Elsevier

World Neurosurgery

Volume 112, April 2018, Pages e425-e430
World Neurosurgery

Original Article
CyberKnife Radiosurgery in the Multimodal Management of Patients with Cushing Disease

https://doi.org/10.1016/j.wneu.2018.01.057Get rights and content

Highlights

  • This retrospective study reports use of CyberKnife in our first cohort with Cushing disease.

  • CyberKnife is an effective treatment for Cushing disease in about half of subjects.

  • Side effects to CyberKnife, including visual impairment and hypopituitarism, are rare.

Background

Surgery is the primary treatment for Cushing disease. When surgery is unsuccessful in normalizing hypercortisolism, adjuvant radiation, such as stereotactic radiosurgery, may be useful to improve biochemical control.

Methods

This retrospective study included a cohort of consecutive patients treated with CyberKnife (CK) radiosurgery for active Cushing disease at Stanford Hospital and Clinics.

Results

As first-line treatment, all patients underwent transsphenoidal surgery with histologic demonstration of an adrenocorticotropic hormone–producing pituitary adenoma. CK was performed as adjuvant therapy for persistent or recurrent disease. The median time between surgery and CK was 14 ± 34 months. Before CK, median maximal diameter of tumors was 9 mm (range, 7–32 mm), with cavernous sinus invasion in all patients (100%) and abutment of the optic chiasm in 1 patient (14.2%). With an average follow-up of 55.4 months, normalization of hypercortisolism was achieved in 4 patients (57.1%): 2 patients (28.5%) achieved normalization of the hypothalamic-pituitary-adrenal axis without glucocorticoid replacement, and 2 patients developed hypoadrenalism (28.5%). The median time to biochemical remission was 12.5 months. Hypopituitarism occurred in only 1 patient (14.2%), and no patients had visual complications. Time between surgery and radiotherapy of <14 months was associated with a significantly improved biochemical remission rate (P = 0.02).

Conclusions

In a cohort of patients with Cushing disease, we demonstrate that CK is an effective treatment with rare complications.

Introduction

Cushing disease (CD) refers to hypercortisolism resulting from an adrenocorticotropic hormone (ACTH)–producing pituitary adenoma and accounts for 70% of cases of Cushing syndrome.1, 2, 3 Approximately 40% of patients have a microadenoma or no visible tumor at presentation.4 The Endocrine Society Clinical Guidelines5 recommend surgery as initial treatment, but failure to achieve surgical remission is common (60% in macroadenomas),6 and patients with recurrent or residual disease often require additional treatment. Adjuvant therapeutic options in both adult and pediatric patients include repeat transsphenoidal (or open) surgery, radiotherapy, medical therapy, and bilateral adrenalectomy.7

Use of stereotactic radiosurgery (SRS) in recurrent or residual CD has increased, but experience is still limited.8, 9 Several small series of patients with CD treated with Gamma Knife (GK) (Elekta AB, Stockholm, Sweden) SRS have reported biochemical remission rates of 17%–87%.10, 11 GK SRS was complicated by hypopituitarism in approximately 30% of patients and optic neuropathy in selected cases.10, 12, 13 CyberKnife (CK) (Accuray Inc., Sunnyvale, California, USA) robotic SRS is a frameless image-guided stereotactic device that was first described by Adler et al.14 in 1997 and is increasingly incorporated into treatment regimens for recalcitrant pituitary tumors. CK appears to be an efficacious adjuvant treatment option in clinically nonfunctioning pituitary adenomas.5 Similar to other forms of SRS, CK may be associated with complications, including visual field deficits and hypopituitarism.13 At the present time, there are virtually no data on outcomes of patients with CD treated with CK. This study aims to review the outcomes and complication profile of the first cohort of patients treated with the CK at Stanford Health Care.

Section snippets

Patient Selection

Following institutional review board approval, a retrospective review of all patients with pituitary adenomas who underwent CK treatment between 2000 and 2016 at Stanford Health Care was performed. This article conforms to the STROBE (STrengthening the Reporting of OBservation studies in Epidemiology) guidelines. Patients met the study inclusion criteria if they had histologically confirmed diagnosis of an ACTH-staining pituitary adenoma, confirmed residual or recurrent tumor based on imaging

Patients

Inclusion criteria were met by 7 patients (2 men and 5 women) with active CD. Age range was 18–67 years (median 35.2 ± 18.7 years) (Table 1). At diagnosis, in addition to typical signs and symptoms of CD, 2 patients (28.5%) presented with visual impairment, and 4 patients (57.1%) presented with headaches. No patients presented with diabetes insipidus. Radiologic evaluation at diagnosis showed an intrasellar location of the tumor in 1 (14.2%) patient, suprasellar extension in 2 (28.6%) patients,

Discussion

In the treatment guidelines for CD, SRS is recommended as a therapeutic option for patients who have failed surgery and/or medical therapy.5 In our initial cohort of patients with CD, we found that CK resulted in biochemical remission in 78% at 5 years in patients who had persistent histologically confirmed CD following initial surgery. This study shows the value of CK as an adjunct treatment in such patients. Only 1 other study has reported the results of CK in 2 patients with CD.20 In this

Conclusions

We described the efficacy and complication profile of CK in the treatment of CD. Our study suggests that CK is a safe and effective treatment for CD, allowing excellent local control and remission of the disease in more than half of patients. The shorter time between surgery and CK appears to result in a higher rate of remission. In this small cohort of patients, biochemical control was achieved without visual complications and only rarely new pituitary deficiency.

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    • Updates in the outcomes of radiation therapy for Cushing's disease

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      The visual defects rate varies from 0 to 1.4% in both CRT and FSRT series with CD patients [11,24]. Hypofractionated SRS (in 2–5 sessions) has been used with success for perioptic tumors, but experience with this method is limited [37]. Clinical case 2 - continued.

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      In our series of mixed PAs, we achieved a tumor growth control rate of 91.6%. This result is concordant with the current literature that reports an excellent and quite homogenous tumor growth control, ranging from 92.3% to 100% for CK treatment [7–10,12,17–22,26], and from 83.3% to 100% for GK-SRS [6]. It is note of worthy that the two patients showing tumor progression harbored aggressive PAs, bigger than the other ones and extensively invasive.

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      Remission rates of RT are therefore comparable to that of SRS, which is also true for the risk of new hypopituitarism. SRS using Cyberknife was used in seven patients with persistent or recurrent CD with sinus cavernosus invasion, reporting a remission rate 57% and no recurrence after a median follow-up of 4 years and 7 months (55 months) [21]. Recently, in 2017 and 2018 the group around Jason Sheehan from the International Gamma Knife Research Foundation published their results from a large, international and multicenter retrospective analysis for patients with CD treated with Gamma Knife.

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    Conflict of interest statement: This work was supported by National Institutes of Health Clinical and Translational Science Awards program REDCap grant UL1 TR001085.

    Justin M. Moore and Elisa Sala co–first authors.

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