MERGE: Multicenter Evaluation of the Effect of Upfront Radiosurgery on Residual Growth Hormone-secreting Pituitary Adenoma

Sponsor

Samsung Medical Center (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT03439709

Collaborator

(none)

Enrollment

Location

Arms

Anticipated Duration (Months)

1.6

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Acromegaly Due to Pituitary Adenoma	Radiation: Gamma knife radiosurgery Drug: Lanreotide 60Mg Solution for Injection	Phase 3

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

90 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

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.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.

Masking:

None (Open Label)

Masking Description:

Technically, the procedure of gamma knife radiosurgery includes fixating stereotactic frame on the head of patients. Therefore, It is not possible to keep masking for participants and other investigators.

Primary Purpose:

Treatment

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

Anticipated Study Start Date :

Mar 1, 2018

Anticipated Primary Completion Date :

Jun 30, 2022

Anticipated Study Completion Date :

Dec 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: intervention Gamma knife radiosurgery (Leksell Gamma Knife, Elekta AB, Stockholm, Sweden) is used for intervention. Administration of standard medical therapy using Lanreotide 60 mg concurrently starts with radiosurgery	Radiation: Gamma knife radiosurgery Minimum 25 Gy of marginal dose is applied for residual tumor or resection cavity. Depending on the size of tumor, the dose can be varied. Drug: Lanreotide 60Mg Solution for Injection Lanreotide injection.
Active Comparator: control Without radiosurgery, standard medical therapy (Lanreotide 60Mg Solution for Injection) same with interventional group is applied	Drug: Lanreotide 60Mg Solution for Injection Lanreotide injection.

Arm

Intervention/Treatment

Experimental: intervention

Gamma knife radiosurgery (Leksell Gamma Knife, Elekta AB, Stockholm, Sweden) is used for intervention. Administration of standard medical therapy using Lanreotide 60 mg concurrently starts with radiosurgery

Radiation: Gamma knife radiosurgery

Minimum 25 Gy of marginal dose is applied for residual tumor or resection cavity. Depending on the size of tumor, the dose can be varied.

Drug: Lanreotide 60Mg Solution for Injection

Lanreotide injection.

Active Comparator: control

Without radiosurgery, standard medical therapy (Lanreotide 60Mg Solution for Injection) same with interventional group is applied

Drug: Lanreotide 60Mg Solution for Injection

Lanreotide injection.

Outcome Measures

Primary Outcome Measures

endocrinologic remission [at 2 year after initial enrollment]
Achieving random growth hormone level below 2.5 ug/L and normalization of insulin-growth factor-1 level

Secondary Outcome Measures

tumor size [1 year interval]
maximum diameter of tumor
drug requirement dosage [at 3 months after initial enrollment and 6 months thereafter for 2 years]
daily total dose requirement (multiplied dose per injection by number of injections)
side effect [at 3 months after initial enrollment and 6 months thereafter for 2 years]
radiation induced and drug related side effects
performance status [at 3 months after initial enrollment and 6 months thereafter for 2 years]
modified Rankin scale; lower values represent a better outcome as followings: 0 - No symptoms. - No significant disability. Able to carry out all usual activities, despite some symptoms. - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities. - Moderate disability. Requires some help, but able to walk unassisted. - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted. - Severe disability. Requires constant nursing care and attention, bedridden, incontinent. - Dead.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

random growth hormone level < 2.5 ug/L
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