This was an ambidirectional descriptive cohort study on 16 consecutive patients with a confirmed Cushing’s disease that underwent Gamma Knife Radiosurgery (GKR). The patients were treated at Nasser Institute Gamma Knife Center in collaboration with the department of Neurosurgery Ain Shams University, Cairo, Egypt.
The study period was from January 2014 to June 2016, a duration of 30 months. Patients who had received GKR before July 2014 were reviewed for outcomes during the study period.
Patients enrolled were diagnosed in a coordinated four step diagnostic approach: Firstly, a general clinical evaluation; secondly, an establishment of an endocrinological diagnosis; thirdly, securing an anatomical diagnosis and finally assessment of the visual apparatus. We included patients with a minimum of two years follow up.
Excluded from the study were patients with Non-Functioning Pituitary Adenomas, functioning adenomas other than Cushing’s disease, cases with a follow up duration of less than 24 months and patients refusing to join the study.
Radiosurgery technique
All Patients were treated with Gamma Knife Radiosurgery either adjuvant (post microsurgical resection) or upfront. Treatment was performed using the Leksell Gamma Unit Model C or Perfexion, Elekta Instruments, Stockholm. The radiosurgery treatment was delivered as an outpatient procedure using a technique previously described [15, 16] as follows:
A local anesthetic agent was applied to the patient’s head followed by placement of the Leksell Stereotactic head frame (Model G, Elekta AB). High-resolution and thin slice (1.6 mm) gadolinium-enhanced MRI (Magnetic Resonance Imaging) was performed using a 1.5-T Genesis Sigma MR unit (General Electric). Magnetic Resonance Imaging was the only imaging technique used. Images were transported to the Gamma Plan 5.32 workstation (Elekta AB). Treatment planning included drawing of the target and delineation of the anterior visual pathway. Radiation coverage was generally intended to be ≥ 90% of the target; however, in some cases in which the tumor was in direct contact with the optic apparatus, coverage was intended to be at least 80%–85% of the tumor receiving the prescribed dose. The maximum dose directed at the optic apparatus was maintained below 9 Gy (Gray) when possible, without significant compromise of the tumor cover. Otherwise, in situations in which the maximum dose exceeded 9 Gy, a dose-volume histogram was created and the volume of anterior visual pathway receiving more than 9 Gy was kept lower than 10 mm3.
The treatment planning was done using HP (Hewlett Packard) computer hardware and Unix software as an operating system. GammaPlan (Elekta Instruments Inc) version 5.32 (Model C) and Leksell GammaPlan version 10.0 (Perfexion) were the planning softwares used.
Outcome
The main outcomes were biochemical remission and tumor volume control. Secondary outcomes were visual field changes and morbidity.
Follow-up
Follow up was bi-annually for the first two years and annually for the rest of the years. Follow up included a clinical, radiological, biochemical and visual assessment.
Clinical follow up
Post-radiosurgery clinical features were reviewed and compared with pre-treatment manifestations.
Radiological follow up
A contrasted MRI sella was reviewed and pre- and post- treatment radiological characteristics compared, especially for any tumor volume changes. Tumor volume changes were evaluated in two ways: By using the micrometer screw gauge in the 3D planes (axial, coronal and sagittal). In addition, a qualitative assessment was done by registering the change in tumor contour or noting tumor retraction away from the normal tissue (e.g., from optic nerves or chiasm). Tumor volume changes were categorized as: shrinkage, stable (stasis) or progression.
Tumor volume shrinkage was defined as a reduction in tumor size in at least two orthogonal planes by more than 20%. Tumor volume stability was defined as no change or change in less than two orthogonal planes. Tumor progression or enlargement was defined an increase in tumor size in at least two orthogonal planes by more than 20%. i.e., tumor growth within the planned treatment volume or adjacent to it was considered tumor progression. Tumor growth control was defined as either overall tumor shrinkage or stability at the last follow-up before time of data analysis comparing the last MRI with the pre-treatment one [17].
Biochemical follow up
Biochemical outcome was categorized into three: hormonal level normalization (or control), reduction or unchanged, with a plus one condition tagged as “pituitary deficiency.”
Biochemical Normalization was defined as a hormonal level within or below the accepted normal reference range. Hormonal reduction (improvement) was defined as the decrease in hormonal levels by more than 50% but not reaching the normal reference range. Otherwise, the hormonal level was described to be unchanged. Pituitary deficiency was defined as a requirement for new hormonal replacement medication after SRS or a requirement for a dose increase in preexisting hormone therapy [17].
Visual field assessment
A computerized Visual field was ordered during each follow up visit. The perimetry findings were compared with respect to overall appearance and quantitative data registered on the forms. Visual outcome was tetrachotomized into: normal, improvement, stable or visual field reduction. Visual deficit due to SRS was regarded if the patient reported post-radiosurgery visual complaints related to damage to the perisellar optic apparatus confirmed by visual field and acuity examinations [17].
Statistical analysis
Data were presented as the median (p25, p75) or mean (± standard deviation (SD)) for continuous variables, and as the frequency and percentage for categorical variables.
Statistics of means were performed using the unpaired Student t-test both with and without equal variance (Levene’s test) or ANOVA (Analysis of Variance) as necessary and the Wilcoxon rank-sum tests Or Kruskal Wallis test when variables were not normally distributed.
Statistical analyses of categorical variables were performed using the Chi square and Fisher exact test, as appropriate. Kaplan–Meier plots for endocrine remission and tumor volume control using the dates of the first SRS, and respective time to remission and shrinkage. Hormone remission and progression-free survival time were calculated from the day of the first SRS by using the Kaplan–Meier’s method. Univariate analysis was performed on the Kaplan–Meier curves using log-rank statistics. Stratified analyses were done for variables to check for confounders.
A p ≤ 0.05 was considered statistically significant. Commercially available statistical processing software (Stata,version 11.0, Stata Corp.) was used (Figs. 1, 2, 3, 4, 5).