Hepatic late adverse effects after antineoplastic treatment for childhood cancer.

BACKGROUND: Survival rates have greatly improved as a result of more effective treatments for childhood cancer. Unfortunately, the improved prognosis has been accompanied by the occurrence of late, treatment-related complications. Liver complications are common during and soon after treatment for childhood cancer. However, among long-term childhood cancer survivors, the risk of hepatic late adverse effects is largely unknown. To make informed decisions about future cancer treatment and follow-up policies, it is important to know the risk of, and associated risk factors for, hepatic late adverse effects. This review is an update of a previously published Cochrane review. OBJECTIVES: To evaluate all the existing evidence on the association between antineoplastic treatment (that is, chemotherapy, radiotherapy involving the liver, surgery involving the liver and BMT) for childhood cancer and hepatic late adverse effects. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2018, Issue 1), MEDLINE (1966 to January 2018) and Embase (1980 to January 2018). In addition, we searched reference lists of relevant articles and scanned the conference proceedings of the International Society of Paediatric Oncology (SIOP) (from 2005 to 2017) and American Society of Pediatric Hematology/Oncology (ASPHO) (from 2013 to 2018) electronically. SELECTION CRITERIA: All studies, except case reports, case series, and studies including fewer than 10 patients that examined the association between antineoplastic treatment for childhood cancer (aged 18 years or less at diagnosis) and hepatic late adverse effects (one year or more after the end of treatment). DATA COLLECTION AND ANALYSIS: Two review authors independently performed the study selection and 'risk of bias' assessment. The 'risk of bias' assessment was based on earlier checklists for observational studies. For the original version of the review, two review authors independently performed data extraction. For the update of the review, the data extraction was performed by one reviewer and checked by another reviewer. MAIN RESULTS: Thirteen new studies were identified for the update of this review. In total, we included 33 cohort studies including 7876 participants investigating hepatic late adverse effects after antineoplastic treatment (especially chemotherapy and radiotherapy) for different types of childhood cancer, both haematological and solid malignancies. All studies had methodological limitations. The prevalence of hepatic late adverse effects, all defined in a biochemical way, varied widely, between 0% and 84.2%. Selecting studies where the outcome of hepatic late adverse effects was well-defined as alanine aminotransferase (ALT) above the upper limit of normal, indicating cellular liver injury, resulted in eight studies. In this subgroup, the prevalence of hepatic late adverse effects ranged from 5.8% to 52.8%, with median follow-up durations varying from three to 23 years since cancer diagnosis in studies that reported the median follow-up duration. A more stringent selection process using the outcome definition of ALT as above twice the upper limit of normal, resulted in five studies, with a prevalence ranging from 0.9% to 44.8%. One study investigated biliary tract injury, defined as gamma-glutamyltransferase (γGT) above the upper limit of normal and above twice the upper limit of normal and reported a prevalence of 5.3% and 0.9%, respectively. Three studies investigated disturbance in biliary function, defined as bilirubin above the upper limit of normal and reported prevalences ranging from 0% to 8.7%. Two studies showed that treatment with radiotherapy involving the liver (especially after a high percentage of the liver irradiated), higher BMI, and longer follow-up time or older age at evaluation increased the risk of cellular liver injury in multivariable analyses. In addition, there was some suggestion that busulfan, thioguanine, hepatic surgery, chronic viral hepatitis C, metabolic syndrome, use of statins, non-Hispanic white ethnicity, and higher alcohol intake (> 14 units per week) increase the risk of cellular liver injury in multivariable analyses. Chronic viral hepatitis was shown to increase the risk of cellular liver injury in six univariable analyses as well. Moreover, one study showed that treatment with radiotherapy involving the liver, higher BMI, higher alcohol intake (> 14 units per week), longer follow-up time, and older age at cancer diagnosis increased the risk of biliary tract injury in a multivariable analysis. AUTHORS' CONCLUSIONS: The prevalence of hepatic late adverse effects among studies with an adequate outcome definition varied considerably from 1% to 53%. Evidence suggests that radiotherapy involving the liver, higher BMI, chronic viral hepatitis and longer follow-up time or older age at follow-up increase the risk of hepatic late adverse effects. In addition, there may be a suggestion that busulfan, thioguanine, hepatic surgery, higher alcohol intake (>14 units per week), metabolic syndrome, use of statins, non-Hispanic white ethnicity, and older age at cancer diagnosis increase the risk of hepatic late adverse effects. High-quality studies are needed to evaluate the effects of different therapy doses, time trends, and associated risk factors after antineoplastic treatment for childhood cancer.

