Letter to the Editor. Upfront GKS for Cushing’s disease and acromegaly: is it suitable?

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  • 1 Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China;
  • 2 China Pituitary Disease Registry Center, China Pituitary Adenoma Specialist Council, Beijing, China; and
  • 3 Key Laboratory of Endocrinology of National Health and Family Planning Commission, Beijing, China
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TO THE EDITOR: We read with great interest the recent article by Gupta et al.3 (Gupta A, Xu Z, Kano H, et al: Upfront Gamma Knife radiosurgery for Cushing’s disease and acromegaly: a multicenter, international study. J Neurosurg [epub ahead of print August 17, 2018. DOI: 10.3171/2018.3.JNS18110]). The authors included 21 patients with Cushing’s disease (CD) and 25 patients with acromegaly undergoing upfront Gamma Knife radiosurgery (GKS). After a median endocrine follow-up of 69.5 months, patients with CD achieved a faster and far better remission rate compared to patients with acromegaly. The authors suggest a possible differential radiosensitivity of two kinds, and then further recommend upfront GKS in CD rather than in acromegaly. We commend the efforts of the authors in carrying out this interesting study. Yet from the perspective of neurosurgeons, some conclusions are questionable.

The biggest concern lies in the posttreatment remission criteria for CD that were used in this study. The authors defined remission as normalization of urinary free cortisol and morning serum cortisol levels, which is not recognized by most endocrinologists and neurosurgeons. According to the latest Endocrine Society Clinical Practice Guideline for CD, as well as other previous literature, remission is generally defined as morning serum cortisol values < 5 µg/dl, a stricter criterion than just normal range.2,5,7 One meta-analysis suggests that patients with CD in whom subnormal cortisol levels are found after treatment have a clearly lower risk of long-term recurrence compared to those within the normal range.8 The reduction of cortisol levels to the normal range after treatment does not necessarily represent the patient’s cure, but rather a higher recurrence rate.9 Regarding this condition as remission could give patients overly optimistic and misleading expectations, and may cause neglect of follow-up. Moreover, the use of different remission criteria hinders direct comparison of outcomes between this GKS study and other surgical treatment studies for CD.

Nevertheless, although the authors have used more easily achievable remission criteria for CD, the remission criteria for acromegaly (i.e., growth hormone [GH] level < 1 ng/ml in response to a glucose challenge) are much stricter and in accordance with the latest guideline.4 These varying degrees of rigor in criteria to assess CD and acromegaly may also make less convincing the conclusion that patients with CD achieve faster and better remission rates and that their disease is more sensitive to GKS than is the case in those with acromegaly.

In addition, this study did not mention the impact of radiotherapy on the growth of younger patients, especially when the youngest patient with CD included in this study was 14 years old. A radiotherapy study in pediatric CD reported that the incidence of GH deficiency after radiation therapy was 36%–68%, and most patients failed to reach the target height.1 In one study from the Mayo Clinic the investigators also believe that the risk of delayed hypopituitarism caused by radiotherapy is significant.6 The risk of this hypopituitarism exists for a lifetime.9 It is therefore recommended that this article add age factors when deriving the conclusion of efficacy for upfront GKS for CD and acromegaly treatment. Especially given the lack of long-term follow-up data, the conclusions should be more cautious for the sake of safety.

Disclosures

The authors report no conflict of interest.

References

  • 1

    Acharya SV, Gopal RA, Goerge J, Menon PS, Bandgar TR, Shah NS: Radiotherapy in paediatric Cushing’s disease: efficacy and long term follow up of pituitary function. Pituitary 13:293297, 2010

    • Search Google Scholar
    • Export Citation
  • 2

    Bansal P, Lila A, Goroshi M, Jadhav S, Lomte N, Thakkar K, : Duration of post-operative hypocortisolism predicts sustained remission after pituitary surgery for Cushing’s disease. Endocr Connect 6:625636, 2017

