Biochemical Control in Acromegaly With Multimodality Therapies

Outcomes From a Pituitary Center and Changes Over Time

Alireza Ghajar; Pamela S. Jones; Francisco J. Guarda; Alex Faje; Nicholas A. Tritos; Karen K. Miller; Brooke Swearingen; Lisa B. Nachtigall

Disclosures

J Clin Endocrinol Metab. 2020;105(3) 

In This Article

Abstract and Introduction

Abstract

Purpose: To determine the prevalence of insulin-like growth factor-1 (IGF-1) normalization with long-term multimodality therapy in a pituitary center and to assess changes over time.

Methods: Patients with acromegaly (N = 409), with ≥1 year of data after surgery and at least 2 subsequent clinic visits were included in long-term analysis (N = 266). Biochemical data, clinical characteristics, and therapeutic interventions were reviewed retrospectively.

Results: At diagnosis, mean [standard deviation] age was 43.4 [14.3] years, body mass index was 28.5 (24.9–32.1) kg/m2 (median, interquartile range), serum IGF-1 index (IGF-1 level/upper limit of normal) was 2.3 [1.7–3.1], and 80.5% had macroadenomas. Patients with transsphenoidal surgery after 2006 were older [46.6 ± 14.3 vs 40.0 ± 13.4 years; P < 0.001]. Age and tumor size correlated inversely. Overall (N = 266), 93.2% achieved a normal IGF-1 level during 9.9 [5.0–15.0] years with multimodality therapy. The interval to first normal IGF-1 level following failed surgical remission was shorter after 2006: 14.0 (95% confidence interval, 10.0–20.0) versus 27.5 (22.0–36.0) months (P = 0.002). Radiation therapy and second surgery were rarer after 2006: 28 (22%) versus 62 (47.0%); P < 0.001 and 12 (9.4%) versus 28 (21.2%); P = 0.010, respectively. Age at diagnosis increased over time periods, possibly reflecting increased detection of acromegaly in older patients with milder disease. Male gender, older age, smaller tumor and lower IGF-1 index at diagnosis predicted long-term sustained IGF-1 control after surgery without adjuvant therapies.

Conclusion: The vast majority of patients with acromegaly can be biochemically controlled with multimodality therapy in the current era. Radiotherapy and repeat pituitary surgery became less frequently utilized over time. Long-term postoperative IGF-1 control without use of adjuvant therapies has improved.

Introduction

Acromegaly is caused by excess secretion of growth hormone (GH), typically arising from tumors located in the pituitary gland.[1] Its prevalence has been estimated at 2.8 to 13.7 per 100 000 and an incidence of 0.2 to 1.1 cases per 100 000 individuals annually.[2] Excess GH increases the secretion of insulin-like growth factor-1 (IGF-1), and together elevated GH and IGF-1 levels cause multisystem comorbidities such as metabolic changes, cardiovascular disease, hypertension, sleep apnea, colonic polyps, joint and skeletal abnormalities, among many others including possibly increased risk of other neoplasms.[3] Epidemiologic studies have identified demographic factors that may be predictive of outcomes.[4,5] Older patients with smaller tumors, milder disease, and lower GH levels have been more frequently diagnosed over the last decade compared to the prior one[6] and are associated with better response to medical therapies.[4,5,7,8] In addition, younger individuals with acromegaly tend to have more aggressive tumors. For example, genetic mutations are more commonly found in patients diagnosed with gigantism or in patients at a younger age who are more likely to develop recurrences and often are resistant to somatostatin analog therapy.[1,9,10]

Experienced dedicated pituitary neurosurgeons have been reported to achieve a higher rate of biochemical remission with primary surgery than those with less experience, ranging from 85% to 91% of patients with microadenomas and 40% to 66% for patients with macroadenomas, results that are similar comparing different surgical techniques.[3,11–15] Nevertheless, persistent disease after transsphenoidal surgery (TSS) or subsequent recurrences cause an extensive economic burden[16] as well as decreased quality of life.[17,18] Among options for patients with persistent disease, consecutive surgeries and/or radiation therapy may result in biochemical control as well as reduction or stabilization of tumor remnants.[19] Medical therapies such as somatostatin analogs (SSAs), dopamine agonists, and the GH receptor antagonist have been widely studied in the management of patients with persistent or recurrent acromegaly after surgery and also may be used as an alternative to primary TSS.[20] First-generation long-acting SSAs (octreotide long-acting release and lanreotide depot) are considered first-line options in patients with recurrent or persistent acromegaly and in selected cases as primary medical therapy, showing variable disease control that range from 38% to 85% depending on study design, dose, and frequency of administration, with similar findings when comparing both formulations.[21,22] Pegvisomant (PEG) has been shown to achieve IGF-1–level normalization in 89% to 100% of patients in initial clinical trials[23–25] and 73% in more recent real-life cohorts.[26] Dopamine agonists, and specifically cabergoline, can be used as a monotherapy or in combination with SSAs or PEG (or both) in order to improve disease control, resulting in normalization of IGF-1 levels in 34% to 39% of patients as a monotherapy and 37% to 52% in combination with SSAs.[27–29] Pasireotide is a second-generation SSA that has demonstrated benefits in 15% to 20% of patients resistant to first-generation SSAs but is also approved as first-line therapy.[30,31] While better efficacy has been shown with pasireotide, adverse events such as hyperglycemia have been shown to occur in more than 50% of patients.[30,31]

Clinical characteristics of patients with acromegaly and their associated comorbidities have been reported in large cohorts.[6,32] Information on the efficacy of different treatment modalities in acromegaly has been widely published, but long-term outcomes after many years of multimodality therapies and the baseline prognostic factors associated with such outcomes have been scarcely reported.[4,33,34] Hence, this report evaluates the proportion of patients achieving IGF-1–level normalization among a large cohort of patients with acromegaly who received multimodality therapies and long-term management at a pituitary center.

Primary objectives were to determine 1) prevalence of normalization of IGF-1 levels in patients with acromegaly and comparison across different time periods; 2) prevalence of use of second surgery, radiation therapy, and medical therapies and comparison of the frequency of administration across different time periods; and 3) the time interval to normalization of IGF-1 levels in patients who did not achieve surgical remission and comparison across different time periods. Secondary goals were to evaluate 1) the association of baseline characteristics with long-term IGF-1–level normalization and 2) the association between baseline characteristics and the use of repeat surgery and/or radiation therapy.

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