The GRADE approach is reproducible in assessing the quality of evidence of quantitative evidence syntheses.

OBJECTIVE: We evaluated the inter-rater reliability (IRR) of assessing the quality of evidence (QoE) using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. STUDY DESIGN AND SETTING: On completing two training exercises, participants worked independently as individual raters to assess the QoE of 16 outcomes. After recording their initial impression using a global rating, raters graded the QoE following the GRADE approach. Subsequently, randomly paired raters submitted a consensus rating. RESULTS: The IRR without using the GRADE approach for two individual raters was 0.31 (95% confidence interval [95% CI] = 0.21-0.42) among Health Research Methodology students (n = 10) and 0.27 (95% CI = 0.19-0.37) among the GRADE working group members (n = 15). The corresponding IRR of the GRADE approach in assessing the QoE was significantly higher, that is, 0.66 (95% CI = 0.56-0.75) and 0.72 (95% CI = 0.61-0.79), respectively. The IRR further increased for three (0.80 [95% CI = 0.73-0.86] and 0.74 [95% CI = 0.65-0.81]) or four raters (0.84 [95% CI = 0.78-0.89] and 0.79 [95% CI = 0.71-0.85]). The IRR did not improve when QoE was assessed through a consensus rating. CONCLUSION: Our findings suggest that trained individuals using the GRADE approach improves reliability in comparison to intuitive judgments about the QoE and that two individual raters can reliably assess the QoE using the GRADE system.

GRADE guidelines: 14. Going from evidence to recommendations: the significance and presentation of recommendations.

This article describes the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to classifying the direction and strength of recommendations. The strength of a recommendation, separated into strong and weak, is defined as the extent to which one can be confident that the desirable effects of an intervention outweigh its undesirable effects. Alternative terms for a weak recommendation include conditional, discretionary, or qualified. The strength of a recommendation has specific implications for patients, the public, clinicians, and policy makers. Occasionally, guideline developers may choose to make "only-in-research" recommendations. Although panels may choose not to make recommendations, this choice leaves those looking for answers from guidelines without the guidance they are seeking. GRADE therefore encourages panels to, wherever possible, offer recommendations.

How to generalize efficacy results of randomized trials: recommendations based on a systematic review of possible approaches.

RATIONALE, AIMS AND OBJECTIVES: Randomized controlled trials (RCTs) are the preferred source for evidence for the effect of treatment. However, patients participating in RCTs often manifest important differences from patients seen in practice. Therefore, guideline developers have to decide whether the results are generalizable to the target population not represented in RCTs. METHOD: A systematic review of the literature was undertaken to identify methods to decide whether to generalize the results from RCTs to patients who were not represented in these trials. RESULTS: One approach is to examine the in- and exclusion criteria of trials and infer from these whether the trial population was sufficiently representative. Other authors suggest, because of the inclusion of a broader range of patients, reliance on observational studies if no direct evidence for the target population is available. Another approach is to apply the relative effect of treatment found in trials to patients in practice unless there is a compelling reason to believe the results would differ substantially as a function of particular characteristics of those patients. Although there are exceptions, this approach is supported by empirical evidence that, in general, relative effect of treatment on benefit outcomes seldom differs to an important extent across subgroups of patients. CONCLUSION: We propose this last approach: focusing on RCTs unless there is a compelling reason not to do so. Compelling reasons will most often be found with respect to issues of rare adverse effects, for which observational studies are likely to provide the best estimates.

GRADE guidelines: 12. Preparing summary of findings tables-binary outcomes.

Summary of Findings (SoF) tables present, for each of the seven (or fewer) most important outcomes, the following: the number of studies and number of participants; the confidence in effect estimates (quality of evidence); and the best estimates of relative and absolute effects. Potentially challenging choices in preparing SoF table include using direct evidence (which may have very few events) or indirect evidence (from a surrogate) as the best evidence for a treatment effect. If a surrogate is chosen, it must be labeled as substituting for the corresponding patient-important outcome. Another such choice is presenting evidence from low-quality randomized trials or high-quality observational studies. When in doubt, a reasonable approach is to present both sets of evidence; if the two bodies of evidence have similar quality but discrepant results, one would rate down further for inconsistency. For binary outcomes, relative risks (RRs) are the preferred measure of relative effect and, in most instances, are applied to the baseline or control group risks to generate absolute risks. Ideally, the baseline risks come from observational studies including representative patients and identifying easily measured prognostic factors that define groups at differing risk. In the absence of such studies, relevant randomized trials provide estimates of baseline risk. When confidence intervals (CIs) around the relative effect include no difference, one may simply state in the absolute risk column that results fail to show a difference, omit the point estimate and report only the CIs, or add a comment emphasizing the uncertainty associated with the point estimate.