    • Search Google Scholar
    • Export Citation
  • 3

    Gupta A, Xu Z, Kano H, Sisterson N, Su YH, Krsek M, : Upfront Gamma Knife radiosurgery for Cushing’s disease and acromegaly: a multicenter, international study. J Neurosurg [epub ahead of print August 17, 2018. DOI: 10.3171/2018.3.JNS18110]

    • Search Google Scholar
    • Export Citation
  • 4

    Katznelson L, Laws ER Jr, Melmed S, Molitch ME, Murad MH, Utz A, : Acromegaly: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 99:39333951, 2014

    • Search Google Scholar
    • Export Citation
  • 5

    Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO, : Treatment of Cushing’s syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 100:28072831, 2015

    • Search Google Scholar
    • Export Citation
  • 6

    Porterfield JR, Thompson GB, Young WF Jr, Chow JT, Fryrear RS, van Heerden JA, : Surgery for Cushing’s syndrome: an historical review and recent ten-year experience. World J Surg 32:659677, 2008

    • Search Google Scholar
    • Export Citation
  • 7

    Savage MO, Chan LF, Grossman AB, Storr HL: Work-up and management of paediatric Cushing’s syndrome. Curr Opin Endocrinol Diabetes Obes 15:346351, 2008

    • Search Google Scholar
    • Export Citation
  • 8

    Sughrue ME, Shah JK, Devin JK, Kunwar S, Blevins LS Jr: Utility of the immediate postoperative cortisol concentrations in patients with Cushing’s disease. Neurosurgery 67:688695, 2010

    • Search Google Scholar
    • Export Citation
  • 9

    Tritos NA, Biller BM, Swearingen B: Management of Cushing disease. Nat Rev Endocrinol 7:279289, 2011

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  • 1 University of Virginia, Charlottesville, VA;
  • 2 House Clinic, Los Angeles, CA;
  • 3 University of Louisville, Louisville, KY; and
  • 4 Mayo Clinic, Jacksonville, FL
Keywords:

Response

We thank Drs. Gao and Xing for their interest in our recent international, multicenter study. In this study, we demonstrated the rates of tumor control and endocrine remission in selected patients with CD and acromegaly who were treated with upfront GKS. The current study cohorts represent a small subset of patients published in our previous studies.2,6 Previous series provide evidence that radiosurgery appears to achieve more rapid remission than fractionated radiotherapy.5 Among functioning pituitary adenomas, there is evidence to support differences in radiosurgical sensitivity in secretory adenomas, as measured by hormone release.9

The authors raise the issue of contemporary definitions of endocrine remission. Endocrine criteria for remission of CD and acromegaly have changed substantially over the 2.5 decades during which our study cohort was accrued. Although applying modern endocrine assays and definitions would be ideal, the approach would be impractical for such a clinical study, and its absence does not negate the significant findings of our study. Not surprisingly, this limitation also holds true for the largest surgical series of pituitary surgery for functioning adenomas.3,4 Moreover, given past experiences, the remission criteria and neuroendocrine assay technology are almost certain to be refined in the future. Thus, the remission criteria will remain a moving target.

Latent effects of radiotherapy are not the same in breadth or frequency as those experienced with GKS. For instance, in the CD and acromegaly studies by our group, as well as a review of the literature, we have not seen a single instance of symptomatic carotid stenosis leading to cerebral ischemia.2,6,7 This sharply contrasts with radiotherapy series for patients with pituitary adenoma.1 The same is true for radiation-induced neoplasia and neurocognitive deficits after radiosurgery as compared with radiotherapy for tumors of the sella.7,8 Nevertheless, one should always weigh the benefit-to-risk profile of GKS with those of other treatment options and take into account the natural history of the underlying disease state. For pituitary adenomas, the long-term consequences of action or inaction must be carefully considered.

