Preoperative Medical Treatments and Surgical Approaches for Acromegaly

A Systematic Review

Christos Papaioannou; Maralyn Druce

Clin Endocrinol. 2023;98(1):14-31.

Abstract and Introduction

Abstract

Objective: Acromegaly is a condition characterized by an overproduction of growth hormone which infers high morbidity and mortality if left untreated. The objective of this review is to analyse and appraise the current evidence for the generalized use of preoperative medications and the various surgical approaches as described in the literature.

Design: A thorough search from MEDLINE via PubMed, EMBASE, and Cochrane Library has been performed which identified a total of 37 papers.

Conclusion: The preoperative use of somatostatin receptor agonists (SAs) in acromegaly is a controversial topic with current guidelines suggesting against their generalized routine use. Most authors noticed an insignificant long-term remission of acromegaly when given SAs compared with nil preoperative therapy, except for invasive macroadenomas as SAs have been found to reduce the tumour volume and aid towards the total resection of the adenoma. Furthermore, according to the evidence available, endoscopic transsphenoidal surgery is the optimum method for hypophysectomy in terms of its remission and safety profile.

Introduction

The clinical features observed in patients with acromegaly result from both an overproduction of growth hormone (GH) but also from the consequent overproduction of the insulin-like growth factor-1 (IGF1) and from the physical enlargement of the pituitary gland. This condition substantially affects the quality of life of patients and increases morbidity and mortality risk.^[1]

Preoperative medical treatment may be employed to either achieve symptom relief or reduction in the size of the pituitary adenoma to aid in the surgical removal of the gland, or to mitigate any intra- and postoperative risks, or all of the above. There is a difficulty in establishing an evidence base that is reliable and of high quality because of the rarity and variability of these tumours. The current guidelines by the Endocrine Society suggest against the generalized routine use of presurgical medical treatment except in very specific cases.^[2] The only preoperative treatments currently available are SAs (in particular octreotide and lanreotide), however, their use is limited to patients with severe nasopharyngeal thickening causing sleep apnoea or severe heart failure.^[3] Following removal of the pituitary gland, the patients must have their IGF1 and GH levels measured. The soonest this should be done to establish the nadir value to assess for remission is at 12 weeks following the completion of surgery or later. Earlier measurements, however, can be of value. The regression of plasma IGF1 takes a long time to be accomplished due to the longer half-life in comparison with GH and due to the bound IGF1 on IGF-binding proteins. SAs—if administered perioperatively—can have a carry-on effect following the surgery due to their long half-life; thus they may still have an impact on residual somatotroph cells and early blood tests could provide inaccurate reassurance of cure.^[4]

According to the current guidelines of the Endocrine Society, the first-line treatment for acromegaly is transsphenoidal surgery (TSS).^[2] However, there are alternative options for the treatment of acromegaly including primary medical treatment, transcranial surgery, and radiation therapy. Treatment should be personalized to allow for an optimum rate of remission with low rates of postoperative morbidity. Surgical procedures could be carried out using a microscope or endoscope.^[5] An older and now rarely used approach for pituitary surgery is via the transcranial route. This might still be used in an extremely large tumour with extensive invasion of nearby structures like the cavernous sinus and a large suprasellar component.

This article will focus on analyzing the evidence for the preoperative medical therapy on patients with acromegaly and on the various surgical approaches described in the literature.

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Abstract and Introduction
Methods
Results
Discussion
Conclusion
References

