Introduction

Acromegaly, which is caused by excess levels of growth hormone (GH) and insulin-like growth factor 1 (IGF1), is usually the result of a pituitary somatotroph adenoma1,2,3. Comorbidities include acral and soft tissue overgrowth, osteoarticular complications, respiratory alterations and hypertension, as well as metabolic abnormalities, such as insulin resistance, diabetes mellitus, malignancy and cardiovascular-related morbidity and mortality4,5,6,7. Treatment is primarily aimed at preventing adenoma growth and normalizing GH and IGF1 levels to ameliorate signs and symptoms of the disease, manage the effects of comorbidities and ultimately reduce excess mortality8,9,10.

Overall, biochemical control is achieved in about 50% of patients in referral centres following surgical adenoma resection, the preferred first-line therapeutic approach11. Approximately half of the patients requiring postoperative medical therapy achieve control of IGF1 levels12. Radiation therapy is an option for persistent active disease and clinically significant adenoma burden8,9,10. The approach to therapy is complex and requires comprehensive treatment by a multidisciplinary expert team to enable a personalized approach8,9,10.

Since the publication of medical management guidelines in 2018, new pharmacological agents and new treatment approaches have been developed. Moreover, the understanding of optimal therapeutic goals and predictive outcome factors has also evolved. Therefore, currently an unmet need exists for updated and extended recommendations for acromegaly management to enable outcome prediction and choice of optimal tailored therapeutic approaches to be maximized to achieve disease control based on specific individual patient characteristics.

Methods

In September 2023, the Acromegaly Consensus Group convened to update consensus guidelines (published in 2018) on medical management of acromegaly8. Since 2018, new pharmacological agents and approaches to treatment algorithms have been developed. Fifty-two worldwide recognized experts in acromegaly management reviewed the current literature for changes in drug use, practice standards and clinical recommendations since the 2018 consensus. The participants were selected on the basis of their recognized expertise in the field as reflected by their peer-reviewed publication record. Differences in geographical area were considered to account for national policies regulating the use of medical therapies. Updated consensus recommendations were graded using the Grading of Recommendations Assessment, Development and Evaluation system13,14, and key recommendations are presented in Boxes 1 and 2. Changes from the 2018 consensus recommendations are presented in Tables 1 and 2. Updated changes between the 2018 and the current consensus recommendations also reflect updated guidelines and information not comprehensively addressed previously.

Table 1 Key changes from the 2018 to the current consensus recommendations on definition and prediction of treatment outcomes
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Table 2 Key changes from the 2018 to the current consensus recommendations on medical therapy outcomes
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Meeting participants were assigned topics related to acromegaly treatment and outcomes by the Consensus Co-Chairs (S.M. and A.G.). Literature searches were conducted using PubMed for English-language papers published between October 2018 and August 2023. Search terms included ‘acromegaly’ and terms associated with each topic: ‘biochemical outcomes’, ‘tumour volume’, ‘clinical symptoms’, ‘somatostatin receptor ligand’, ‘dopamine agonist’, ‘GH receptor antagonist’, ‘oestrogen’, ‘selective oestrogen receptor modulator’, ‘medical therapy’, ‘mortality’, ‘complications’, ‘surgical outcomes’ and ‘guidelines’. After a brief presentation on each topic to the group, subgroups discussed the topic and then reported to the entire group. Consensus recommendations were developed based on the presentations, discussions and reports. All participants voted orally on each recommendation. Divergences and differences between participant opinions were reconciled with an audience general vote, and the majority approved final statements included in the current manuscript after approval by all authors.

Studies presented and discussed during the Consensus were reported in the manuscript and included in the reference list. Evidence strength was graded as very low quality (VLQ), low quality (LQ), moderate quality (MQ) or high quality (HQ)8, and consensus recommendations were classified as discretionary (DR) or strong (SR). Introductory sentences providing background evidence were graded with VLQ if based on expert opinion supported by one or a few small uncontrolled studies; with LQ if supported by a large series of small uncontrolled studies; with MQ if supported by one or a few large uncontrolled studies or meta-analyses; with HQ if supported by controlled studies or a large series of large uncontrolled studies with sufficiently long follow-up. Consensus statements and recommendations were classified as DR if based on VLQ or LQ evidence and as SR if based on MQ or HQ evidence. Statements were initially proposed by each work-subgroup after assigned topic discussion. Group outcomes were then presented to the entire group for further discussion and consensus finalization.

Definition and prediction of treatment outcomes

Excess levels of GH and/or IGF1 lead to systemic complications, which, in turn, contribute to morbidity and excess mortality (HQ)1,2,3,15,16,17,18,19. Treatment is aimed to prevent adenoma growth and progression, achieve biochemical and clinical disease control, decrease the risk of acral and soft tissue overgrowth, decrease the risk of developing metabolic, cardiorespiratory, musculoskeletal and neoplastic complications and reduce mortality risk.

Criteria for defining surgical control

Transsphenoidal surgery might lead to cure when undertaken by an experienced pituitary surgeon or when GH levels are judged to be too high to be controlled by medical therapy without pituitary mass debulking (HQ)8,11,12. As the term ‘cure’, defined as an absolute return to the premorbid condition, is seldom achieved, the term ‘disease control’ on medical treatment or ‘remission’ after surgery or radiotherapy is the preferred management goal12.