A large, multicenter, prospective study of patients with pituitary adenomas would probably take at least 5 years from the accrual of patients for intermediate results to be meaningful and more than a decade for long-term results. Furthermore, such an undertaking would require hundreds of patients and millions of dollars to achieve study validity. During that time, it is likely that the study would be confounded by changing technologies (e.g., radiosurgery devices, radiology sequencing, endocrine assays), evolving medical and microsurgical approaches, varied treatment paradigms, and potentially changing criteria for endocrine remission. Until then, the pituitary adenoma radiosurgery studies by the International Radiosurgery Research Foundation (IRRF) will probably remain the highest level of evidence available to guide clinicians.2,6

References

  • 1

    Brada M, Burchell L, Ashley S, Traish D: The incidence of cerebrovascular accidents in patients with pituitary adenoma. Int J Radiat Oncol Biol Phys 45:693698, 1999

    • Search Google Scholar
    • Export Citation
  • 2

    Ding D, Mehta GU, Patibandla MR, Lee CC, Liscak R, Kano H, : Stereotactic radiosurgery for acromegaly: an international multicenter retrospective cohort study. Neurosurgery [epub ahead of print], 2018

    • Search Google Scholar
    • Export Citation
  • 3

    Hofmann BM, Hlavac M, Martinez R, Buchfelder M, Müller OA, Fahlbusch R: Long-term results after microsurgery for Cushing disease: experience with 426 primary operations over 35 years. J Neurosurg 108:918, 2008

    • Search Google Scholar
    • Export Citation
  • 4

    Jagannathan J, Smith R, DeVroom HL, Vortmeyer AO, Stratakis CA, Nieman LK, : Outcome of using the histological pseudocapsule as a surgical capsule in Cushing disease. J Neurosurg 111:531539, 2009

    • Search Google Scholar
    • Export Citation
  • 5

    Loeffler JS, Shih HA: Radiation therapy in the management of pituitary adenomas. J Clin Endocrinol Metab 96:19922003, 2011

  • 6

    Mehta GU, Ding D, Patibandla MR, Kano H, Sisterson N, Su YH, : Stereotactic radiosurgery for Cushing disease: results of an international, multicenter study. J Clin Endocrinol Metab 102:42844291, 2017

    • Search Google Scholar
    • Export Citation
  • 7

    Sheehan JP, Niranjan A, Sheehan JM, Jane JA Jr, Laws ER, Kondziolka D, : Stereotactic radiosurgery for pituitary adenomas: an intermediate review of its safety, efficacy, and role in the neurosurgical treatment armamentarium. J Neurosurg 102:678691, 2005

    • Search Google Scholar
    • Export Citation
  • 8

    Tooze A, Hiles CL, Sheehan JP: Neurocognitive changes in pituitary adenoma patients after gamma knife radiosurgery: a preliminary study. World Neurosurg 78:122128, 2012

    • Search Google Scholar
    • Export Citation
  • 9

    Trifiletti DM, Xu Z, Dutta SW, Quiñones-Hinojosa A, Peterson J, Vance ML, : Endocrine remission after pituitary stereotactic radiosurgery: differences in rates of response for matched cohorts of Cushing disease and acromegaly patients. Int J Radiat Oncol Biol Phys 101:610617, 2018

    • Search Google Scholar
    • Export Citation

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Contributor Notes

Correspondence Bing Xing: xingbingemail@aliyun.com.

INCLUDE WHEN CITING Published online November 2, 2018; DOI: 10.3171/2018.9.JNS182542.

Disclosures The authors report no conflict of interest.

  • 1

    Acharya SV, Gopal RA, Goerge J, Menon PS, Bandgar TR, Shah NS: Radiotherapy in paediatric Cushing’s disease: efficacy and long term follow up of pituitary function. Pituitary 13:293297, 2010

    • Search Google Scholar
    • Export Citation
  • 2

    Bansal P, Lila A, Goroshi M, Jadhav S, Lomte N, Thakkar K, : Duration of post-operative hypocortisolism predicts sustained remission after pituitary surgery for Cushing’s disease. Endocr Connect 6:625636, 2017

    • Search Google Scholar
    • Export Citation
  • 3

    Gupta A, Xu Z, Kano H, Sisterson N, Su YH, Krsek M, : Upfront Gamma Knife radiosurgery for Cushing’s disease and acromegaly: a multicenter, international study. J Neurosurg [epub ahead of print August 17, 2018. DOI: 10.3171/2018.3.JNS18110]