Table 1. Study characteristics and findings about the preoperative medical therapy of patients with acromegaly
Author and publication year (reference)	Study design	Number of participants	Intervention used and duration (Group A)	Comparators and duration (Group B)	Consensus criteria used	Remission timeframe (months)	Findings
Abe and Lüdecke, 2001³⁷	Retrospective cohort	124* *excluding 23 patients with non-resectable adenomas	Octreotide for 3–21 months	No pre-surgical treatment	2000	>6	• Overall remission: 87.3% Group A vs. 83.0% Group B p > .05 • Microadenoma remission 100% Group A vs. 92.9% Group B p > .05 • Macroadenoma remission: 85.9% Group A vs. 79.4% Group B p > .05 • Postoperative complications (statistically insignificant): Nasal bleeding (2 Group A vs. 2 Group B), transient DI (3 Group A vs. 4 Group B), CSF leak (1 Group A vs. 1 Group B), CN VI palsy (1 Group B vs. nil Group B), traumatic carotid cavernous fistula (1 Group A vs. nil Group B)
Albarel et al., 2018¹⁶	Retrospective cohort	110	Octreotide or Lanreotide for median duration of 5 months	No pre-surgical treatment	2010	>6	• Overall remission: 61.1% Group A vs. 36.6% Group B p= .03 • Duration of SA pre-op treatment insignificant • Postoperative statistically insignificant complications: 3 patients with DI, 22 patients with hypopituitarism, 1 patient with CSF leak, 5 patients with infection (mild); long-term hyponatraemia (13 Group A vs. 1 Group B) p < .01 • Cavernous sinus invasion and no pre-op SA treatment associated with less remissions
Carlsen et al., 2008¹⁷	RCT	62	Octreotide for 6 months	No pre-surgical treatment	2000	≤6	• Overall remission: 45% Group A vs. 23% Group B (p = .11) • Microadenoma remission: 20% Group A vs. 60% Group B (p = .52) • Macroadenoma remission: 50% Group A vs. 16% Group B (p = .017) • No differences in rates of complications and hospital stay [3 patients with rhinorrhoea, 1 patient with haematoma, 1 patient with transient DI, 1 patient with sinusitis, 2 patients with hypopituitarism, 2 patients with permanent DI, 3 patients with CN palsies]
Duan et al., 2017¹⁸	Retrospective cohort	358	Octreotide or lanreotide for median duration of 4 months	No pre-surgical treatment	2000	≤6	• Overall remission: 40.5% Group A vs. 32.6% Group B (p = .19) • Microadenoma remission: 100% Group A vs. 62.1% Group B (p = .037) • Macroadenoma remission: 37.7% Group A vs. 32.2% Group B (p = .39) • Invasive macroadenoma remission: 43.2% Group A vs. 17.6% Group B (p = .004) • SAs treatment for >6 months associated with greater remission than <6 months
Fougner et al., 2014 (5 year continuation of study by Carlsen et al., 2008) ²⁹	RCT	62	Octreotide for 6 months	No pre-surgical treatment	2000	>6	• Overall remission: 32% Group A vs. 27% Group B (p = .63) • Microadenoma remission: 0% Group A vs. 40% Group B (p = .44) • Macroadenoma remission: 38% Group A vs. 24% Group B (p = .27)
Korkmaz et al., 2019¹⁴	Retrospective cohort study	135	Octreotide or Lanreotide for median duration of 12 months	No pre-surgical treatment	2000	≤6	• Overall remission: 61.5% Group A vs. 31.2% Group B (p = .002) • Microadenoma remission: 75.0% Group A vs. 73.3% Group B (p = 1.0) • Macroadenoma remission: 52.2% Group A vs. 23.5% Group B (p = .02) • Invasive macroadenoma remission: 35.7% Group A vs. 4.8% Group B (p = .002)
