Due to the wide availability of different treatment options for hypercalcemia of malignancy, the aim of this systematic review is to identify important contextual and decisional factors that affect choices for therapies of hypercalcemia of malignancy in adult patients.
We have completed the search, screening and selection, and data collection stages.
Information sources and search strategy
We conducted a comprehensive search using the following online databases: Medline (OVID), Pubmed, Embase.com, the Cochrane Library and CINAHL (EBSCO). The research team developed a search strategy for each data base using MESH terms and keywords related to malignancy, hypercalcemia and factors guiding therapy decision such as patients’ values and preferences, acceptability, equity, cost-effectiveness and feasibility, that was applied to adults, and limited to the last 10 years. We did not include any language restrictions. The strategy was reviewed and verified by the medical librarian at the American university of Beirut (LH), and two methodologists, at the Mayo Evidence Based Center (MHM) and the McMaster University (TP) (Appendix 2A). We also developed and executed another independent search using Medline, without any time limit, and the results were combined with the original search (Appendix 2B). We also tried to identify papers by hand searching references from the included studies..Eligibility criteria
We included observational studies, trials, reviews and qualitative studies conducted in adult patients (≥ 18 years of age) with hypercalcemia of malignancy. We included studies reporting on pharmacological therapy such as bisphosphonates, denosumab, diuretics, calcitonin, and calcimimetics as well as conservative management including hydration, avoiding calcium rich diet and vitamin D supplementation. We excluded case reports, studies conducted in the pediatric population or in patients with hypercalcemia from a condition unrelated to malignancy for example parathyroid disease, Familial Hypocalciuric Hypercalcemia (FHH), vitamin D intoxication, and side effects of medications.Outcomes
Our outcomes of interest are EtD factors:
- Patients or physicians values (how patients or physicians value each outcome in terms of its importance to their context and daily life)
- Cost and resources (cost effectiveness, actual charges, out of pocket costs)
- Acceptability (of treatment options and their method of administration)
- Feasibility (of the intervention as it relates to the health care environment)
- Equity (whether the intervention would exacerbate health disparities or create inequities)
We excluded studies with inadequate outcome measurement or reporting.
We downloaded the literature search results into Covidence software (Covidence 2020) (24). We developed and pilot tested a screening sheet for title and abstract and another for the full texts (Appendix 3), based on our exclusion and inclusion criteria of individual studies. We performed a calibration exercise to familiarize the reviewers with the screening process.
All reviewers (AB, MR, TP, MHM, GEHF) contributed to pilot testing the screening at the title and abstract level for 100 citations. Two reviewers (AB, MR) then independently screened the remaining titles and abstracts using the screening sheet developed (Appendix 3A). We retrieved the full texts of all included citations. Two reviewers (AB, MR) screened these records independently and in duplicate using the full text screening guide (Appendix 3B). All disagreements throughout the screening process were resolved through discussion or with the help of a third reviewer as needed (TP, MHM, GEHF). All reasons for exclusion were recorded.
Data collection and abstraction
Following the full text screening, two reviewers (AB, MR) completed data abstraction independently and in duplicate using standardized data collection tables (Appendix 4). We implemented a calibration exercise to familiarize the reviewers with the process. Disagreements were resolved through discussion or with the help of a third reviewer as needed (TP, MHM, GEHF). We extracted the first author’s name, date of publication and the study design, and will collect data on the characteristics, methodology and results of each of the included studies (Appendix 4). In case of any missing data, we will contact the authors of the individual studies to obtain the relevant information.
Quality assessment of included studies
The methodological quality of the included studies will be evaluated using tools appropriate for each study design, including randomized trials, cohort and case control studies, case series, and qualitative research (25-30). Quality assessment will be done independently and in duplicate.
To assess the quality of any identified RCTs, we will use the Cochrane Risk of Bias tool which assesses the following domains: bias due to sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessors, incomplete outcome data, and selective outcome reporting(26). To assess the quality of observational studies we will use the New Castle-Ottawa quality assessment scale assessing the following categories: Selection, comparability, and outcome(27). For case series we will assess four domains: selection, ascertainment, causality and reporting (28). Finally, for qualitative articles, we will use the CASP appraisal checklist (29).
Data will be analyzed thematically and presented narratively. Two independent reviewers will identify themes from each article until saturation and reach consensus on how the themes would converge into unique. A third reviewer will adjudicate when consensus is not reached.
The certainty of evidence derived from the studies will be evaluated using the GRADE-CERQual approach which appraises qualitative research domains analogous to GRADE. This approach focuses on four domains: methodological limitations, coherence, adequacy and relevance (30). The overall assessment of confidence in the review findings will be based on the assessment of these individual domains.
The methodological limitations domain is assessed in individual studies based on the appropriate design, conduct, and data collection and analysis methods (31). The coherence domain assesses how clear and consistent the individual studies data are with the overall results of the review (32). The adequacy domain assesses the extent of details and available information provided in the review(33). Finally, the relevance domain assesses the extent to which the gathered individual data answers the review’s objectives and questions(34).