    • Search Google Scholar
    • Export Citation
  • 4

    Katznelson L, Laws ER Jr, Melmed S, Molitch ME, Murad MH, Utz A, : Acromegaly: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 99:39333951, 2014

    • Search Google Scholar
    • Export Citation
  • 5

    Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO, : Treatment of Cushing’s syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 100:28072831, 2015

    • Search Google Scholar
    • Export Citation
  • 6

    Porterfield JR, Thompson GB, Young WF Jr, Chow JT, Fryrear RS, van Heerden JA, : Surgery for Cushing’s syndrome: an historical review and recent ten-year experience. World J Surg 32:659677, 2008

    • Search Google Scholar
    • Export Citation
  • 7

    Savage MO, Chan LF, Grossman AB, Storr HL: Work-up and management of paediatric Cushing’s syndrome. Curr Opin Endocrinol Diabetes Obes 15:346351, 2008

    • Search Google Scholar
    • Export Citation
  • 8

    Sughrue ME, Shah JK, Devin JK, Kunwar S, Blevins LS Jr: Utility of the immediate postoperative cortisol concentrations in patients with Cushing’s disease. Neurosurgery 67:688695, 2010

    • Search Google Scholar
    • Export Citation
  • 9

    Tritos NA, Biller BM, Swearingen B: Management of Cushing disease. Nat Rev Endocrinol 7:279289, 2011

  • 1

    Brada M, Burchell L, Ashley S, Traish D: The incidence of cerebrovascular accidents in patients with pituitary adenoma. Int J Radiat Oncol Biol Phys 45:693698, 1999

    • Search Google Scholar
    • Export Citation
  • 2

    Ding D, Mehta GU, Patibandla MR, Lee CC, Liscak R, Kano H, : Stereotactic radiosurgery for acromegaly: an international multicenter retrospective cohort study. Neurosurgery [epub ahead of print], 2018

    • Search Google Scholar
    • Export Citation
  • 3

    Hofmann BM, Hlavac M, Martinez R, Buchfelder M, Müller OA, Fahlbusch R: Long-term results after microsurgery for Cushing disease: experience with 426 primary operations over 35 years. J Neurosurg 108:918, 2008

    • Search Google Scholar
    • Export Citation
  • 4

    Jagannathan J, Smith R, DeVroom HL, Vortmeyer AO, Stratakis CA, Nieman LK, : Outcome of using the histological pseudocapsule as a surgical capsule in Cushing disease. J Neurosurg 111:531539, 2009

    • Search Google Scholar
    • Export Citation
  • 5

    Loeffler JS, Shih HA: Radiation therapy in the management of pituitary adenomas. J Clin Endocrinol Metab 96:19922003, 2011

  • 6

    Mehta GU, Ding D, Patibandla MR, Kano H, Sisterson N, Su YH, : Stereotactic radiosurgery for Cushing disease: results of an international, multicenter study. J Clin Endocrinol Metab 102:42844291, 2017

    • Search Google Scholar
    • Export Citation
  • 7

    Sheehan JP, Niranjan A, Sheehan JM, Jane JA Jr, Laws ER, Kondziolka D, : Stereotactic radiosurgery for pituitary adenomas: an intermediate review of its safety, efficacy, and role in the neurosurgical treatment armamentarium. J Neurosurg 102:678691, 2005

    • Search Google Scholar
    • Export Citation
  • 8

    Tooze A, Hiles CL, Sheehan JP: Neurocognitive changes in pituitary adenoma patients after gamma knife radiosurgery: a preliminary study. World Neurosurg 78:122128, 2012

    • Search Google Scholar
    • Export Citation
  • 9

    Trifiletti DM, Xu Z, Dutta SW, Quiñones-Hinojosa A, Peterson J, Vance ML, : Endocrine remission after pituitary stereotactic radiosurgery: differences in rates of response for matched cohorts of Cushing disease and acromegaly patients. Int J Radiat Oncol Biol Phys 101:610617, 2018

    • Search Google Scholar
    • Export Citation

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