reduced mortality by 16 % ( 95 % CI 4–26 ) versus clodronic acid ( hazard ratio [ HR ] 0·84 , 95 % CI 0·74–0·96 ; p=0·0118 ) , and extended median overall survival by 5·5 months ( 50·0 months , IQR 21·0 to not reached vs 44·5 months , IQR 16·5 to not reached ; p=0·04 ) . Zoledronic acid also significantly improved progression-free survival by 12 % ( 95 % CI 2–20 ) versus clodronic acid ( HR 0·88 , 95 % CI 0·80–0·98 ; p=0·0179 ) , and increased median progression-free survival by 2·0 months ( 19·5 months , IQR 9·0–38·0 vs 17·5 months , IQR 8·5–34·0 ; p=0·07 ) . Rates of complete , very good partial , or partial response did not differ significantly between the zoledronic acid and clodronic acid groups for patients receiving intensive induction chemotherapy ( 432 patients [ 78 % ] vs 422 [ 76 % ] ; p=0·43 ) or non-intensive induction chemotherapy ( 215 [ 50 % ] vs 195 [ 46 % ] ; p=0·18 ) . Both bisphosphonates were generally well tolerated , with similar occurrence of acute renal failure and treatment-emergent serious adverse events , but zoledronic acid was associated with higher rates of confirmed osteonecrosis of the jaw ( 35 [ 4 % ] ) than was clodronic acid ( 3 [ < 1 % ] ) . Interpretation Consistent with the potential anticancer activity of zoledronic acid , overall survival improved independently of prevention of skeletal-related events , showing that zoledronic acid has treatment benefits beyond bone health . These findings support immediate treatment with zoledronic acid  in patients with newly diagnosed multiple myeloma , not only for prevention of skeletal-related events , but also for potential antimyeloma benefits . Funding Medical Research Council ( London , UK ) , with unrestricted educational grants from Novartis , Schering Health Care , Chugai , Pharmion , Celgene , and Ortho Biotech Objective Questions remain regarding the optimal use of bone-targeted agents in patients with metastatic bone disease . The purpose of this study was to assess current clinical practice regarding the use and administration of bone-targeted agents by Canadian oncologists in patients with metastatic breast and prostate cancer . Methods A survey was design ed to explore ; bone-targeted agent use in metastatic bone disease , variability in the choice and the frequency of administration of these agents . Opinions were sought on potential outcomes for future trials . Results A total of 193 clinicians were contacted and 90 completed our survey ( response rate 49 % after adjustment for inactivity ) . Survey respondents were medical oncologists ( 71.1 % ) , radiation oncologists ( 21.1 % ) and urologists ( 7.8 % ) . The findings suggest that once bone-targeted agents are started they are rarely discontinued . More agents are used in breast cancer than in prostate cancer . There was considerable interest in performing studies of de-escalated therapy in both breast and prostate cancer . Physicians requested ( 86 % ) that the primary study endpoint be the occurrence of skeletal related events and not biomarker driven . Conclusions Despite clinical practice guidelines and widespread use , significant areas of clinical equipoise with respect to use of bone-targeted agents exist . Findings from this survey suggest that physicians are interested in de-escalated therapy for both breast and prostate patients . However , the use of multiple agents in breast cancer and the desire for skeletal related events to be the primary endpoint means that very large r and omized studies will be required The aim of this open‐label , multicenter , r and omized phase II trial was to evaluate the efficacy and safety of zoledronic acid in combination with docetaxel in previously treated patients with non‐small‐cell lung cancer ( NSCLC ) and bone metastases . In this study , patients r and omly received docetaxel ( 60 mg/m2 )  with ( group DZ ) or without ( group D ) zoledronic acid every 21 days . There were 50 patients in each group , and the primary endpoint was progression‐free survival . In an efficacy analysis of 94 patients ( DZ , 48 ; D , 46 ) , the median progression‐free survival was 2.7 months ( 95 % confidence interval [ CI ] , 1.5–3.5 months ) for the DZ group and 2.6 months ( 95 % CI , 1.5–3.4 months ) for the D group ( stratified log‐rank test , P = 0.89 ) . The median overall survival was 10.4 months ( 95 % CI , 7.0–15.8 months ) for the DZ group and 9.7 months ( 95 % CI , 6.1–12.5 months ) for the D group ( stratified log‐rank test , P = 0.62 ) . There were no clinical ly relevant differences in the frequencies of grade 3 or 4 adverse events between the two groups . No treatment‐related deaths occurred in the DZ group . Zoledronic acid combined with docetaxel was well tolerated but did not meet the primary endpoint of demonstrating a longer progression‐free survival in advanced NSCLC patients with bone metastases compared with docetaxel alone . This trial was registered with the University Hospital Medical Information Network ( UMIN000001098 ) Men with prostate cancer are at high risk of developing bone metastases that can lead to clinical ly significant skeletal morbidity . Recently , a r and omized , placebo-controlled , phase III trial in 422 men with hormone-refractory prostate cancer and bone metastases demonstrated that zoledronic acid ( 4 mg every 3 weeks ) significantly reduced the incidence and onset of skeletal complications and provided significant long-term reductions in bone pain compared with placebo . Patients received zoledronic acid for a 15-month core phase , with the option to continue therapy for 9 more months on the extension phase . To evaluate the continuing benefit of long-term zoledronic acid therapy , retrospective exploratory analyses were conducted based on the incidence of skeletal-related events ( SREs ; defined as pathologic bone fracture , spinal cord compression , surgery or radiation therapy to bone , or change in antineoplastic therapy for bone pain ) occurring only during the extension phase of this trial . Quality of life parameters included assessment with the Brief Pain Inventory . Similar to results reported for the 15-month core phase and the entire 24-month study , the 9-month extension phase demonstrated that zoledronic acid significantly reduced the percentage of patients with an SRE ( P = 0.017 ) , prolonged the median time to first SRE ( P = 0.036 ) , reduced the annual incidence of SREs by 52 % ( P = 0.016 ) , and reduced the risk of SREs by 53 % ( P = 0.022 ) compared with placebo . Furthermore , zoledronic acid was safe and well tolerated . Therefore , zoledronic acid provides long-term continuing clinical benefit for men with prostate cancer and bone metastases and represents a new therapeutic option for this population PURPOSE Cisplatin plus gemcitabine is a st and ard regimen for first-line treatment of advanced non-small-cell lung cancer ( NSCLC ) . Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting . PATIENTS AND 
    Output:
    
Study -specific results suggested that bone-modifying agents reduce the incidence of SREs and bone pain in lung cancer patients .
Data from included trials suggests benefit of bone-targeted agents in lung cancer for the prevention of SREs and bone pain .