Biochemical criteria

Consensus statements (Box 1):

  • The Consensus group considers that suppressed GH after an oral glucose tolerance test (OGTT) predicts long-term remission but remission rates can be influenced by the assay cut-off and reproducibility, timing of measurement after surgery and the patient and phenotypic adenoma characteristics (SR).

  • GH nadir levels <1 ng/ml during OGTT reflect postoperative long-term remission. However, when using modern ultrasensitive GH assays with OGTT, a GH cut-off of 0.4 ng/ml is recommended (DR).

  • The Consensus group recommends measuring GH levels, both basal and during OGTT, and IGF1 levels 3 months after surgery (SR).

  • An IGF1 level within the age-stratified normal range is indicative of biochemical control (SR).

  • As residual tumour might persist after surgery, or, rarely, relapse even in the setting of postsurgical biochemical control, we recommend biochemical follow-up for at least 5 years and individualized monitoring strategies should be applied (SR).

Currently, no unique single parameter with published age and sex population-specific thresholds that define long-term remission after surgery is available (VLQ). GH and IGF1 measurements have been considered predictive of long-term surgical remission or the probability of disease recurrence8,12 (HQ). Measuring random GH or GH during OGTT early after surgery is a helpful determinant, unless patients have been pretreated with a somatostatin receptor ligand (SRL) (MQ). However, remission rates using these parameters are influenced by the assay cut-off and reproducibility, timing of measurement after surgery and patient and phenotypic adenoma characteristics (LQ).

In general, postoperative GH measurements are most accurate for predicting disease recurrence, in particular after OGTT12 (LQ). Measuring GH 1 day after surgery in 94 patients showed that GH levels >1.55 ng/ml predicted lack of hormonal remission with a sensitivity of 75% and a specificity of 59% (ref. 20). Results from 17 patients in whom postoperative levels of GH during an OGTT were measured 1 week after surgery showed that GH levels <0.5 ng/ml were highly predictive of surgical remission21. When GH was measured in 81 patients postoperatively, GH nadir levels during OGTT stabilized by postoperative days 2–5 (ref. 22). By contrast, IGF1 levels might continue to decrease for up to 1–2 years after surgery22,23,24,25. OGTT-suppressed GH and IGF1 measurements were concordant in 250 patients; 92% achieved postoperative GH normalization and had normalized IGF1 levels at 36 months24. In 97 patients with postoperative levels of IGF1 within the normal range, an abnormal postoperative GH suppression after surgery was predicted in most patients26. In patients treated with preoperative SRLs, biochemical assessment should be repeated at 3–6 months to confirm remission12 (Box 2).

After surgery, residual adenoma tissue might persist or, rarely, recur (HQ). Therefore, even in the setting of biochemical control, postoperative biochemical follow-up is recommended for at least 5 years and individualized follow-up strategies are recommended27, reflecting histopathological, molecular and radiological adenoma heterogeneity (MQ)2,12. Within the first year after surgery, IGF1 measurements every 3–6 months are appropriate to confirm remission, and then every 6–12 months to monitor for potential recurrence, and OGTT might be helpful in evaluating patients with borderline IGF1 levels12.

Imaging criteria

Consensus statements (Box 1):

  • Postoperative imaging assessment is not sufficient to define surgical remission even with complete visible adenoma removal (DR).

  • The first follow-up MRI should be performed no sooner than 3 months after surgery to allow for involution of initial local damage, gel foam and adipose packing (DR).

  • MRI should be performed at 3–6 months postoperatively as a baseline for subsequent assessment12. Regular MRI follow-up is not indicated for all patients and should be determined on the basis of biochemical parameters and clinical features considering histopathological, molecular and radiological adenoma heterogeneity2 (SR).

  • The recommendation is to continue evaluating maximal mass diameter reduction rather than overall adenoma volume, which is not standardized (DR).

  • If MRI cannot identify residual tissue, PET imaging using [11]C-methionine (Met-PET), although not widely available, might be useful in patients with persistent GH hypersecretion and active clinical disease (DR).

After the first follow-up MRI, which can be used as a baseline for further postoperative assessment, MRI should be performed upon signs of biochemical or clinical disease activity, or with changing a therapeutic modality, such as before second surgery or radiotherapy. Sometimes, MRI might not visualize small lesions or might misinterpret scar tissue as adenoma postoperatively (LQ). Repeated gadolinium administration could have adverse effects28 and, furthermore, adenoma size rarely increases when biochemical parameters are controlled (LQ)12. Although not widely available, Met-PET might be useful for localization of residual adenoma when MRI cannot identify residual tissue with persistent GH hypersecretion29,30 and when performed in conjunction with volumetric MRI (Met-PET/MRI) (Box 1).

Clinical criteria

Consensus statements (Box 1):

  • There are no specific criteria for clinical remission of acromegaly (DR).

  • To improve long-term outcomes, a comprehensive approach to patient management is recommended to ensure optimal management of comorbidities regardless of biochemical control and disease activity (SR).

