Clinical Study
Cushing’s disease: A single centre’s experience using the linear accelerator (LINAC) for stereotactic radiosurgery and fractionated stereotactic radiotherapy

https://doi.org/10.1016/j.jocn.2013.04.007Get rights and content

Abstract

Cushing’s disease is hypercortisolaemia secondary to an adrenocorticotrophic hormone secreting pituitary adenoma. Primary management is almost always surgical, with limited effective medical interventions available. Adjuvant therapy in the form of radiation is gaining popularity, with the bulk of the literature related to the Gamma Knife. We present the results from our own institution using the linear accelerator (LINAC) since 1990. Thirty-six patients who underwent stereotactic radiosurgery (SRS), one patient who underwent fractionated stereotactic radiotherapy (FSRT) and for the purposes of comparison, 13 patients who had undergone conventional radiotherapy prior to 1990, were included in the analysis. Serum cortisol levels improved in nine of 36 (25%) SRS patients and 24 hour urinary free cortisol levels improved in 13 of 36 patients (36.1%). Tumour volume control was excellent in the SRS group with deterioration in only one patient (3%). The patient who underwent FSRT had a highly aggressive tumour refractory to radiation.

Introduction

Cushing’s disease is the most common cause of endogenous hypercortisolaemia, representing 70% of patients,1 but with an estimated relatively low incidence of 2.4 patients per million per year and a prevalence of 39.1 per million.2 It is more common in women, but in men it has been reported to occur at a younger age, have higher levels of urinary free cortisol (UFC) and adrenocorticotrophic hormone (ACTH), and be more clinically severe.3 Clinical findings include central fat accumulation, features of protein wasting including skin thinning, muscle wasting and osteoporosis, as well as impaired immunological function. Other clinical sequelae include hypertension which may lead to cardiac hypertrophy and congestive cardiac failure, hirsutism, gonadal dysfunction, and psychological disturbances.4 Due to the excess glucocorticoid activity, diabetes mellitus or at least glucose intolerance is also prevalent.5 Importantly, there is an increase in mortality due to vascular disease,6 with an increased risk in patients with pituitary tumours post-surgery and conventional radiotherapy (CRT) from cerebrovascular disease,7 as well as an increased mortality in patients with Cushing’s disease, in particular when compared to non-functioning pituitary adenomas.8 A systematic review of mortality in Cushing’s syndrome found that patients with Cushing’s disease with persistent elevated cortisol levels post-initial surgery had a standardised mortality rate (SMR) of 3.7 when compared to the general population, whereas patients who achieved remission post-surgery, and those with Cushing’s syndrome due to a benign cortisol-producing adrenal adenoma had no significant difference in SMR.9

Primary management of these tumours is almost always surgical. In experienced hands, impressive long-term remission rates of 80% overall with a rate of 90% in non-invasive, well-defined microadenomas have been reported, with low peri-operative morbidity and mortality usually less than 1%.10 This has shown to be true in the ageing population as well, defined by Gaini et al. as patients aged 65 years and older, without a significant increase in morbidity and mortality despite generally higher pre-operative American Society of Anesthesiologists scores.11 Management of recurrent disease has been discussed previously with an algorithm advocating the use of repeat surgery, radiation, medical therapy and bilateral adrenalectomy.12 Medical intervention at present is less effective than desired although new therapies are promising.13 Bilateral adrenalectomy is effective in controlling hypercortisolaemia, but condemns a patient to lifelong adrenal hormone replacement therapy, including the risk of Addisonian crises,14 as well as exposing them to the risk of developing Nelson’s syndrome.15

CRT has previously been used for the control of ACTH-secreting pituitary adenomas, and more recently stereotactic radiosurgery (SRS) has been employed with the theoretical benefit of increased efficacy and safety achieved in a single treatment. Most of the data regarding outcomes that is available in the literature at present is based on Gamma Knife (GK; Elekta AB, Stockholm, Sweden) based series,16 with only a few series of patients post-SRS with the linear accelerator (LINAC).17, 18, 19, 20, 21, 22 Limited data are available in regards to fractionated stereotactic radiotherapy (FSRT), with a series of 12 patients published previously,23, 24 as well as a report of two other patients.18

The purpose of this study was to audit our centre’s outcomes in providing focused radiation in the form of SRS which has been our practice since 1990. SRS is not feasible where the tumour is within 3 mm of the optic chiasm; these patients were treated with FSRT to focus the radiation to the target tissue with minimisation of the collateral effects. A comparison to previous patients managed with CRT at our institution was also made.

