Diagnostic accuracy of growth hormone stimulation tests for growth hormone deficiency following radiotherapy involving the hypothalamic-pituitary axis: protocol for a systematic review and planned meta-analysis.

INTRODUCTION: Radiotherapy is part of the treatment for many intracranial tumours, head and neck cancers and haematological malignancies. In these cases, the hypothalamic-pituitary (HP) axis is often included within the radiation field and can be damaged as an organ at risk. As survival improves, an increasing number of patients are living with late endocrine complications, particularly growth hormone deficiency (GHD). Diagnosing GHD in this context is challenging, as much of the evidence supporting growth hormone (GH) stimulation tests comes from populations with fundamentally different disease mechanisms. We aim to conduct a systematic review, and meta-analysis where feasible, to assess the diagnostic accuracy of GH stimulation tests for diagnosing GHD in children, teenagers, young adults and adults who have received radiotherapy involving the HP axis.

METHODS AND ANALYSIS: Eligible studies will include patients exposed to radiotherapy involving the HP axis, who subsequently underwent GH stimulation testing for suspected GHD. Index tests will include commonly used stimulation tests such as the insulin tolerance test, glucagon stimulation test, arginine stimulation test, clonidine stimulation test, GH-releasing hormone-arginine stimulation test and macimorelin stimulation test. Reference standards will include clinical criteria (≥2 additional pituitary hormone deficiencies) or alternative GH stimulation tests. Searches will be conducted in MEDLINE, Embase, Cochrane Library and PubMed. Two independent reviewers will screen studies, collect data, evaluate risk of bias using Quality Assessment of Diagnostic Accuracy Studies-2 and assess reporting quality using the Standards for Reporting of Diagnostic Accuracy Studies criteria. Sensitivity and specificity will be extracted. Where studies are sufficiently comparable, results will be pooled using hierarchical bivariate and summary receiver operating characteristic models. Prespecified subgroup analyses will explore heterogeneity by age group, body mass index, ethnicity, radiotherapy dose and time since treatment.

ETHICS AND DISSEMINATION: Ethical approval is not required as this systematic review summarises published data only. We will share our findings through peer-reviewed publications, conference presentations and engagement with relevant clinical teams to improve diagnostic decision-making in our population of interest.

PROSPERO REGISTRATION NUMBER: CRD420261415689.