Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases.

BACKGROUND: This is an update to the review published in the Cochrane Library (2012, Issue 4).It is estimated that 20% to 40% of people with cancer will develop brain metastases during the course of their illness. The burden of brain metastases impacts quality and length of survival. OBJECTIVES: To assess the effectiveness and adverse effects of whole brain radiotherapy (WBRT) given alone or in combination with other therapies to adults with newly diagnosed multiple brain metastases. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase to May 2017 and the National Cancer Institute Physicians Data Query for ongoing trials. SELECTION CRITERIA: We included phase III randomised controlled trials (RCTs) comparing WBRT versus other treatments for adults with newly diagnosed multiple brain metastases. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and abstracted information in accordance with Cochrane methods. MAIN RESULTS: We added 10 RCTs to this updated review. The review now includes 54 published trials (45 fully published reports, four abstracts, and five subsets of data from previously published RCTs) involving 11,898 participants.Lower biological WBRT doses versus controlThe hazard ratio (HR) for overall survival (OS) with lower biological WBRT doses as compared with control (3000 cGy in 10 daily fractions) was 1.21 (95% confidence interval (CI) 1.04 to 1.40; P = 0.01; moderate-certainty evidence) in favour of control. The HR for neurological function improvement (NFI) was 1.74 (95% CI 1.06 to 2.84; P = 0.03; moderate-certainty evidence) in favour of control fractionation.Higher biological WBRT doses versus controlThe HR for OS with higher biological WBRT doses as compared with control (3000 cGy in 10 daily fractions) was 0.97 (95% CI 0.83 to 1.12; P = 0.65; moderate-certainty evidence). The HR for NFI was 1.14 (95% CI 0.92 to 1.42; P = 0.23; moderate-certainty evidence).WBRT and radiosensitisersThe addition of radiosensitisers to WBRT did not confer additional benefit for OS (HR 1.05, 95% CI 0.99 to 1.12; P = 0.12; moderate-certainty evidence) or for brain tumour response rates (odds ratio (OR) 0.84, 95% CI 0.63 to 1.11; P = 0.22; high-certainty evidence).Radiosurgery and WBRT versus WBRT aloneThe HR for OS with use of WBRT and radiosurgery boost as compared with WBRT alone for selected participants was 0.61 (95% CI 0.27 to 1.39; P = 0.24; moderate-certainty evidence). For overall brain control at one year, the HR was 0.39 (95% CI 0.25 to 0.60; P < 0.0001; high-certainty evidence) favouring the WBRT and radiosurgery boost group.Radiosurgery alone versus radiosurgery and WBRTThe HR for local brain control was 2.73 (95% CI 1.87 to 3.99; P < 0.00001; high-certainty evidence)favouring the addition of WBRT to radiosurgery. The HR for distant brain control was 2.34 (95% CI 1.73 to 3.18; P < 0.00001; high-certainty evidence) favouring WBRT and radiosurgery. The HR for OS was 1.00 (95% CI 0.80 to 1.25; P = 0.99; moderate-certainty evidence). Two trials reported worse neurocognitive outcomes and one trial reported worse quality of life outcomes when WBRT was added to radiosurgery.We could not pool data from trials related to chemotherapy, optimal supportive care (OSC), molecular targeted agents, neurocognitive protective agents, and hippocampal sparing WBRT. However, one trial reported no differences in quality-adjusted life-years for selected participants with brain metastases from non-small-cell lung cancer randomised to OSC and WBRT versus OSC alone. AUTHORS' CONCLUSIONS: None of the trials with altered higher biological WBRT dose-fractionation schemes reported benefit for OS, NFI, or symptom control compared with standard care. However, OS and NFI were worse for lower biological WBRT dose-fractionation schemes than for standard dose schedules.The addition of WBRT to radiosurgery improved local and distant brain control in selected people with brain metastases, but data show worse neurocognitive outcomes and no differences in OS.Selected people with multiple brain metastases from non-small-cell lung cancer may show no difference in OS when OSC is given and WBRT is omitted.Use of radiosensitisers, chemotherapy, or molecular targeted agents in conjunction with WBRT remains experimental.Further trials are needed to evaluate the use of neurocognitive protective agents and hippocampal sparing with WBRT. As well, future trials should examine homogeneous participants with brain metastases with focus on prognostic features and molecular markers.