The relationship between volume or surgeon specialty and outcome in the surgical treatment of lung cancer: a systematic review and meta-analysis.

BACKGROUND: Whether improvement of quality of surgical cancer care can be achieved by centralizing care in high-volume specialized centers is a subject of ongoing debate. We have conducted a meta-analysis of the literature on the effect of procedural volume or surgeon specialty on outcome of lung resections for cancer. METHODS: A systematic search of articles published between January 1, 1990 and January 20, 2011 on the effects of surgeon specialty and hospital or surgeon volume of lung resections on mortality and survival was conducted. After strict inclusion, meta-analysis assuming a random-effects model was performed. Meta-regression was used to identify volume cutoff values. Heterogeneity and the risk of publication bias were evaluated. RESULTS: Nineteen relevant studies were found. Studies were heterogeneous, especially in defining volume categories. The pooled estimated effect size was significant in favor of high-volume hospitals regarding postoperative mortality (odds ratio [OR] 0.71; confidence interval 0.62-0.81), but not for survival (OR 0.93; confidence interval 0.84-1.03). Surgeon volume showed no significant effect on outcome. General surgeons had significantly higher mortality risks than general thoracic (OR 0.78; 0.70-0.88) or cardiothoracic surgeons (OR 0.82; 0.69-0.96). A minimal annual volume of resections for lung cancer could not be identified. CONCLUSIONS: Hospital volume and surgeon specialty are important determinants of outcome in lung cancer resections, but evidence-based minimal-volume standards are lacking. Evaluation of individual institutions in a national audit program might help elucidate the influence of individual quality-of-care parameters, including hospital volume, on outcome.

GRADE guidelines: 8. Rating the quality of evidence--indirectness.

Direct evidence comes from research that directly compares the interventions in which we are interested when applied to the populations in which we are interested and measures outcomes important to patients. Evidence can be indirect in one of four ways. First, patients may differ from those of interest (the term applicability is often used for this form of indirectness). Secondly, the intervention tested may differ from the intervention of interest. Decisions regarding indirectness of patients and interventions depend on an understanding of whether biological or social factors are sufficiently different that one might expect substantial differences in the magnitude of effect. Thirdly, outcomes may differ from those of primary interest-for instance, surrogate outcomes that are not themselves important, but measured in the presumption that changes in the surrogate reflect changes in an outcome important to patients. A fourth type of indirectness, conceptually different from the first three, occurs when clinicians must choose between interventions that have not been tested in head-to-head comparisons. Making comparisons between treatments under these circumstances requires specific statistical methods and will be rated down in quality one or two levels depending on the extent of differences between the patient populations, co-interventions, measurements of the outcome, and the methods of the trials of the candidate interventions.

Hepatic late adverse effects after antineoplastic treatment for childhood cancer.

BACKGROUND: Survival rates have greatly improved as a result of more effective treatments for childhood cancer. Unfortunately the improved prognosis has resulted in the occurrence of late, treatment-related complications. Liver complications are common during and soon after treatment for childhood cancer. However, among long-term childhood cancer survivors the risk of hepatic late adverse effects is largely unknown. To make informed decisions about future cancer treatment and follow-up policies it is important to know the risk of, and associated risk factors for, hepatic late adverse effects. OBJECTIVES: To evaluate the existing evidence on the association between antineoplastic treatment for childhood cancer and hepatic late adverse effects. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, Issue 2), MEDLINE (1966 to June 2009) and EMBASE (1980 to June 2009). In addition, we searched reference lists of relevant articles and conference proceedings. SELECTION CRITERIA: All studies except case reports, case series and studies including less than 10 patients that examined the association between antineoplastic treatment for childhood cancer (aged 18 years or less at diagnosis) and hepatic late adverse effects (one year or more after the end of treatment). DATA COLLECTION AND ANALYSIS: Two review authors independently performed the study selection, risk of bias assessment and data extraction. MAIN RESULTS: We identified 20 cohort studies investigating hepatic late adverse effects after antineoplastic treatment for childhood cancer. All studies had methodological limitations. The prevalence of hepatic late adverse effects varied widely, between 0% and 84.2%. Selecting studies where the outcome of hepatic late adverse effects was well defined as alanine aminotransferase (ALT) above the upper limit of normal resulted in five studies. In this subgroup the prevalence of hepatic late adverse effects ranged from 8.0% to 52.8%, with follow-up durations varying from one to 27 years after the end of treatment. A more stringent selection process using the outcome definition of ALT as above twice the upper limit of normal resulted in three studies, with a prevalence ranging from 7.9% to 44.8%. Chronic viral hepatitis was identified as a risk factor for hepatic late adverse effects in univariate analyses. It is unclear which specific antineoplastic treatments increase the risk of hepatic late adverse effects AUTHORS' CONCLUSIONS: The prevalence of hepatic late adverse effects ranged from 7.9% to 52.8% when selecting studies with an adequate outcome definition. It has not been established which childhood cancer treatments result in hepatic late adverse effects. There is a suggestion that chronic viral hepatitis increases the risk of hepatic late adverse effects. More well-designed studies are needed to reliably evaluate the prevalence of, and risk factors for, hepatic late adverse effects after antineoplastic treatment for childhood cancer.