Li et al., 2012¹³	RCT	49	Lanreotide 3 months	No pre-surgical treatment	2000	≤6	• Invasive macroadenoma remission: 45.8% Group A vs. 20% Group B (p < .05) • No significant differences in intra or postoperative complications including DI, CSF leak, visual field defects, CN III palsy
Losa et al., 2019 ¹⁹	Retrospective cohort study	211	Octreotide or Lanreotide for median duration of 12 months	No pre-surgical treatment	2010	>6	• Overall remission: 61.7% Group A vs. 71.9% Group B (p = .16) • Intra-operative complications insignificant including SBP, HR, peripheral O₂ saturations, administered medications (NO, atropine and antibiotics), operating time • Postoperative complications insignificant including epistaxis, rhinorrhoea, severe hyponatraemia, UTI, 4 patients with permanent DI, zero perioperative mortality • Young age, cavernous sinus invasion and high basal GH level associated with reduced rates of remission (p < .05) [pre-op GH reduced in Group A by 17.9 μg/L]
Lucas et al., 2003²⁰	Prospective cross-sectional multicentre	104	Lanreotide for >1 month	–	2000	≤6	• Overall remission: 25% of patients • Volume reduction: 29% of patients had a >20% tumour reduction • High pre-op IGF1, cavernous sinus invasion, and large tumour volume associated with reduced rates of remission (p < .05)
Lv et al., 2018²¹	Retrospective cohort	100	Octreotide or Lanreotide for median duration of 3 months	No pre-surgical treatment	2000	≤6	• Overall remission: 45% • Macroadenoma remission: 45% Group A vs. 45% Group B p = 1.00 • Total resection of tumour associated with more remissions • High pre-op GH, large tumour, Knosp grade 3–4 associated with significantly less total tumour resections • Group A: 15.8% of patients achieved reduction of tumour vol by >20% and 55.3% of patients achieved pre-op GH reduction by >50%
Mao et al., 2010¹⁵	RCT	108	Lanreotide for 4 months	No pre-surgical treatment	2000	≤6	• Overall remission: 49% Group A vs. 18.4% Group B (p = .001) • Postsurgical complications insignificant including hospital stay, hyponatraemia, rhinorrhoea, sinusitis; zero perioperative mortality
Oshino et al., 2006³⁸	Retrospective cross-sectional study	32	Octreotide for 2 or 3 weeks	–	2000	≤6	• Overall remission: 50% • Pre-op analysis: basal GH and IGF1 significantly reduced pre-operatively, 52% of patients had a mean 68% tumour volume reduction
Petrossians et al., 2005³⁹	Retrospective single centre cross-sectional	24	Octreotide or Lanreotide for mean duration of 7.4± 10 months	–	2000	≤6	• Overall remission: 54.2%
Shen et al., 2010¹²	RCT	39	Octreotide for 3 months	No pre-surgical treatment	2000	≤6	• Invasive macroadenoma remission: 42.1% Group A vs. 10% Group B p = .044 • Postoperative complications: CSF leak (10.5% Group A vs. 45.0% Group B) p = .031. Other insignificant differences: DI, hypopituitarism, visual deterioration, electrolyte disturbance and liver and cardiac dysfunction • Significant less remission: Knosp 3–4 (treated group significant more tumour size reduction pre-op → more remissions)