Decision making about healthcare-related tests and diagnostic test strategies. Paper 4: International guidelines show variability in their approaches.

OBJECTIVES: The objective of the study was to describe and compare current practices in developing guidelines about the use of healthcare-related tests and diagnostic strategies (HCTDS). STUDY DESIGN AND SETTING: We sampled 37 public health and clinical practice guidelines about HCTDS from various sources without language restrictions. RESULTS: Detailed descriptions of the systems used to assess the quality of evidence and develop recommendations were challenging to find within guidelines. We observed much variability among and within organizations with respect to how they develop recommendations about HCTDS. Twenty-four percent of the guidelines did not consider health benefits and harms but based decisions solely on test accuracy. We did not identify guidelines that described the main potential care pathways involving tests for a healthcare problem. In addition, we did not identify guidelines that systematically assessed, described, and referenced the evidence that linked test accuracy and patient-important outcomes. CONCLUSION: There is considerable variability among the processes used and factors considered in developing recommendations about the use of tests. This variability may be the cause for the disagreement we observed in recommendations about testing for the same condition.

Decision making about healthcare-related tests and diagnostic test strategies. Paper 3: a systematic review shows limitations in most tools designed to assess quality and develop recommendations.

OBJECTIVES: The objective of this study was to identify and describe critical appraisal tools designed for assessing the quality of evidence (QoE) and/or strength of recommendations (SoRs) related to health care-related tests and diagnostic strategies (HCTDSs). STUDY DESIGN AND SETTING: We conducted a systematic review to identify tools applied in guidelines, methodological articles, and systematic reviews to assess HCTDS. RESULTS: We screened 5,534 titles and abstracts, 1,004 full-text articles, and abstracted data from 330 references. We identified 29 tools and 14 modifications of existing tools for assessing QoE and SoR. Twenty-three out of 29 tools acknowledge the importance of assessing the QoE and SoR separately, but in 8, the SoR is based solely on QoE. When making decisions about the use of tests, patient values and preferences and impact on resource utilization were considered in 6 and 8 tools, respectively. There is also confusion about the terminology that describes the various factors that influence the QoE and SoR. CONCLUSION: Although at least one approach includes all relevant criteria for assessing QoE and determining SoR, more detailed guidance about how to operationalize these assessments and make related judgments will be beneficial. There is a need for a better description of the framework for using evidence to make decisions and develop recommendations about HCTDS.

Systematic reviews and meta-analyses of the accuracy of HPV tests, visual inspection with acetic acid, cytology, and colposcopy.

BACKGROUND: Cervical cancer screening is offered to women to identify and treat cervical intraepithelial neoplasia (CIN). OBJECTIVES: To support WHO guidelines, a systematic review was performed to compare test accuracy of the HPV test, cytology (cervical smear), and unaided visual inspection with acetic acid (VIA); and to determine test accuracy of HPV and colposcopy impression. SEARCH STRATEGY: Medline and Embase were searched up to September 2012, and experts were contacted for references. SELECTION CRITERIA: Studies of at least 100 nonpregnant women (aged ≥18years) not previously diagnosed with CIN were included. DATA COLLECTION AND ANALYSIS: Two investigators independently screened and collected data. Pooled sensitivity and specificity, and absolute differences were calculated, and the quality of evidence assessed using GRADE (Grading of Recommendations Assessment, Development and Evaluation). MAIN RESULTS: High to moderate quality evidence was found. The greatest difference in overtreatment occurred with VIA instead of the cervical smear (58 more per 1000 women). Differences in missed treatment ranged from 2-5 per 1000 women. For 1000 women screened positive and then sent to colposcopy, 464 would be falsely diagnosed with CIN grade 2-3 and treated. CONCLUSIONS: Although differences in sensitivity between tests could be interpreted as large, absolute differences in missed diagnoses were small. By contrast, small differences in specificity resulted in fairly large absolute differences in overtreatment.

Systematic reviews and meta-analyses of benefits and harms of cryotherapy, LEEP, and cold knife conization to treat cervical intraepithelial neoplasia.