Section snippets

Materials and methods

This series of patients was analysed as part of a broader audit of the LINAC at our institution, as a form of quality assurance. Patients who were managed at our institution between 1971 and 2007 were deemed eligible for inclusion in this ethics approved study. A custom pituitary database was created using the Statistical Package for the Social Sciences (SPSS; SPSS Inc., Chicago, IL, USA) for this process and included all appropriately referred patients to our service. Inclusion criteria for

Results

Patient data was extracted from the database and organised in regards to treatment modality (SRS, FSRT and CRT). Tumour data for the CRT category was from the pre-MRI era and is based on CT imaging findings. In all, 65 patients with Cushing’s disease were referred to our service. Fifteen patients had no radiation and were further managed by their referring surgeon or physician. Thirty-six patients underwent SRS, of which one required follow-up SRS. Only one patient required FSRT who ultimately

Discussion

A recent review of radiation therapy by Starke et al. in 2010, including both CRT and SRS, identified a broad range of endocrine remission and tumour control for both modalities, with no correlation between endocrine and remission and reduction of tumour volume. For CRT patients, endocrine remission rates range from 46–100%, and tumour control in 93–100% of patients. For SRS, remission rates were more widely distributed at 10–100% with inconsistencies in regards to definition of remission

Conclusions

Biochemical improvements in our series of Cushing’s disease post-SRS were modest, and more pronounced in 24 hour urinary cortisol results than morning serum cortisol levels. Morphological control was excellent with the exception of one patient with a biologically aggressive tumour despite SRS, and one initially large tumour that was unresponsive to FSRT. Treatment related morbidity was very low.

Conflicts of interest/disclosures

The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.

Acknowledgements

This study received funding from the Head and Neck Cancer Research Fund, Prince of Wales Hospital, Randwick, NSW 2031, Australia.

References (31)

  • M. Sherlock et al.

    Mortality in patients with pituitary disease

    Endocr Rev

    (2010)
  • M. Brada et al.

    Cerebrovascular mortality in patients with pituitary adenoma

    Clin Endocrinol (Oxf)

    (2002)
  • O.M. Dekkers et al.

    Mortality in patients treated for Cushing’s disease is increased, compared with patients treated for nonfunctioning pituitary macroadenoma

    J Clin Endocrinol Metab

    (2007)
  • D.F. Kelly

    Transsphenoidal surgery for Cushing’s disease: a review of success rates, remission predictors, management of failed surgery, and Nelson’s Syndrome

    Neurosurg Focus

    (2007)
  • Locatelli M, Bertani G, Carrabba G, et al. The trans-sphenoidal resection of pituitary adenomas in elderly patients and...
  • Cited by (35)

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

      2021, Best Practice and Research: Clinical Endocrinology and Metabolism
    • Outcomes After Gamma Knife Stereotactic Radiosurgery in Pediatric Patients with Cushing Disease or Acromegaly: A Multi-Institutional Study

      2019, World Neurosurgery
      Citation Excerpt :

      The current retrospective analysis shows almost similar long-term remission and developed pituitary hormone deficiency rates of 60% and 20.8%, respectively. Table 4 shows the outcomes of 3 of the largest single-center studies in the last decade.21,18,22,19 The results in these adult series are comparable to those of the current pediatric series.

    • The risk/benefit ratio of radiotherapy in pituitary tumors

      2019, Best Practice and Research: Clinical Endocrinology and Metabolism
    View all citing articles on Scopus
    View full text