  • Available clinical scores require further refinement and validation to enable their clinical application for evaluation of clinical outcomes (DR).

  • Although disease control is mainly defined by evaluating biochemical parameters, assessments of clinical burden and management of complications still require long-term follow-up (SR).

There is limited and controversial information regarding the course of symptoms, signs and comorbidities after surgical adenoma resection (LQ). Most studies evaluating outcomes focus on biochemical measures and rarely evaluate clinical improvement as an end point. Hypertension, diabetes mellitus, osteoarthrosis and sleep apnoea persist in a considerable proportion of patients even with biochemical control7 (HQ).

Joint pain is reported in almost all patients and typically correlates with a radiological sign of osteoarthrosis in at least two joints in 90% of patients3,7. Although arthralgia and stiffness improve after biochemical control, hip, knee, ankle, shoulder and hand pain were still present in about 40–70% of patients despite biochemical control31 (LQ). However, to date, available clinical scores are still not sufficiently validated and studies are needed to improve their application in patients after surgical resection32.

The prevalence of diabetes mellitus in patients with active acromegaly ranges between 15% and 35%, and diabetes mellitus and impaired glucose tolerance statistically significantly improve with GH control6,7. Patients with associated diabetes mellitus have a 50% higher risk of cardiovascular disease and a twofold increased cardiovascular mortality than patients without associated diabetes mellitus33. However, another study showed that diabetes mellitus and hypertension prevalence were similar at diagnosis and after a median postoperative follow-up of 7.4 years34. Artificial intelligence (AI) algorithms have identified acromegaly-specific facial features to predict the clinical diagnosis35,36. An AI model based on paired hand photographs taken at diagnosis and 3 months postoperatively predicts biochemical remission with 80% accuracy37. Although promising, these algorithms require further investigation to be implemented clinically (VLQ).

Predictors of response to medical therapy

There have been advances in the elucidation of a predictive role for imaging, molecular and biochemical markers of medical therapy responsiveness (Box 1).

Imaging determinants

Consensus statements:

  • Radiological acquisition and interpretation should be overseen by neuroradiologists with specific pituitary expertise, ideally as part of an interdisciplinary team in alignment with criteria of a pituitary tumour centre of excellence, and following standardized imaging protocols (SR).

  • A standardized approach should be used in reporting MRI results (SR).

MRI has a key role in evaluating acromegaly, and the adoption of a standardized approach in imaging evaluation is important for subsequent comparison38,39 (Box 1).

Both T1-weighted and T2-weighted spin echo MRI sequences are helpful (MQ). Coronal and sagittal (±axial) planes are required for analysis of mass size and extension and/or invasion; 1.5 T MRIs are a minimal requirement but ideally 3 T images, gadolinium-enhanced and 2–3 mm slice thickness (with no or minimal spacing) of the sellar region should be undertaken40.

MRI reports should include mass diameters, suprasellar extension, degree of parasellar extension using the Knosp classification41, absence or presence of cystic regions and T2 intensity compared with temporal lobe grey matter (or normal pituitary).

The role of imaging in supporting a decision for medical therapy is evolving (MQ). Associations between hormonal responses to SRL therapy and T2 MRI intensity have been proposed42,43,44,45,46. Hypointense adenomas were consistently associated with more favourable SRL responses, whereas hyperintense and isointense adenomas were identified as less responsive42,43,44,45,46. In contrast to previous observations with lanreotide or octreotide, increased T2 MRI adenoma intensity was associated with a more favourable biochemical response to pasireotide47.

Machine learning with quantitative texture analysis, permitting detection of MRI-specific features not visually perceptible, has been proposed as being reliable for predicting SRL responsiveness (LQ). In 47 patients (24 responsive and 23 resistant), machine-learning-based MRI texture analysis correctly predicted SRL response in >80% of patients, with better performance than conventional qualitative and quantitative relative T2 signal intensity and immunohistochemical evaluations48. Similarly, radiomic features have predicted both densely and sparsely somatotroph granulation patterns, which might be extrapolated to predict SRL responsiveness49.

Functional imaging with radiotracers targeting somatostatin (somatostatin receptor 2–5 (SSTR2–5)) and dopamine receptor expression predicted response to SRLs and dopamine agonist therapies, respectively50 (LQ). However, uptake by remnant normal pituitary tissue confounds interpretations (LQ).

Molecular markers of SRL response

Consensus statements:

  • Assessment of whether the adenoma is densely or sparsely granulated is considered a minimum requirement to determine SRL responsiveness (SR).

  • When available, SSTR2 immunostaining intensity might predict postoperative SRL responses (DR).

  • Testing for genetic variants is only recommended in selected patients, including those with familial disorders, suspected multiple endocrine neoplasia type 1 or with onset of acromegaly at <18 years old (DR).

  • The presence or absence of GNAS mutations should not be included in the outcome predictive algorithm as they do not predict SRL responsiveness (DR).

  • Models integrating multiple biomarkers might be helpful in predicting SRL responsiveness (DR).

  • Use of pathological and molecular predictors of SRL responsiveness should be complementary (DR).