BACKGROUND: Cervical intraepithelial neoplasia (CIN) stage 2-3 is a premalignant lesion that can progress to cervical cancer in 10-20 years if untreated. OBJECTIVES: To conduct systematic reviews of randomized and nonrandomized studies for effects of cryotherapy, loop electrosurgical excision procedure (LEEP), and cold knife conization (CKC) as treatment for CIN 2-3. SEARCH STRATEGY: Medline, Embase, and other databases were searched to February 2012 for benefits, and to July 2012 for harms. Additionally, experts were contacted. Keywords for CIN, cervical cancer, and the treatments were used. SELECTION CRITERIA: Studies of nonpregnant women 18 years or older not previously treated for CIN were included. DATA COLLECTION AND ANALYSIS: Two investigators independently screened and collected data. Relative risks and proportions were calculated and evidence assessed using GRADE (Grading of Recommendations Assessment, Development and Evaluation). MAIN RESULTS: Recurrence rate was 5.3% 12 months after cryotherapy or LEEP, and 1.4% after CKC. There seemed to be little or no differences in frequency of complications after LEEP or cryotherapy, but they occurred more often after CKC. Evidence suggests premature delivery is most common with CKC, but it also occurs after LEEP and cryotherapy. CONCLUSIONS: Despite a comprehensive search, there is very low quality evidence and often no evidence for important outcomes, including reproductive outcomes and complications. Studies assessing these outcomes are needed.

Strategies to enhance venous thromboprophylaxis in hospitalized medical patients (SENTRY): a pilot cluster randomized trial.

BACKGROUND: Venous thromboembolism (VTE) is a common preventable cause of mortality in hospitalized medical patients. Despite rigorous randomized trials generating strong recommendations for anticoagulant use to prevent VTE, nearly 40% of medical patients receive inappropriate thromboprophylaxis. Knowledge-translation strategies are needed to bridge this gap. METHODS: We conducted a 16-week pilot cluster randomized controlled trial (RCT) to determine the proportion of medical patients that were appropriately managed for thromboprophylaxis (according to the American College of Chest Physician guidelines) within 24 hours of admission, through the use of a multicomponent knowledge-translation intervention. Our primary goal was to determine the feasibility of conducting this study on a larger scale. The intervention comprised clinician education, a paper-based VTE risk assessment algorithm, printed physicians' orders, and audit and feedback sessions. Medical wards at six hospitals (representing clusters) in Ontario, Canada were included; three were randomized to the multicomponent intervention and three to usual care (i.e., no active strategies for thromboprophylaxis in place). Blinding was not used. RESULTS: A total of 2,611 patients (1,154 in the intervention and 1,457 in the control group) were eligible and included in the analysis. This multicomponent intervention did not lead to a significant difference in appropriate VTE prophylaxis rates between intervention and control hospitals (appropriate management rate odds ratio = 0.80; 95% confidence interval: 0.50, 1.28; p = 0.36; intra-class correlation coefficient: 0.022), and thus was not considered feasible. Major barriers to effective knowledge translation were poor attendance by clinical staff at education and feedback sessions, difficulty locating preprinted orders, and lack of involvement by clinical and administrative leaders. We identified several factors that may increase uptake of a VTE prophylaxis strategy, including local champions, support from clinical and administrative leaders, mandatory use, and a simple, clinically relevant risk assessment tool. CONCLUSIONS: Hospitals allocated to our multicomponent intervention did not have a higher rate of medical inpatients appropriately managed for thromboprophylaxis than did hospitals that were not allocated to this strategy.

Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases.

