Clinical trial NCT03439709: Multicenter Evaluation of the Effect of Upfront Radiosurgery on Residual Growth Hormone-secreting Pituitary Adenoma
Official title: Multicenter Evaluation of the Effect of Upfront Radiosurgery on Residual Growth Hormone-secreting Pituitary Adenoma From an Endocrinological Point of View (MERGE Study): a Randomized, Phase 3 Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Acromegaly Due to Pituitary Adenoma
Keywords: acromegaly
pituitary adenoma
gamma knife radiosurgery
adjuvant treatment
Lead sponsor: Samsung Medical Center
Sponsor class: OTHER
First posted: 2018-02-20
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The patients with acromegaly due to growth hormone secreting pituitary adenoma who receive primary surgical resection and fail to achieve endocrinologic remission at 3 months after surgical resection are enrolled. They are devided into two groups; One consists of patients underwent upfront stereotactic radiosurgery combinated with standard drug therapy, and another group consists of patients receiving only standard drug therapy.
Primary purpose: TREATMENT

Brief summary: In this study, the investigators hypothesize that upfront gamma knife radiosurgery with drug therapy is superior in the treatment of growth hormone-secreting pituitary tumors after primary surgical treatment compared with the drug therapy alone. This study can provide useful clinical information in the treatment of patients with acromegaly.

Detailed description: Acromegaly is often caused by growth hormone (GH)-secreting pituitary adenoma and causes anatomic changes in the body and various metabolic disorders caused by increased GH and insulin-like growth factor-1 (IGF1). Surgical treatment of pituitary tumors is the preferred standard of care, but only 40-70% of patients can be treated with surgical treatment alone. In many cases, complete resection of the tumor is not possible and the hormone imbalance persists after surgery. After surgical treatment, several additional treatments are needed to prevent hypersecretion of GH and to normalize blood levels of IGF-1.

As first-line treatment after surgical resection, there are typically drug therapy and radiation therapy. The most common used drugs are octreotide and lanreotide, which are growth hormone analogues. However, according to the recent guideline, the endocrine remission rate obtained from post-operative drug therapy is only 17-35%. Although clinical trials are underway for new drugs, the burden of expensive drug costs, recurrence during drug withdrawal, and drug side effects remains major drawbacks. There is a need for therapeutic intervention to reduce the dose and duration of therapy, to prevent tumor recurrence, and to achieve rapid endocrinologic remission.

Stereotactic radiosurgery (SRS), such as gamma knife radiosurgery, has been actively introduced worldwide to control residual pituitary tumors and has been applied to more than 200 cases of intractable acromegaly. The effect of SRS on endocrine remission in patients who did not receive endocrine therapy was confirmed in the literature. In a study of 136 patients who underwent preoperative radiotherapy followed by more than 5 years of follow-up, 65.4% of patients reported endocrine remission. According to the recently published meta-analysis, SRS showed 93-100% tumor growth control and size reduction within 5 to 10 years after surgery. The endocrinologic remission rate was reported to be 40-60% at 5 years.

To date, SRS has been recommended for the treatment of growth hormone - secreting pituitary tumors in cases where surgical removal is not feasible from the beginning or if drug treatment fails after surgical removal. Only the retrospective study of SRS was performed and no prospective study was conducted at all. However, many institutions already prefer preemptive SRS treatment for residual tumor after surgery and have been practiced in many patients. Therefore, prospective clinical trials are needed to establish the basis for upfront SRS and establish the treatment strategy for patients who do not have endocrine remission after surgical treatment of GH secretory pituitary tumor.

Eligibility criteria: Inclusion Criteria:

* Among patients with acromegaly due to growth hormone secreting pituitary adenoma who underwent primary surgical resection, patients who fail to achieve endocrinologic remission at 3 months after surgery.
* On brain MRI scan at 3months after surgery, residual tumor is confirmed by clinicians

  * the definition of endocrinologic remission

    1. random growth hormone level \< 2.5 ug/L
    2. normalization of age-matched insulin growth factor-1 level

Exclusion Criteria:

* patients with contraindication of stereotactic radiosurgery; e.g. pregnancy or planning pregnancy, or claustrophobia
* recurrent pituitary adenoma
* limited life expectancy due to systemic disease; e.g. malignant tumor, genetic disease, and terminal stage of renal or hepatic failure
* disability to clinic visit due to postoperative complications

Primary outcomes:
measure: endocrinologic remission
timeFrame: at 2 year after initial enrollment
Secondary outcomes:
measure: tumor size
timeFrame: 1 year interval
measure: drug requirement dosage
timeFrame: at 3 months after initial enrollment and 6 months thereafter for 2 years
measure: side effect
timeFrame: at 3 months after initial enrollment and 6 months thereafter for 2 years
measure: performance status
timeFrame: at 3 months after initial enrollment and 6 months thereafter for 2 years
Other outcomes:
Locations:
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
Study officials:
affiliation: Samsung Medical Center
name: Doo0Sik Kong, MD,Ph.D
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gheorghiu ML. Updates in outcomes of stereotactic radiation therapy in acromegaly. Pituitary. 2017 Feb;20(1):154-168. doi: 10.1007/s11102-016-0783-5.
citation: Lee CC, Vance ML, Xu Z, Yen CP, Schlesinger D, Dodson B, Sheehan J. Stereotactic radiosurgery for acromegaly. J Clin Endocrinol Metab. 2014 Apr;99(4):1273-81. doi: 10.1210/jc.2013-3743. Epub 2014 Jan 28.
citation: Shin SS, Tormenti MJ, Paluzzi A, Rothfus WE, Chang YF, Zainah H, Fernandez-Miranda JC, Snyderman CH, Challinor SM, Gardner PA. Endoscopic endonasal approach for growth hormone secreting pituitary adenomas: outcomes in 53 patients using 2010 consensus criteria for remission. Pituitary. 2013 Dec;16(4):435-44. doi: 10.1007/s11102-012-0440-6.
citation: Giustina A, Chanson P, Kleinberg D, Bronstein MD, Clemmons DR, Klibanski A, van der Lely AJ, Strasburger CJ, Lamberts SW, Ho KK, Casanueva FF, Melmed S; Acromegaly Consensus Group. Expert consensus document: A consensus on the medical treatment of acromegaly. Nat Rev Endocrinol. 2014 Apr;10(4):243-8. doi: 10.1038/nrendo.2014.21. Epub 2014 Feb 25.
citation: Hazer DB, Isik S, Berker D, Guler S, Gurlek A, Yucel T, Berker M. Treatment of acromegaly by endoscopic transsphenoidal surgery: surgical experience in 214 cases and cure rates according to current consensus criteria. J Neurosurg. 2013 Dec;119(6):1467-77. doi: 10.3171/2013.8.JNS13224. Epub 2013 Sep 27.
citation: Katznelson L, Laws ER Jr, Melmed S, Molitch ME, Murad MH, Utz A, Wass JA; Endocrine Society. Acromegaly: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014 Nov;99(11):3933-51. doi: 10.1210/jc.2014-2700. Epub 2014 Oct 30.