Pathological and molecular predictors of SRL responsiveness have shown different predictive roles and results. Although tumour histopathological granulation patterns and SSTR immunochemical expression were consistently demonstrated to be useful in predicting therapeutic response (MQ), genetic and molecular investigations have been less useful as accurate outcome determinants (LQ). For instance, a large multicentre study, including >150 patients, showed that patients with GH-secreting pituitary adenomas with low SSTR2 immunochemical expression exhibited lower biochemical control rates with SRLs than patients with high SSTR2 expression51. In another study, low SSTR2 expression showed an odds ratio of 4.17 for SRL resistance52. Patients with densely granulated adenomas were more likely to achieve biochemical control than those with sparsely granulated adenomas53,54.

Germline AIP mutations, as well as other mutations associated with specific syndromes, are extremely rare in adults (MQ). Patients with AIP germline mutation and with X-linked acrogigantism have a suboptimal response to SRLs55,56,57. Furthermore, two large studies demonstrated that biochemical control rates were similar between patients with or without GNAS mutations58,59.

Models combining multiple biomarkers52,53,60,61,62,63 were tested in predicting SRL responsiveness. A model based on machine learning, including assessing SSTR2, SSTR5, cytokeratin granulation pattern, sex, age and pretreatment levels of GH and IGF1 levels, had an accuracy of 86% to predict SRL responsiveness51.

Biochemical parameters determining medical response

Consensus statements:

  • Measurements of circulating levels of GH and IGF1 are the most important biochemical markers to determine response to medical therapies (SR).

  • Both random and nadir GH concentrations during OGTT are predictive of responses to medical therapies (DR).

  • The acute octreotide test does not reliably predict the subsequent biochemical response to SRL therapy (DR).

Both GH and IGF1 assays exhibit methodological problems that are challenging to interpret (MQ). Low baseline IGF1 levels are associated with more favourable SRL biochemical responsiveness than high baseline levels64,65,66 (MQ). Circulating levels of IGF1 are more likely to be suppressed with low initial IGF1 levels at diagnosis64. High IGF1 levels are also associated with more adverse responses to pegvisomant and pasireotide61 (MQ).

High GH levels have been consistently associated with less favourable SRL responsiveness53,61,67 (MQ). Patients with a paradoxical increase in GH levels during OGTT (≥20% GH increase versus baseline) exhibit a modestly favourable IGF1 reduction after SRL treatment, compared with the non-paradoxical responding group (VLQ).

GH reduction measured 2 h after a subcutaneous injection of 100 μg octreotide (short acute octreotide test) was investigated in predicting subsequent biochemical response68, but the predictive usefulness of this test was precluded by overlap of biochemical outcome of extended SRL therapy in responders and non-responders to the acute test (LQ).

Definition of medical treatment resistance

Compared with other patients, those with acromegaly that is resistant to treatment are more likely to have adenoma compressive mass effects, poor biochemical control, treatment-related burdens, related comorbidities and impaired quality of life (QoL)6,7,8,9 (HQ) (Box 2).

Biochemical response

Consensus statements:

  • IGF1 measurements, using modern, well-characterized assays, are the best indicators of biochemical disease activity during medical therapy (SR)12,69,70.

  • The recommended biochemical treatment goal of medical therapy is normalization of IGF1 levels within the age-related reference range specific for the assay used and also with a sex-specific reference range when assessing patients during puberty (SR)8,12.

  • In patients treated with a GH receptor antagonist, GH assessment is not informative (SR)12.

  • Random GH assessment is not likely to provide additional information in all patients but could be considered for symptomatic patients with IGF1 levels at the higher end of the upper limit of normal (ULN) (DR)12.

Adenoma mass effects

Consensus statements:

  • Standardized criteria for adenoma progression (including changes in size, shape, location and growth rate) and imaging protocols should be established (SR).

  • Rapid growth or largest diameter increase during medical therapy should be considered a sign of adenoma resistance requiring a change of therapeutic strategy (SR).

  • Whether the adenoma shrinks could not be considered a major component of the definition of ‘resistance to medical therapy’ (DR)71.

  • MRI follow-up 6 months after initiation or switch to different medical therapies is recommended (SR).

  • Medical treatment should aim to achieve clinical and biochemical control in patients with visible postoperative residual adenoma tissue or microadenomas stable on serial imaging evaluations with MRI (DR).

In patients with large adenomas, mass reduction is particularly clinically relevant under the following conditions: when adenoma is contiguous with or in close proximity to the optic apparatus; when headaches or vision changes are caused by the mass; when pregnancy is desired; and when the adenoma presents histopathological markers of therapeutic resistance (MQ).

A 20% increase in largest diameter and/or an unusually rapid growth was suggested as a criterion of resistance and disease progression72 (MQ). Minor changes in a high-risk location (for example, close to the optic chiasm) should also be considered clinically relevant (LQ). The same standards for imaging and results reporting should be used in follow-up as for diagnosis12.

Clinical features

Consensus statements:

  • Medical treatment should aim to achieve clinical and biochemical control in patients with visible postoperative residual adenoma tissue or microadenomas stable on serial imaging evaluations with MRI (DR).

  • Age, germline mutations, histopathological characteristics, cytokeratin granulation, SSTR2 expression and proliferation markers are usually associated with enhanced risk of SRL resistance (DR).