BACKGROUND: Brain metastases represent a significant healthcare problem. It is estimated that 20% to 40% of patients with cancer will develop metastatic cancer to the brain during the course of their illness. The burden of brain metastases impacts on quality and length of survival. Presenting symptoms include headache (49%), focal weakness (30%), mental disturbances (32%), gait ataxia (21%), seizures (18%), speech difficulty (12%), visual disturbance (6%), sensory disturbance (6%) and limb ataxia (6%).Brain metastases may spread from any primary site. The most common primary site is the lung, followed by the breast then gastrointestinal sites. Eighty-five per cent of brain metastases are found in the cerebral hemispheres, 10% to 15% in the cerebellum and 1% to 3% in the brainstem. Brain radiotherapy is used to treat cancer participants who have brain metastases from various primary malignancies.This is an update to the original review published in Issue 3, 2006. OBJECTIVES: To assess the effectiveness and adverse effects of whole brain radiotherapy (WBRT) in adult participants with multiple metastases to the brain. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 3, 2011), MEDLINE and EMBASE to July 2011. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing WBRT either alone or with other treatments in adults with newly diagnosed multiple metastases to the brain from any primary cancer. Trials of prophylactic WBRT were excluded as well as trials that dealt with surgery or WBRT, or both, for the treatment of single brain metastasis. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and abstracted information. Adverse effects information was also collected from the trials. MAIN RESULTS: Nine RCTs involving 1420 participants were added in this updated review. This updated review now includes a total of 39 trials involving 10,835 participants.Eight published reports (nine RCTs) showed no benefit of altered dose-fractionation schedules as compared to the control fractionation (3000 cGy in 10 fractions daily) of WBRT for overall survival. These studies also showed no improvement in symptom control nor neurologic improvement among the different dose-fractionation schemes as compared to 3000 cGy in 10 daily fractions of WBRT. This updated review includes two trials comparing 4000 cGy in 20 fractions given twice daily versus 2000 cGy in 4 or 5 daily fractions. Overall, there was no survival advantage (hazard ratio (HR) 1.18, 95% confidence interval (CI) 0.89 to 1.56, P = 0.25) with the use of 4000 cGy in 20 fractions given twice daily compared to 2000 cGy in 4 or 5 daily fractions.The addition of radiosensitizers in six RCTs did not confer additional benefit to WBRT in either the overall survival times (HR 1.08, 95% CI 0.98 to 1.18, P = 0.11) or brain tumour response rates (HR 0.87, 95% CI 0.60 to 1.26, P = 0.46).Two RCTs found no benefit in overall survival (HR 0.61, 95% CI 0.27 to 1.39, P = 0.24) with the use of WBRT and radiosurgery boost as compared to WBRT alone for selected participants with multiple brain metastases (up to four brain metastases). Overall, there was a statistically significant improvement in local brain control (HR 0.35, 95% CI 0.20 to 0.61, P = 0.0003) favouring the WBRT and radiosurgery boost arm. Only one trial of radiosurgery boost with WBRT reported an improved Karnofsky performance score outcome and improved ability to reduce the dexamethasone dose.In this updated review, a total of three RCTs reported on selected patients (with up to three or four brain metastases) treated with radiosurgery alone versus WBRT and radiosurgery. Based on two trials, there was no difference in overall survival (HR 0.98, 95% CI 0.71 to 1.35, P = 0.88). The addition of WBRT when added to radiosurgery significantly improved locally treated brain metasatases control (HR 2.61, 95% CI 1.68 to 4.06, P < 0.0001) and distant brain control (HR 2.15, 95% CI 1.55 to 2.99, P < 0.00001). On the other hand, one trial concluded that patients treated with WBRT and radiosurgery boost were significantly more likely to show a decline in learning and memory function as compared to those treated with radiosurgery alone.One RCT examined the use of WBRT and prednisone versus prednisone alone and produced inconclusive results. AUTHORS' CONCLUSIONS: None of the RCTs with altered WBRT dose-fractionation schemes as compared to standard (3000 cGy in 10 daily fractions or 2000 cGy in 4 or 5 daily fractions) found a benefit in terms of overall survival, neurologic function, or symptom control.The use of radiosensitizers or chemotherapy in conjunction with WBRT remains experimental.Radiosurgery boost with WBRT may improve local disease control in selected participants as compared to WBRT alone, although survival remains unchanged for participants with multiple brain metastases.This updated review now includes a total of three RCTs examining the use of radiosurgery alone versus WBRT and radiosurgery. The addition of WBRT to radiosurgery improves local and distant brain control but there is no difference in overall survival. Patients treated with radiosurgery alone were found to have better neurocognitive outcomes in one trial as compared to patients treated with WBRT and radiosurgery.The benefit of WBRT as compared to supportive care alone has not been studied in RCTs. It may be that supportive care alone, without WBRT, is appropriate for some participants, particularly those with advanced disease and poor performance status.