A systematic review and meta-analysis of the relationship between hospital/surgeon volume and outcome for radical cystectomy: an update for the ongoing debate.

CONTEXT: There is an ongoing debate about centralisation of radical cystectomy (RC) procedures. OBJECTIVE: To conduct a systematic review of the literature on the volume-outcome relationship for RC for bladder cancer (BCa) with consideration for the methodologic quality of the available evidence and to perform a meta-analysis on the studies meeting predefined quality criteria. EVIDENCE ACQUISITION: A systematic search was performed to identify all articles examining the effects of procedure volume on clinical outcome for cystectomy. Reviews, opinion articles, and surveys were excluded. All articles were critically appraised for methodologic quality and risk of bias. Meta-analysis was performed to calculate the overall effect of higher surgeon or hospital volume on patient outcome. EVIDENCE SYNTHESIS: Ten studies of good methodologic quality were included for meta-analysis. Eight studies were based on administrative data, two studies on clinical data. The results showed a significant association between high-volume hospitals and low mortality. A meta-analysis of the seven studies on hospital mortality showed a pooled estimated effect of odds ratio (OR) 0.55 (range: 0.44-0.69). The result was moderate heterogeneity (I(2)=50). A large variation in cut-off points used was observed. Sensitivity analyses did not show different effects in any of the subgroup analyses. Also, no significant differences in effect sizes were observed for different cut-off points. The data were not suggestive for publication bias. One study showed a positive effect of hospital volume on survival (hazard ratio [HR]: 0.89; p=0.06). Two studies showed a beneficial effect of surgeon volume on mortality (OR: 0.55; OR: 0.64). Only one study on the impact of surgeon volume on survival was found; it showed no significant positive effect for higher volume (HR: 0.83; p=0.26). CONCLUSIONS: Postoperative mortality after cystectomy is significantly inversely associated with high-volume providers. However, additional quality criteria, such as infrastructure and level of specialisation, should be formulated to direct centralisation initiatives. The Dutch Association of Urology in 2010 implemented a national quality of care (QoC) registration programme for all patients treated by surgery for muscle-invasive BCa, including multiple parameters defining QoC.

The relation between volume and outcome of coronary interventions: a systematic review and meta-analysis.

AIMS: Although various studies reported better outcomes in centres performing a high volume of procedures of coronary artery bypass grafting (CABG) or percutaneous coronary interventions (PCIs), it is unclear how strong this relation is and whether it pertains to today's practice. METHODS AND RESULTS: Medline, Embase, and conference reports were searched for studies reporting the effect of high volume of CABG or PCI on in-hospital mortality, adjusted for differences in case-mix. Of 140 potentially relevant papers, 15 were included, 2 of which reported data on both CABG and PCI. Meta-analysis of 10 studies on PCI, comprising 1 322 342 patients in 1746 hospitals, indicated an odds ratio (OR) of in-hospital mortality for patients treated in a high-volume hospital of 0.87 (95% confidence interval (CI) 0.83-0.91) compared to those treated in a low-volume hospital. The 7 CABG studies taken together, comprising 1 470 990 patients in 2040 hospitals, also revealed a significant effect of high volume (OR 0.85; CI 0.79-0.92). A differential effect for specific cut-off points could not be identified. Meta-regression did not show notable changes in the effect size over the years. CONCLUSIONS: Patients undergoing CABG or PCI in a high-volume hospital exhibit lower in-hospital mortality than those treated at low-volume hospitals. Our meta-analysis does not support the view that this relation has attenuated over time.

Do specialized centers and specialists produce better outcomes for patients with chronic diseases than primary care generalists? A systematic review.