  • Besides biochemical parameters, information regarding persistent comorbidities, symptoms and treatment-related adverse events are often overlooked in patients not responding optimally to treatments, but they should be considered of importance (SR).

Poorly controlled acromegaly leads to increased morbidity and mortality caused by adenoma growth and long-term exposure to excess levels of GH and IGF1, as well as to persistent comorbidities, symptoms, multiple interventions and treatment-related adverse events (HQ). More information on comorbidities, treatment-related adverse events, patient-reported outcome measures and QoL in poorly responsive acromegaly is required (MQ). A description of treatment-related adverse events should include information on hypopituitarism and burden of treatments and medications, especially for those requiring multiple therapies.

The prevalence and severity of cardiovascular, metabolic, respiratory and musculoskeletal comorbidities might improve but might not revert to premorbid normalcy even with biochemical control73,74 (MQ). Studies that characterize comorbidities specifically in patients with poorly controlled acromegaly are lacking (LQ). Psychopathology is linked to impaired physical functioning, poor body image, negative illness perception, mood disorders and treatment burden73. Impaired QoL might improve with biochemical control but does not necessarily normalize75 (LQ). Overall, there is a paucity of data on patient-reported outcomes in treatment-resistant acromegaly76. Specific patient-related outcome measures for treatment-resistant acromegaly are needed to clarify the clinical burden, needs and treatment approaches.

Medical therapy outcomes

Medical therapies (including SRLs and the dopamine agonist cabergoline) bind to somatostatin and dopamine receptors on the adenoma and suppress GH secretion (HQ). The GH receptor antagonist pegvisomant blocks peripheral GH actions, which leads to reduced IGF1 production (HQ). The synthetic SRLs lanreotide autogel, octreotide long-acting repeatable (LAR) injections or oral octreotide capsules (OOCs) mainly show affinity for SSTR2, whereas the multiligand SRL pasireotide has a broader affinity for four of the five SSTRs12 (HQ). SRLs typically represent a first-line medical approach and are mostly used as adjuvant treatments for persistent active disease after surgery (HQ). SRLs could be prescribed as a primary therapy in selected patients when surgery is declined or contraindicated (for example, because of high anaesthesia or cardiovascular risk)8 (LQ). The aims of medical therapy are to achieve comprehensive control of biochemical, clinical and tumoural features associated with the disease (Box 2).

Somatostatin receptor ligands: treatment outcomes

Consensus statements:

  • Adequate drug injection instructions are required (SR).

  • SRL-induced biochemical outcomes should be evaluated with IGF1 measurements after the first three monthly injections, preferably immediately before the ensuing one, and further IGF1 measurements depend on the degree and rate of IGF1 reduction77 (SR).

  • SRL doses should be titrated according to IGF1 values using dose escalation and adjustments to dose interval in selected patients (SR).

  • As no additional adverse effects are encountered with high-dose SRLs, this approach could be recommended in selected patients (DR).

  • When available, OOCs should be considered equally effective with similar adverse effects to injectable SRLs and should be recommended on the basis of patient preference (DR).

  • IGF1 levels are the most useful biomarker to assess disease control and should be measured after 2–4 weeks to determine optimal OOC dose titration (DR).

  • Clinicians should be aware that over-treatment might lead to IGF1 over-suppression, especially in those treated with pasireotide, justifying decreasing the dose with time or after radiotherapy (DR)78.

GH and IGF1 levels

A review that included 18 studies with octreotide LAR and 15 with lanreotide reported achievement of biochemical control ranging from 17% to 80% for octreotide LAR and from 27% to 78% for lanreotide79,80. Increasing maximal lanreotide injection doses to 180 mg every 28 days or shortening the interval of 120 mg to 21 days normalizes IGF1 concentrations in about one-third of patients with acromegaly, which is inadequately controlled by conventional SRL therapy with no additional adverse effects81. High-dose (60 mg every 28 days) or high-frequency (30 mg every 21 days) octreotide LAR reduced or normalized IGF1 levels in patients with acromegaly that was not controlled with conventional doses and dosing intervals; the high-dose scheme being superior to the high-frequency scheme82.

OOCs at doses of 40–80 mg per day were effective in patients with acromegaly that was previously biochemically controlled on injectable SRLs (MQ). After 36 weeks, IGF1 concentrations remained in the reference range in 58.2% of patients and GH concentrations <2.5 ng/ml were seen in 77.7% of patients83. OOC was non-inferior to injectable SRLs, with a more favourable patient-reported symptom benefit84. A phase II, open-label, single-arm exploratory study showed that GH and IGF1 concentrations remained unchanged after switching injectable SRLs to paltusotine, an oral non-peptide small SSTR2 agonist85.

After unsuccessful pituitary surgery or without prior treatment, pasireotide LAR at doses up to 60 mg every 28 days demonstrated superior efficacy over octreotide LAR at doses up to 30 mg every 28 days (31.3% versus 19.2% biochemical control at 12 months)86. In different studies, pasireotide LAR induced biochemical control in 11.4–20% of patients with acromegaly that was inadequately controlled with maximally approved doses of lanreotide or octreotide LAR87,88,89.