Barriers and potential solutions toward optimal prophylaxis against deep vein thrombosis for hospitalized medical patients: a survey of healthcare professionals.

OBJECTIVE: Deep vein thrombosis (DVT) prophylaxis remains underused in hospitalized medical patients despite strong recommendations that at-risk patients should receive prophylaxis. To understand this gap between knowledge and practice, we surveyed clinicians' perceptions about the importance of DVT prophylaxis, barriers to guideline implementation, and interventions to optimize prophylaxis. METHODS: Paper- and electronic mail-based surveys were sent to 1553 internists, nurses, pharmacists, and physiotherapists in Ontario, Canada. Responses were scored on 7-point Likert scales. An important barrier to optimal DVT prophylaxis was 1 with a mean score ≥5, and interventions with high potential success or feasibility were those with mean scores ≥5. RESULTS: DVT prophylaxis was perceived as important by all clinician groups but this did not appear to translate into knowledge about underutilization of current DVT prophylaxis strategies. Physicians and pharmacists recognized the underuse of DVT prophylaxis in medical patients, while nurses and physiotherapists tended to perceive prophylaxis strategies as appropriate. Lack of clear indications and contraindications for prophylaxis and concerns about bleeding risks were perceived as important barriers. Preprinted orders were considered the most potentially successful and feasible way to optimize prophylaxis. CONCLUSIONS: A considerable barrier to optimal DVT prophylaxis utilization may be that those healthcare providers best able to conduct a daily assessment of patients' need for prophylaxis underrecognize the problem that prophylaxis is underutilized in this population. Interventions to bridge the gap between knowledge and practice should consider preprinted orders outlining DVT risk factors, and educating front-line care providers prior to implementation of a top-down approach.

Safety of uninterrupted anticoagulation in patients requiring elective coronary angiography with or without percutaneous coronary intervention: a systematic review and metaanalysis.

BACKGROUND: Patients who are receiving vitamin K antagonist (VKA) therapy pose challenges when they require surgery or invasive procedures because the risk for bleeding during the procedure must be balanced against the risk of an atherothrombotic event if the VKA is interrupted. However, it may be possible to safely perform some procedures, such as coronary angiography with or without percutaneous coronary intervention (PCI), without VKA interruption. METHODS: We undertook a systematic review and metaanalysis to assess the safety of a periprocedural management strategy of uninterrupted VKA (U-VKA) vs interrupted VKA (I-VKA) with or without bridging with low-molecular-weight heparin in patients undergoing elective coronary angiography with or without PCI. RESULTS: Eight studies were included in the review. Most were of moderate to very low quality. A strategy of U-VKA appears to confer approximately one-half the risk (odds ratio, 0.43; 95% CI, 0.26-0.73) of experiencing an access site bleeding complication within 1 week of the procedure compared with a strategy of I-VKA. The U-VKA strategy was associated with a pooled access site bleeding complication rate of 4.0% (95% CI, 3.0-7.0), and although high heterogeneity precluded pooling of such a rate in the I-VKA group, these rates ranged from 2% to 14%. CONCLUSION: Although it appears that coronary angiography with or without PCI can be safely performed without interrupting VKA, the low methodologic quality of existing studies precludes any definitive conclusions. Randomized trials assessing different anticoagulation strategies are needed to establish evidence-based practice guidelines in this setting.

The management of dyspnea in cancer patients: a systematic review.