Table 2. Study characteristics and findings relating to the surgical approach of patients with acromegaly
Author and publication year (reference)	Study design	Number of participants	Intervention used and duration (Group A)	Comparators and duration (Group B)	Consensus criteria used	Remission timeframe (months)	Findings
Abbassioun et al.,⁴⁰	Prospective cross-sectional	151	Microscopic TSS	–	-	-	• No report on remission • Postoperative complications: 6.6% CSF leak, 13% transient DI, 1.5% permanent DI, 0.7% meningitis and 9.3% hypopituitarism • Average hospital stay: 7 days
Anik et al., 2017²⁷	Retrospective cross-sectional	401	Endoscopic TSS	–	2010	≤6	• Overall remission: 68.1% • Macroadenoma remission: 63.3% • Microadenoma remission: 81.3% • Postoperative complications: 3% transient DI, 0.2% permanent DI, 3% hypogonadism, 1.75% pituitary insufficiency, 1.4% AI, 2.7% CSF leak, 2% epistaxis, 1.24% sellar haematoma, <1% CN injury and meningitis • Remission significantly reduced in cavernous sinus invasion, large volume/size, pre-op GH >60 μg/L
Araujo-Castro et al., 2021⁴¹	Ambispective cross-sectional	49	Endoscopic TSS	–	2000	>6	• Overall remission: 73.5% • Microadenoma remission: 100% • Macroadenoma remission: 68.3% (p = .063 compared to microadenomas) • Significant predictors of remission: Knosp grade, preoperative GH, age
Aydin et al., 2020⁴²	Retrospective cross-sectional	106	Endoscopic TSS	–	2000	≤6	• Overall remission: 66.3% • Microadenoma remission: 76.9% • Macroadenoma remission: 66.7% (p = .045 compared to microadenomas) • Postoperative complications: 9.4% transient DI and 1 with permanent DI • Significant less remissions associated with young age, high pre-op GH levels (not pre-op IGF1), subtotal resection and suprasellar extension
Beauregard et al., 2003⁴³	Retrospective cross-sectional	103	TSS	–	2000	>6	• Overall remission: 52% • High Knosp grade and high preop GH associated with low rates of remission • Postoperative complications: 11 patients with hypopituitarism
Biermasz et al., 2000⁴⁴	Retrospective cross-sectional	75	Microscopic TSS	–	2000	>6	• Overall remission: 37%
Campbell et al., 2010⁴⁵	Retrospective cross-sectional	26	Endoscopic TSS	–	2000	>6	• Overall remission: 57.7% • Microadenoma remission: 75% • Macroadenoma remission: 54.5% • Postoperative complications: 3 patients with transient DI and 1 patient with CSF leak which was resolved using lumbar drain • Large and invasive tumours statistically less likely to achieve remission
Fathalla et al., 2015²³	Retrospective cohort	65	Microscopic TSS	Endoscopic TSS	2010	>6	• Overall remission: 34.7% Group A vs. 45.2% Group B p = .40 • Invasive adenoma total resection: 14.2% Group A vs. 48% Group B p = .09 • Significant post-op complications: Permanent DI (4.8% Group A vs. 17.3% Group B p = .04); transient DI (17% Group A vs. 34.7% Group B p = .05) • Nonsignificant post-op complications: sinusitis (9.5% Group A vs. 8.6% Group B), pituitary insufficiency (11.9% Group A vs. 4.3% Group B), CSF leak (4.7% Group A vs. 8.6% Group B), epistaxis (2.3% Group A vs. 4.3% Group B); mean hospital stay (3.6 days Group A vs. 4 days Group B)
Hofstetter et al., 2010⁴⁶	Retrospective cross-sectional	24	Endoscopic TSS	–	2010	>6	• Overall remission: 46% • Macroadenoma remission: 42% • Postoperative complications: 8.4% CSF leak, 8.4% panhypopituitarism, 8.4% sinusitis and 4.2% diplopia • Mean hospital stay: 3.6 ± 1.8 days; Mean operative time: 181.6 ± 57.3 min • Increased tumour size associated with reduced remission rates
Jane et al., 2011⁴⁷	Retrospective cross-sectional	60	Endoscopic TSS	–	2010	≤6	• Overall remission: 69.7% • Microadenoma remission: 100% • Macroadenoma remission: 60.9% • Mean hospital stay: 2.32 days • Postoperative complications: 8.5% DI (persisted in 5%), 5% new steroid dependence; 28% and 16% new hypogonadism in males and females, respectively, 10% symptomatic hyponatraemia, 3% with sellar graft problem, 30% with CSF leak, 1.7% with carotid artery injury, 1.7% with meningitis • No mortality
Kim et al., 2009⁴⁸	Retrospective cross-sectional	42	TSS	–	2000	>6	• Overall remission: 64% • Microadenoma remission: 67% • Macroadenoma remission: 60% • Postoperative complications: 1 patient with CSF leak, 1 patient with meningitis and 1 patient with panhypopituitarism • Significantly less remissions associated with cavernous sinus invasion and high preoperative GH levels
Sarkar et al., 2014²⁴	Retrospective cohort	113	Endoscopic TSS	Microscopic TSS	2010	>6	• Overall remission: 31.9% • Remission: 28.8% Group A vs. 36.2% Group B p = .421 • Macroadenoma remission: 27.8% • Microadenoma remission: 56% • Significant less remissions: macroadenomas, pre-op GH, cavernous sinus invasion • Complications: At least 1 new hormone deficiency (18.2% Group A vs. 38.3% Group B p = .029); other insignificant: 34.5% intra-op CSF leak, 2.7% post-op CSF leak, 2.7% meningitis, 7.1% transient DI