Effects on adenoma shrinkage

Consensus statements:

  • In patients with visual loss and optic chiasm compression, surgery is indicated (SR).

  • In selected patients with large adenomas, therapeutic goals of SRL treatment should include adenoma mass shrinkage and prevention of persistent growth (DR).

  • Reductions in maximal mass dimension of at least 20% are preferred, rather than overall volume, which has not been standardized (DR).

  • Ideally, treatment should result in adenoma diameter reduction of 20–25%, which is considered clinically significant (DR).

  • Critical local structures at risk should be considered (SR)8.

  • Adenoma diameter, rather than volume, is considered easier to measure and more accurately correlates to mass changes (DR)90,91.

  • Volume reduction can represent a better measure of favourable response and there is a need for methodologies to specifically measure adenoma volume using novel imaging software and AI tools (DR).

  • Biochemical results during SRL therapy might be useful to guide follow-up imaging frequency, and routine MRI surveillance is not suggested (DR).

  • Imaging follow-up should be prompted specifically with the appearance of either visual or eye movement symptoms or withdrawal of treatment or in assessing radiation therapy outcomes (SR).

  • Adenoma shrinkage induced by preoperative SRL treatment might not consistently result in improved surgical outcomes (DR).

Reported volume measurements are often inconsistent, particularly considering adenoma shape, scan details, interobserver differences and the methodology used (LQ). As such, reported volume measurements are not routinely performed.

T2 hypointensity at diagnosis is predictive of adenoma shrinkage with SRL treatment8. In this setting, 50% of patients exhibit adenoma shrinkage in the first month of both preoperative and postoperative SRL treatment, and there is a reasonable correlation with biochemical control8. Preoperative therapy with lanreotide 120 mg reduced adenoma size and visual symptoms in newly diagnosed patients with macroadenoma and optic chiasm compression92. Volume reduction (>25%) was observed in 61.9% of patients at the first month, and visual fields improved concomitantly with decreased GH and IGF1 levels.

Pasireotide might be associated with a greater effect on adenoma shrinkage than lanreotide and octreotide44,88 (LQ). A systematic review and meta-analysis on the effectiveness of pasireotide that included six studies reported that 37.7% of patients achieved significant (25% of baseline volume) shrinkage93. Mutations in AIP or X-linked acrogigantism are typically associated with less favourable mass reduction than other forms of acromegaly56.

In patients with SRL-induced hormone control, adenoma growth and progression are rarely reported, and routine MRI surveillance is not suggested, especially if initial MRI responses were favourable94 (LQ).

Clinical response

Consensus statements:

  • Although SRL-induced biochemical control is achieved in >40% of patients overall95, this metric might not properly reflect clinical disease control (DR).

  • Increased research focus on patient-reported outcome measures in acromegaly is required (DR).

  • Clinical parameters and outcomes should be standardized, and criteria that have been validated for defining clinical improvements are needed (DR).

  • Acromegaly and treatment-related symptoms, comorbidities and potential adverse effects of therapy should be monitored at each visit (DR).

  • Clinicians should be aware of discrepancies between clinical and biochemical outcomes; however, symptom burden should still be considered when deciding on therapeutic approaches, and the use of clinical tools and questionnaires is helpful (DR).

Headache, arthralgias, soft tissue swelling, hyperhidrosis and QoL frequently improve with SRLs (LQ). In a prospective study using health-related QoL, with three validated questionnaires (RAND-36, Acromegaly Quality of Life (AcroQoL) and the Appearance Self-Esteem), patients reported improvement in all overall scores during the first 2.5 years of treatment96.

Wide variability in patient-reported assessments and reporting is evident27,97,98,99,100 (LQ). A systematic review and meta-analysis of patient-reported outcome measures reported that of 14 different patient-reported outcome measures used, only one (AcroQoL) was previously validated in this setting101. In general, reporting of patient-reported outcome measures was poor, and 34% of studies showed discrepancies between patient-reported outcome measures and biochemical outcomes, mostly revealing improvements in biochemical outcomes but not in patient-reported outcomes.

Discordance between biochemical parameters and symptoms is well recognized, and many patients report ongoing symptoms even when acromegaly is well controlled biochemically (LQ). In a study of patients on stable SRL doses, more than 80% experienced joint pain, swelling of soft tissue and fatigue and/or weakness. These symptoms occurred constantly and affected daily activities and were even present among those with biochemical control102. In a randomized phase III study including patients with biochemically controlled acromegaly receiving SRLs, about two-thirds still reported symptoms that interfered with daily life activities103.

Adverse effects

Consensus statements:

  • Routine periodic abdominal ultrasound monitoring in patients receiving SRLs is not recommended (DR).

  • Geographical (or dietary) differences might determine a need for performing more frequent gallbladder ultrasounds as cholelithiasis requiring cholecystectomy has been reported104 (DR).

  • Routine fasting glucose and HbA1c measurements should be undertaken in all patients receiving SRLs and particularly in those receiving pasireotide (SR).

  • Electrocardiograms are not required before starting or during SRL therapy (DR).