GOALS OF WORK: The goal of the study is to evaluate the effectiveness of four drug classes (opioids, phenothiazines, benzodiazepines, and systemic corticosteroids) for relieving dyspnea experienced by advanced cancer patients. MATERIALS AND METHODS: A systematic literature review was conducted to July 2006. Search sources included MEDLINE, EMBASE, HealthSTAR, CINAHL, and the Cochrane Library. Four reviewers selected evidence using predefined criteria: controlled trials not limited to cancer and involving the specified drug classes for dyspnea treatment. MAIN RESULTS: Three systematic reviews, one with meta-analysis, two practice guidelines, and 28 controlled trials were identified. Most examined the effect of opioids, generally morphine, on dyspnea. Although the results of individual trials were mixed, the systematic review with meta-analysis detected a significant benefit for dyspnea with systemic opioids; two small placebo-controlled trials in cancer patients found systemic morphine reduced dyspnea, and dihydrocodeine also significantly reduced dyspnea in four placebo-controlled trials. Nebulized morphine was not effective in controlling dyspnea in any study or the meta-analysis. No controlled trials examined systemic corticosteroids in the treatment of cancer patients, and of the other non-opioid drugs examined, only oral promethazine, a phenothiazine, showed some benefit in the relief of dyspnea. Studies varied in methodological quality. CONCLUSIONS: Systemic opioids, administered orally or parenterally, can be used to manage dyspnea in cancer patients. Oral promethazine may also be used, as a second-line agent if systemic opioids cannot be used or in addition to systemic opioids. Nebulized morphine, prochlorperazine, and benzodiazepines are not recommended for the treatment of dyspnea, and promethazine must not be used parenterally.

The treatment of depression in cancer patients: a systematic review.

GOALS OF THE WORK: To evaluate the efficacy of pharmacological and nonpharmacological treatments for depression in cancer populations. MATERIALS AND METHODS: The Supportive Care Guidelines Group conducted a systematic review of the published literature through June 2005. Search sources includes MEDLINE, EMBASE, CINAHL, PsycInfo, and the Cochrane Library. Comparative studies of treatments for depression in cancer patients were selected for review by two group members based on predefined criteria. MAIN RESULTS: Seven trials of pharmacological agents and four of nonpharmacological interventions were identified. Two trials detected a significant reduction in depressive symptoms for mianserin compared with placebo, and one trial found alprazolam to be superior to progressive muscle relaxation. Four drug trials found no significant difference between groups on depression measures although posttreatment reduction of symptoms was observed for all groups in two trials comparing active treatments (fluoxetine vs desipramine and paroxetine vs amitriptyline). Of the four trials involving nonpharmacological therapies for the management of depression, two detected a benefit for treatment (a multicomponent nurse delivered intervention and an orientation program) over usual care. CONCLUSION: There is limited evidence for the effectiveness of pharmacological and psychosocial interventions in the treatment of cancer patients with depressive disorders, and no evidence for the superiority of one treatment modality over another. Based on evidence from the general population and other medically ill populations, combined approaches to the treatment of depression may be the most effective. Further research is necessary in cancer patients to determine the relative effectiveness of psychosocial, pharmacological, and combined treatments.

The prevention and management of acute skin reactions related to radiation therapy: a systematic review and practice guideline.

GOALS OF WORK: To develop a practice guideline report on the questions: What are the optimal methods to prevent acute skin reactions (occurring within the first 6 months of irradiation) related to radiation therapy? What are the optimal methods to manage acute skin reactions related to radiation therapy? MATERIALS AND METHODS: Cancer Care Ontario's Supportive Care Guidelines Group (SCGG) conducted a systematic review of literature on this topic. Evidence-based recommendations were formulated to guide clinical decision making, and a formal external review process was conducted to validate the relevance of these opinions for Ontario practitioners. MAIN RESULTS: Twenty-eight trials meeting the inclusion criteria were identified. Of the twenty-three trials that evaluated preventative methods, washing was the only practice which significantly prevented skin reaction. Some evidence suggested topical steroid creams and calendula ointment might be effective. None of the five trials evaluating skin reaction management detected a positive effect using steroid cream, sucralfate cream, or dressings. CONCLUSIONS: Skin washing, including gentle washing with water alone with or without mild soap, should be permitted in patients receiving radiation therapy to prevent acute skin reaction. There is insufficient evidence to support or refute specific topical or oral agents for the prevention or management of acute skin reaction. In the expert opinion from the SCGG, the use of a plain, non-scented, lanolin-free hydrophilic cream may be helpful in preventing radiation skin reactions. In addition, a low dose (i.e., 1%) corticosteroid cream may be beneficial in the reduction of itching and irritation.

The use of chemotherapy in patients with advanced malignant pleural mesothelioma: a systematic review and practice guideline.

