PROSPERO International prospective register of systematic reviews Prophylactic cranial irradiation in patients with non-small-cell lung cancer: a systematic review and meta-analysis of randomized controlled trials Karine Al Feghali, Fady Geara, Rami Ballout, Elie Akl Citation Karine Al Feghali, Fady Geara, Rami Ballout, Elie Akl. Prophylactic cranial irradiation in patients with non-small-cell lung cancer: a systematic review and meta-analysis of randomized controlled trials. PROSPERO 2015:CRD42015023982 Available from http://www.crd.york.ac.uk/prospero_rebranding/display_record.asp?id=crd42015023982 Review question(s) To examine whether prophylactic cranial irradiation (PCI) reduces incidence of brain metastasis in patients with nonsmall-cell lung cancer treated with a curative intent To examine whether prophylactic cranial irradiation improves overall survival as compared to no PCI in patients with non-small-cell lung cancer treated with a curative intent To examine how PCI impacts quality of life as compared to no PCI in patients with non-small-cell lung cancer treated with a curative intent Searches A systematic search of the literature will be conducted using the electronic databases EMBASE, MEDLINE, PubMed and the Cochrane Central Register of Controlled Trials (CENTRAL) with search dates between 1946 and February 2014. All randomized controlled trials comparing PCI to no PCI in patients with NSCLC treated with a curative intent will be included. No restriction on language, publication date or publication status (published, unpublished material and abstracts) will be imposed. Search terms will include non-small-cell lung carcinoma, cranial irradiation and randomized controlled trials. The Cochrane Database for Systematic Reviews will also be reviewed. We will also search for ongoing trials in clinical trials registers: ClinicalTrials.gov, EU Clinical Trials Register (EU-CTR), and the International Clinical Trial registry Platform (ICTRP), and contact their principal investigators. The search will also be guided by reference lists of published studies (trials or reviews) and pertinent books, as well as proceedings of meetings, such as abstracts from the American Society of Clinical Oncology. Experts in the field will be consulted for information on potential unpublished data. Types of study to be included All randomized controlled trials comparing PCI to no PCI in patients with NSCLC treated with a curative intent will be included. No restriction on language, publication date or publication status (published, unpublished material and abstracts) will be imposed. Condition or domain being studied Lung cancer is among the most common malignancies worldwide. It is predicted to be the second most commonly diagnosed cancer and the most common cause of cancer deaths in 2015 in men and women in the United States, with non-small-cell lung cancer (NSCLC) accounting for approximately 80 to 85% of lung cancer cases. Brain has been reported across multiple studies as first site of failure after curative treatment in 14-28% of patients with NSCLC. Page: 1 / 5
Prophylactic cranial irradiation is recommended in the management of small cell lung cancer and has been demonstrated to confer a survival advantage over observation in patients who achieved a complete remission with chemotherapy. However, prophylactic cranial irradiation has not been shown to be associated with superior survival and is not routinely recommended in the management of NSCLC. The current systematic review aims at updating the 2005 Cochrane review. Participants/ population Studies including participants of any age with NSCLC who completed definitive therapy with no progression will be selected. Intervention(s), exposure(s) Studies included will be comparing PCI to no PCI. We will not segregate studies based on PCI dose or radiation therapy technique used. Comparator(s)/ control Observation (no PCI) is the comparator group. Outcome(s) Primary outcomes - Incidence of brain metastasis - Time to brain metastasis - Overall survival - Quality of life The primary measures of treatment effect in this meta-analysis are the relative risks (RR) of mortality reduction and incidence of brain metastasis comparing prophylactic cranial irradiation to observation, as well as hazard ratios of the time to death and the time to brain metastasis. Another outcome measure is the mean difference in quality of life scores using validated scales used in the selected studies, such as the QLQ-C30 and QLQ-BN20 scales. We will combine results of different scales using standardized mean differences. Secondary outcomes None Data extraction, (selection and coding) We devised a data abstraction form that the two reviewers will use independently. This form will be pilot-tested on 2 studies, randomly selected among the included studies to check for consistency between the reviewers and will be refined accordingly. All the data extraction will be performed in duplicate. Disagreements between the two reviewers