  • The risks to benefits balance of SRLs should be evaluated and caution is required when they are administered concomitantly with other medications that effect QT intervals (DR).

As SSTRs are ubiquitously expressed, adverse effects of SRL treatment might manifest in multiple organs. In pooled analyses, up to 90–95% of patients experienced adverse effects with SRL treatment, which were mainly mild and transient89,105 (HQ). However, in selected patients, down-titration might be required (VLQ). A drop-out of ~3–10% was reported for lanreotide and octreotide66,102. Effects of SRLs in the gastrointestinal tract lead to altered pancreatic exocrine enzyme secretion and reduced bowel motility106.

More than half of patients receiving SRLs report gastrointestinal symptoms, including loperamide-responsive diarrhoea (10–55%), bloating (10–35%), nausea and vomiting (8–15%), steatorrhea (<10%) or general discomfort and/or pain, which usually resolve after 3–6 injections. Abnormalities in the biliary system owing to reduced bile flow and gallbladder motility might predispose patients to choledocholithiasis or cholecystolithiasis106 (LQ). Although these latter events are fairly frequent (up to 35%), they are often asymptomatic in most study cohorts and gallbladder surgery is infrequently required66,89,106.

Hyperglycaemia and diabetes mellitus are frequent complications of acromegaly (HQ). Nevertheless, SRLs might have detrimental effects on glucose metabolism66,107 (MQ). Two meta-analyses confirm an overall marginal negative effect of octreotide and lanreotide on fasting glycaemia108,109. However, as SSTR5 is widely expressed on pancreatic β-cells and on enteroendocrine cells, pasireotide reduces secretion of insulin and glucagon-like peptide 1 (refs. 110,111,112) (MQ). More than 50% of patients receiving pasireotide LAR experienced hyperglycaemia and diabetes mellitus, with an increased risk in those with pre-existing prediabetes88,113. For most patients, these symptoms are adequately managed with metformin and glucagon-like peptide 1 receptor agonists or dipeptidyl peptidase 4 inhibitors114 (LQ).

In addition, cutaneous injection reactions occur in up to 20–25% of patients, ranging from mild local erythema to fibrous scars with lymphoid follicles115 (LQ). Furthermore, SRLs have been associated with bradycardia and increased QT interval, possibly leading to decreased ventricular premature beats116 (LQ).

Pegvisomant treatment outcomes

Pegvisomant is a GH receptor antagonist that blocks GH actions, which leads to reduced IGF1 production117,118 (HQ). Although pegvisomant acts peripherally, the drug has the limitation of not specifically targeting the primary adenoma source of excess GH secretion; however, it has the advantage of blocking GH actions irrespective of the hypersecreting adenoma properties (HQ).

Consensus statements:

  • Continuous yearly MRI monitoring during pegvisomant treatment is no longer necessary (SR).

  • In specific circumstances, such as SRL withdrawal, further imaging might be performed within 6–12 months after initiation of pegvisomant (DR).

  • Imaging intervals should be scheduled on the basis of adenoma size and past growth characteristics independently of pegvisomant administration (DR).

  • Diabetes mellitus (especially when managed with insulin) and obesity are factors that require increased pegvisomant doses to achieve biochemical control (DR)119.

  • Symptoms (particularly fluid retention), QoL and comorbidities often improve with pegvisomant treatment and should be monitored during treatment (SR).

  • Disease control on pegvisomant treatment is accompanied by improved sleep apnoea syndrome, hypertension, arthralgias and glucose homeostasis (DR).

  • Injection sites should be rotated to prevent lipohypertrophy (SR).

  • Liver function tests should be obtained before starting pegvisomant and monitored during dose titration, and pegvisomant should be discontinued when transaminase levels exceed five times the ULN (SR).

IGF1 levels

More than 90% of patients receiving pegvisomant monotherapy in clinical trials achieved biochemical control; however, reported efficacy was 66% at 5 years and >70% at 10 years in most real-world safety surveillance studies9. In the ACROSTUDY cohort, which includes 2,221 patients treated with pegvisomant, monotherapy or in combination with SRLs120. The IGF1 normalization rate improved over time, increasing from 11.4% at initiation of pegvisomant to 75.4% at year 10 with the use of ≥30 mg pegvisomant per day. In a single-centre study including 45 patients treated for at least 5 years, 41 (91.1%) achieved normalized IGF1 levels121. Evaluation at 10 years (22 patients) showed that 91% of patients maintained full control. In the German ACROSTUDY subset, patients with diabetes mellitus had lower rates of IGF1 normalization (64% in the cohort with diabetes mellitus versus 75% in the cohort without diabetes mellitus)122. The maximal IGF1 lowering effect for a fixed pegvisomant dose is achieved within 4–6 weeks, and dose titration until normalization of IGF1 should occur at such time intervals120.