BACKGROUND: This clinical practice guideline, based on a systematic review, was developed to determine which chemotherapeutic agents (or combinations of agents) show the highest response rates, improved survival, quality of life, or symptom control in patients with advanced malignant pleural mesothelioma. METHODS: A thorough systematic search of the literature was conducted for published articles and conference proceedings for applicable abstracts. Relevant trials, published as articles and abstracts, were selected and assessed. External feedback was obtained from Ontario clinicians, and the guideline was approved by the provincial Lung Cancer Disease Site Group. RESULTS: One hundred nineteen studies were eligible, including eight randomized trials and 111 phase II trials. The pooled response rates from phase II trials suggest that response rates with combination chemotherapy are higher than with single agents. Data from the largest randomized controlled trial demonstrated that chemotherapy with cisplatin and pemetrexed significantly improves response rates (41% versus 17%, p < 0.001), time to progression (5.7 months versus 3.9 months, p = 0.001), and overall survival (median, 12.1 months versus 9.3 months, hazard ratio = 0.77, p = 0.020) in comparison to single-agent cisplatin. A second trial demonstrated cisplatin and raltitrexed significantly improved median survival compared to single-agent cisplatin (11.4 months versus 8.8 months; hazard ratio = 0.76, p = 0.0483). Overall response rate (24% versus 14%, p = 0.056) was greater in the combination treatment arm, but this difference was not statistically significant. CONCLUSIONS: There is good evidence to recommend chemotherapy with pemetrexed and cisplatin for adult patients with symptomatic advanced malignant pleural mesothelioma. Such treatment should be administered with supplementation of vitamin B12 and folic acid. If pemetrexed is not available, cisplatin plus raltitrexed is a reasonable alternative.

Radiotherapeutic management of brain metastases: a systematic review and meta-analysis.

BACKGROUND: The management of brain metastases is a significant health care problem. An estimated 20-40% of cancer patients will develop metastatic cancer to the brain during the course of their illness. METHODS: A systematic review of randomized trials on adult cancer patients with single or multiple brain metastases from cancer of any histology was conducted. Eligible studies investigated external beam radiotherapy or radiosurgery in one of the study arms. Outcomes of interest included survival, intracranial progression-free duration, response of brain metastases to therapy, quality of life, symptom control, neurological function, and toxicity. RESULTS: Twenty-seven trials were included in this systematic review of the evidence. Pooled results from three randomized trials of surgical excision combined with whole brain radiotherapy (WBRT) showed no improvement in overall survival as compared to WBRT alone in patients with single brain metastasis. One randomized study of postoperative WBRT following excision of a single brain metastasis versus surgery alone detected a significant reduction in intracranial tumour recurrence rates but no corresponding difference in overall survival. Nine trials of altered dose-fractionation schedules compared to a standard control fractionation schedule (3000 cGy in 10 fractions) of WBRT showed no difference in probability of survival at 6 months. The addition of radiosensitizers, as assessed in five trials, did not confer additional benefit to WBRT in terms of overall survival or the frequency of brain metastases response. Three trials examined the use of WBRT and radiosurgery boost versus WBRT alone in selected patients with brain metastases. Overall survival did not improve for patients with multiple brain metastases. However, one trial reported an improvement in survival for patients with single brain metastasis treated with WBRT and radiosurgery boost. One older randomized trial examined the use of WBRT versus supportive care alone (using oral prednisone). Results were not conclusive. CONCLUSION: For patients with a single brain metastasis, good performance status, and minimal or no evidence of extracranial disease, surgical excision and postoperative WBRT improves survival (as compared to WBRT alone). There may be a small survival advantage associated with the use of radiosurgery boost and WBRT as compared to WBRT alone in selected patients with a single brain metastasis. There is no difference in overall survival or in neurologic function improvement with the use of altered whole brain dose-fractionation schedules as compared to standard fractionation schedules (3000 cGy in 10 fractions or 2000 cGy in 5 fractions). There is no survival benefit associated with the use of radiosurgery boost and WBRT versus WBRT alone in patients with multiple brain metastases. Currently, neither chemotherapy nor radiosensitizers show a clear benefit in the objective parameters of survival and progression-free survival. For patients with poor performance status and active extracranial disease, steroids and supportive care are an option.

Clinical practice guideline on the optimal radiotherapeutic management of brain metastases.