Shimon et al., 2001²⁸	Retrospective cross-sectional	98	Microscopic TSS	–	2000	>6	• Overall remission: 74% • Microadenoma remission: 84% • Macroadenoma remission: 64% • Postoperative complications: 4 patients with at least 1 new hormonal deficiency, 9 patients with permanent DI, 2 patients with meningitis (1 of which died from it)
Shirvani et al., 2014⁴⁹	Retrospective cross-sectional	130	Microscopic TSS	–	2000	>6	• Overall remission: 56.9% • Microadenoma remission: 66.7% • Macroadenoma remission: 56% • Invasive macroadenoma remission: 0% • Post-op complications: 13.8% had at least 1 hormone deficiency, 10% CFS rhinorrhoea, 2.3% meningitis, 0.8% DI • Cavernous sinus invasion and large tumours associated with reduced remission
Starke et al., 2013²⁵	Retrospective cohort	113	Endoscopic TSS	Microscopic TSS	2010	>6	• No significant difference in remission between 2 groups • Overall remission: 69.9% • Microadenoma remission: 87.0% • Macroadenoma remission: 65.6% (p =.016 compared to microadenomas) • Post-op insignificant complications: 15.3% new endocrine deficit, 27.1% new endocrine gain of function, 4.9% epistaxis, 33.5% CSF leak intra or post-op, 7.1% transient DI, 2.7% permanent DI • Only self-reported sinusitis was significantly different between groups • Significant less remission associated with Knosp grade 3–4, pre-op GH>50 μg/L and young age
Sun et al., 2014⁵⁰	Retrospective cross-sectional	59	Microscopic TSS	–	2010	>6	• Overall remission: 52.5% • Microadenoma remission: 81.8% • Macroadenoma remission: 45.8% • Intra-operative complications: CSF leaks • Postoperative complications: 4 patients with transient DI and 2 patients with permanent DI • Old age, small tumours, Knosp grade 0–2, lower preop GH and IGF1 levels, SSRT2A positive tumours associated with significantly more remission
Taghvaei et al., 2018⁵¹	Prospective cross-sectional	68	Endoscopic TSS	–	2010	>6	• Overall remission: 64.7% • Microadenoma remission: 75% • Macroadenoma remission: 61.5% • Postoperative complications: 4.4% panhypopituitarism, 16.2% transient DI, 5.9% permanent DI, 2.9% CSF leak • Young age, cavernous sinus invasion, near-total resection associated with reduced remission rates
Taweesomboonyat et al., 2021⁵²	Retrospective cross-sectional	51	Endoscopic TSS	–	2010	≤6	• Overall remission: 47.1% • Microadenoma remission: 100% • Microadenoma remission: 43.8% • Significant less remissions: pre-op IGF1, Knosp grades 3–4 • Post-op complications: 5.9% CSF leak, 5.9% new hypopituitarism, 2% permanent DI, 5.9% epistaxis
Wagenmakers et al., 2011⁵³	Retrospective cross-sectional	40	Endoscopic TSS of macroadenomas only	–	2000	>6	• Macroadenoma remission: 50% • Postoperative complications: 1 patient with transient DI, 4 patients with epistaxis, 3 patients with CSF leak, 10 patients with at least 1 new hormonal deficiency • Large tumour size associated with reduced remission rates
Xie et al., 2016²⁶	Retrospective cohort	43	Endoscopic TSS with extra-capsular resection	Endoscopic TSS without extra-capsular resection	2010	>6	• Overall remission: 85.7% Group A vs. 54.5% Group B p < .05 • Overall complications (nil significance between groups): 37.2% intra-op CSF leak, 13.9% post-op CSF leak, 6.9% meningitis, 9.3% at least 1 new endocrine deficiency, 20.9% transient DI
Yao et al., 2021²²	Multicentre retrospective	546	TSS	Transcranial	2000	≤6	• Overall remission: 37.6% Group A vs. 21.4% Group B (p > .05) • Overall microadenoma remission: 62.5% • Overall macroadenoma remission: 31.9% (p < .001) • Significant predictors of low remission: pre-op GH >28, knosp 3–4, pre-op use of medications* • Complications: 26.0% hyponatraemia, 18.5% DI, 6.8% CSF leak, 0.4% meningitis, 0.2% with internal carotid artery injury • *SAs or dopamine agonists or GH receptor antagonists
Zheng et al., 2020⁵⁴	Retrospective cross-sectional	33	Endoscopic TSS	-	2010	>6	• Overall remission: 66.7% • Microadenoma remission: 100% • Macroadenoma remission: 72.2% • Pre-op GH, Knosp grade 3&4, micro/macroadenomas associated with significantly altered remission • Post-op complications: 9.1% transient DI and 6.1% CSF leak
Zhou et al., 2014⁵⁵	Prospective cross-sectional	133	Endoscopic TSS	–	2000	≤6	• Overall remission: 66.2% • Post-op complications: 9.0% transient DI, 0.8% transient visual impairment, 0.8% transient CN III/VI paralysis, 0.8% meningitis, 2.3% hypopituitarism, 3.8% dysosmia, 1.5% nasal bleeding

Abbreviations: CN, cranial nerves; CSF, cerebrospinal fluid; DI, diabetes insipidous; TSS, transsphenoidal surgery.

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Preoperative Medical Treatments and Surgical Approaches for Acromegaly

A Systematic Review

Abstract and Introduction

Abstract

Introduction

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

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