will be resolved by discussion. If agreement cannot reached, then the senior author will make the final decision, after getting in contact with trial authors in order to confirm accuracy of the information or to gather missing information. Authors will be contacted by emails (if need be) explaining the purpose of our review, and a reminder email will be sent to those who did not reply after one week of the initial one. In case of no reply to the second email, the study will be excluded for lack of adequate information. Data will be extracted from each one of the included trials on the following: - Study design, year of publication - Inclusion/exclusion criteria - Trial participants: Age, gender, performance status, stage, type of non-small-cell lung cancer with histologic confirmation of the diagnosis (adenocarcinoma, large cell carcinoma, and/or squamous cell carcinoma), type of treatment received (surgery and/or chemotherapy and/or thoracic radiation therapy) Page: 2 / 5
- Intervention: Dose and fractionation of the prophylactic cranial irradiation, versus observation - Type of outcome measure: Incidence of brain metastasis, time to brain metastasis, overall survival, time to death and effect on quality of life (using a validated score) Risk of bias (quality) assessment Two independent reviewers will be assessing the risk of bias in each of the eligible randomized controlled trials using the Cochrane risk of bias tool, which evaluates generation of random sequence, concealment of allocation, blinding of subjects, healthcare providers, data collectors and outcome assessors, completeness of data, adherence to the intentionto-treat analysis as well as other biases (such as selective outcome reporting). Studies will be classified as having low risk, high risk or unclear risk of bias. We will not exclude studies based solely on the risk of bias. Strategy for data synthesis Synthesis of results: Analyses will be carried out on an intention-to-treat basis. The meta-analyses will be performed by computing RR (or HR) and 95% CI for each outcome using the random effect model. Statistical heterogeneity among trials will be assessed using the Chi square tests with significance at p-value = 0.1. We will quantitatively assess it using I-squared. Risk of bias across studies: We will use the funnel-plot method to assess and correct for publication bias. We will assess symmetry of the funnel plot visually and formally using Egger s test.we acknowledge however that asymmetry in funnel plots could be due to various factors other than publication bias, such as selective outcome reporting, differences in trial quality or true heterogeneity in intervention effect. We will also look for selective reporting within studies by comparing the outcomes reported in the published report to the outcomes outlined in the protocol, if available, or in abstracts of presentations that preceded publication of the study. Analysis of subgroups or subsets A subgroup analysis will be performed if possible to evaluate the effect of PCI on survival in highest risk patients (stage III) as opposed to stage I-II patients.we also plan to assess outcomes based on radiation therapy doses, and on NSCLC histology. Sensitivity analyses will also be performed, excluding older studies, as we expect the potential benefit of PCI to be more evident in more recent studies. Contact details for further information Dr Al Feghali Centre Sarah Saadeh - 2nd floor Wadi Chahrour Lebanon ka39@aub.edu.lb Organisational affiliation of the review American University of Beirut www.aub.edu.lb Review team Dr Karine Al Feghali, American University of Beirut Dr Fady Geara, American University of Beirut Page: 3 / 5
Mr Rami Ballout, American University of Beirut Dr Elie Akl, American University of Beirut Anticipated or actual start date 01 June 2015 Anticipated completion date 30 September 2015 Funding sources/sponsors No funding sources/sponsors Conflicts of interest None known Language English Country Lebanon Subject index terms status Subject indexing assigned by CRD Subject index terms Carcinoma, Non-Small-Cell Lung; Cranial Irradiation; Humans Stage of review Ongoing Date of registration in PROSPERO 17 July 2015 Date of publication of this revision 17 July 2015 DOI 10.15124/CRD42015023982 Stage of review at time of this submission Started Completed Preliminary searches Yes No Piloting of the study selection process Yes No Formal screening of search results against eligibility criteria Yes No Data extraction No No Risk of bias (quality) assessment No No Data analysis No No PROSPERO International prospective register of systematic reviews The information in this record has been provided by the named contact for this review. CRD has accepted this information in good faith and registered the review in PROSPERO. CRD bears no responsibility or liability for the content of this registration record, any associated files or external websites. Page: 4 / 5
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