BACKGROUND: An evidence-based clinical practice guideline on the optimal radiotherapeutic management of single and multiple brain metastases was developed. METHODS: A systematic review and meta-analysis was performed. The Supportive Care Guidelines Group formulated clinical recommendations based on their interpretation of the evidence. External review of the report by Ontario practitioners was obtained through a mailed survey, and final approval was obtained from Cancer Care Ontario's Practice Guidelines Coordinating Committee (PGCC). RESULTS: One hundred and nine Ontario practitioners responded to the survey (return rate 44%). Ninety-six percent of respondents agreed with the interpretation of the evidence, and 92% agreed that the report should be approved. Minor revisions were made based on feedback from external reviewers and the PGCC. The PGCC approved the final practice guideline report. CONCLUSIONS: For adult patients with a clinical and radiographic diagnosis of brain metastases (single or multiple) we conclude that: surgical excision should be considered for patients with good performance status, minimal or no evidence of extracranial disease, and a surgically accessible single brain metastasis. Postoperative whole brain radiotherapy (WBRT) should be considered to reduce the risk of tumour recurrence for patients who have undergone resection of a single brain metastasis. Radiosurgery boost with WBRT may improve survival in select patients with unresectable single brain metastases. The whole brain should be irradiated for multiple brain metastases. Standard dose-fractionation schedules are 3000 cGy in 10 fractions or 2000 cGy in 5 fractions. Radiosensitizers are not recommended outside research studies. In select patients, radiosurgery may be considered as boost therapy with WBRT to improve local tumour control. Radiosurgery boost may improve survival in select patients. Chemotherapy as primary therapy or chemotherapy with WBRT remains experimental. Supportive care is an option but there is a lack of Level 1 evidence as to which subsets of patients should be managed with supportive care alone. Qualifying statements addressing factors to consider when applying these recommendations are provided in the full report. The rigorous development, external review and approval process has resulted in a practice guideline that is strongly endorsed by Ontario practitioners.

Radiotherapy fractionation for the palliation of uncomplicated painful bone metastases - an evidence-based practice guideline.

BACKGROUND: This practice guideline was developed to provide recommendations to clinicians in Ontario on the preferred standard radiotherapy fractionation schedule for the treatment of painful bone metastases. METHODS: A systematic review and meta-analysis was performed and published elsewhere. The Supportive Care Guidelines Group, a multidisciplinary guideline development panel, formulated clinical recommendations based on their interpretation of the evidence. In addition to evidence from clinical trials, the panel also considered patient convenience and ease of administration of palliative radiotherapy. External review of the draft report by Ontario practitioners was obtained through a mailed survey, and final approval was obtained from the Practice Guidelines Coordinating Committee. RESULTS: Meta-analysis did not detect a significant difference in complete or overall pain relief between single treatment and multifraction palliative radiotherapy for bone metastases. Fifty-nine Ontario practitioners responded to the mailed survey (return rate 62%). Forty-two percent also returned written comments. Eighty-three percent of respondents agreed with the interpretation of the evidence and 75% agreed that the report should be approved as a practice guideline. Minor revisions were made based on feedback from the external reviewers and the Practice Guidelines Coordinating Committee. The Practice Guidelines Coordinating Committee approved the final practice guideline report. CONCLUSION: For adult patients with single or multiple radiographically confirmed bone metastases of any histology corresponding to painful areas in previously non-irradiated areas without pathologic fractures or spinal cord/cauda equine compression, we conclude that: Where the treatment objective is pain relief, a single 8 Gy treatment, prescribed to the appropriate target volume, is recommended as the standard dose-fractionation schedule for the treatment of symptomatic and uncomplicated bone metastases. Several factors frequently considered in clinical practice when applying this evidence such as the effect of primary histology, anatomical site of treatment, risk of pathological fracture, soft tissue disease and cord compression, use of antiemetics, and the role of retreatment are discussed as qualifying statements.Our systematic review and meta-analysis provided high quality evidence for the key recommendation in this clinical practice guideline. Qualifying statements addressing factors that should be considered when applying this recommendation in clinical practice facilitate its clinical application. The rigorous development and approval process result in a final document that is strongly endorsed by practitioners as a practice guideline.