PURPOSE: Although specialized centers are generally accepted for treatment of relatively uncommon diseases, such as cystic fibrosis, statements regarding the amount of expertise or minimum number of patients treated are increasingly included in guidelines for the treatment of other chronic diseases such as rheumatoid arthritis and diabetes mellitus. DATA SOURCES: Medline and Embase from 1987 through March 2008 were searched. STUDY SELECTION: Studies reporting the effect of treatment in a specialized or high-volume center or by subspecialists on a clinically relevant outcome. Data extraction Two reviewers extracted the data independently and assessed the methodological quality. RESULTS OF DATA SYNTHESIS: We included 22 articles. Two randomized-controlled trials and a quasi-experimental study compared the effect of outpatient team care with traditional outpatient care for patients with rheumatoid arthritis. These studies showed no difference or were inconsistent. Studies on the outcomes of care for diabetic patients (5 prospective or historical cohort studies and 10 retrospective cohort studies) were generally of poor quality. Studies comparing the subspecialist care with the care provided by general internists or primary care providers produced inconsistent results. Similar inconsistency and poor quality were found for three observational studies on cystic fibrosis. CONCLUSION: The available literature suggests that among patients with rheumatoid arthritis, diabetes mellitus or cystic fibrosis, outcomes are not superior in specialized centers or with subspecialists compared with other forms of chronic illness care.

Rising incidence of clinically evident Barrett's oesophagus in The Netherlands: a nation-wide registry of pathology reports.

OBJECTIVE: The incidence of oesophageal adenocarcinoma has increased steadily over the past few decades, but little information is available on trends in the incidence of its presumed precursor, Barrett's oesophagus (BO). MATERIAL AND METHODS: The nation-wide registry of pathology reports (PALGA) was used to investigate time trends in the incidence of BO in The Netherlands. Standardized morbidity ratios (SMRs) were calculated to examine the magnitude of the changes. RESULTS: The study comprised 105,283 patients with a first-time biopsy taken from the oesophagus. Of these patients, 33,365 had BO, 6168 squamous cell carcinoma and 9854 had adenocarcinoma of the oesophagus, diagnosed between 1992 and 2003. The age-adjusted incidence of BO increased among men by 41% (95% confidence interval (CI) 38-44%). Among women, the increase was 23% (CI 19-26%) in 1996-99, followed by a slight decline in 2000-03. The increase was most notable among younger patients (<60 years), whereas the incidence remained stable among men and decreased among women aged 75 or older. Although the number of oesophageal biopsies increased by 21% among men and by 6% among women, the proportion of biopsies with a diagnosis of BO increased to a larger extent, by 33% (CI 30-36%) for men and by 25% (CI 22-29%) for women. The incidence of adenocarcinoma of the oesophagus increased by 28% for men and by 22% for women. CONCLUSIONS: Our findings show a significant increase in the incidence of clinically evident BO. Although changes in endoscopic practice may partly explain these findings, a true increase in the incidence of BO seems likely.

Routine duplex surveillance does not improve the outcome after carotid endarterectomy: a decision and cost utility analysis.

BACKGROUND: Doppler ultrasound (duplex) tests are commonly applied after carotid endarterectomy to detect possible recurrent stenosis. The appropriate frequency and the benefits are unknown. We investigated the costs and effects of various follow-up strategies to determine the optimal strategy after carotid endarterectomy. METHODS: Using decision-analytic methods, a Monte Carlo Markov model was constructed. Probabilities and costs were obtained by systematic literature review. From empirical data regarding restenosis, a disease model was constructed to test the effect of various follow-up strategies using duplex testing and angiography. Main outcome measures were quality-adjusted life-years (QALYs), probability of stroke, and costs (for both the Dutch and the American situation). RESULTS: The average quality-adjusted life expectancy for a 66-year-old patient was 6.31 years for the symptom-guided strategy (with duplex scanning only being performed in case of symptoms of cerebral ischemia). The mean lifetime costs for this strategy were $5 600 for the US and 4 600 Euro for the Netherlands. The cumulative probability of stroke was 13%. Yearly routine duplex tests up to 5 years after operation resulted in similar QALYs and a similar probability of stroke, but higher costs ($7 300 for the US and 5 600 Euro for The Netherlands situation). No other strategy, including routine duplex surveillance, increased QALYs. When MR instead of conventional angiography was used as confirmatory test, no improvement was observed either. CONCLUSIONS: Routine duplex surveillance does not result in an increase in quality-adjusted life expectancy, but it does increase costs. After successful carotid endarterectomy, a symptom-guided follow-up is an appropriate approach.