Adenoma mass

In 2,090 patients treated with pegvisomant and imaged at least twice, locally reported MRIs showed that most patients (72.2%) had no change in adenoma size relative to prior imaging; 16.8% had a decrease, 6.8% an increase and 4.3% had both123. Changes in adenoma size were reported as adverse events for 90 patients (4.3%), of which 21 (1%) were related to treatment. Of those, eight patients (0.4%) had pegvisomant withdrawn123. In 2021, in an analysis of the ACROSTUDY database (2004–2017) of 2,221 patients, locally reported MRIs showed that 7.1% of patients had increased adenoma sizes120. However, for 264 of 519 patients, MRI results were re-assessed by central reading, which showed adenoma volume increased in 54 (3.0%) patients. A retrospective single-centre study derived from 10 years of pegvisomant treatment showed that maximal adenoma diameter was stable121. A meta-analysis showed an overall adenoma growth rate of 7.2% in patients receiving pegvisomant monotherapy124. These findings confirmed that in large observational studies using centralized MRI serial readings, an increase is adenoma size after pegvisomant is uncommon (~3%) and is similar to that observed in those not treated with medical therapy8 (MQ).

Clinical features

An improved clinical outcome with pegvisomant is variable and dependent on the duration of disease and on associated comorbidities125,126 (MQ). An extension study of ACROSTUDY evaluated changes in symptoms with the Patient-Assessed Acromegaly Symptom Questionnaire (PASQ) and QoL with AcroQoL127. Overall, patients treated with pegvisomant had small improvements in PASQ but there was no significant difference between groups with or without IGF1 control (LQ). In a 4-year longitudinal interim analysis of ACROSTUDY113, patients with diabetes mellitus had a mean decrease in fasting blood levels of glucose of 20.2 mg/dl from baseline to year 4, whereas mean HbA1c remained unchanged125. In ACROSTUDY, the prevalence of comorbidities after pegvisomant versus before pegvisomant significantly decreased for hypertension from 51.3% to 10.5%, diabetes mellitus from 32.2% to 23.8%, sleep apnoea from 20.8% to 2.3% and symptomatic osteoarthritis from 21.3% to 7.6% (ref. 120). Data on glucose metabolism were in accordance with findings from other studies125,128.

Adverse effects

In ACROSTUDY, 613 of 5,567 adverse effects considered treatment-related were reported in 16.5% of patients treated with pegvisomant. The most common adverse effects were increased transaminase levels (1.5%), lipohypertrophy (1.2%) and IGF1 levels below the lower limit of the reference range (1.1%)120.

A multicentre retrospective study reported that lipodystrophy developed in 15% of patients129. According to a meta-analysis, lipohypertrophy was reported in 1.6% (ref. 124). In ACROSTUDY, adverse effects related to the administration site were reported in 3.5% of patients120. The most common treatment-related adverse effects linked to administration site that led to pegvisomant withdrawal were lipohypertrophy in 1.2% of patients and injection-site reaction adverse events in 0.8% (MQ).

A meta-analysis found evidence of elevated levels of transaminases in 3% of patients treated with pegvisomant124. In ACROSTUDY, 3.2% of patients had an alanine aminotransferase and/or aspartate transaminase value of more than three times the ULN at any time point during pegvisomant treatment120. Overall, hepatobiliary-related adverse effects were reported in 10.1% of patients, which led to pegvisomant withdrawal in 1.7% of patients. No liver failure was reported in the study. In a meta-analysis evaluating effects of the combination of SRLs with pegvisomant130, elevated transaminase levels were reported in 14% of patients131,132,133.

Combination treatments

Consensus statements:

  • Monotherapy should be switched to another class of drug when disease control is not achieved at maximum tolerated doses and/or when treatment-related adverse events occur (SR).

  • Combination therapy with SRLs and pegvisomant is a useful therapeutic approach in patients partially responsive to SRLs alone, or in those with an increase in adenoma size during pegvisomant monotherapy or in patients with diabetes mellitus (DR).

  • Liver enzymes should be monitored before and after starting combination SRL and pegvisomant treatment as it could be associated with an increased risk of increased liver enzyme levels compared with pegvisomant monotherapy (SR).

  • The addition of cabergoline with pegvisomant might be considered with the potential to lower costs in patients with acromegaly that does not respond to SRLs, which is not controlled by pegvisomant alone and is responsive to cabergoline; however, the evidence is insufficient to enable definitive conclusions regarding this combination (DR).

  • Use of combination pasireotide plus pegvisomant is suggested in patients with acromegaly that does not respond to first-line and second-line medical treatment, or in those in whom adenoma mass control is required. However, this approach should be considered with caution considering the high costs of these therapies and limited safety and efficacy results (DR).

When management goals are not achieved with drug monotherapy, a combination of two drugs of different classes is suggested8,9,10. These combinations have been studied with sufficient detail to recommend their use in selected patients. However, use of combination therapies might be hampered by country-specific differences in cost re-imbursement134 (VLQ).

SRLs and pegvisomant

In patients with acromegaly that is partially responsive to SRLs, the addition of pegvisomant enables normalization of IGF1 levels in most patients together with improved symptoms and glucose tolerance (HQ)133,135,136. Achievement of IGF1 levels within the normal range was observed in 55–96% of patients in a short-term prospective study that enrolled 52 patients136. Similarly, an efficacy of 91% was reported in a long-term prospective study121. Optimal disease control was maintained over time without requiring notable dose increases, as demonstrated when IGF1 levels were normalized in about 90% of patients treated with SRLs and pegvisomant for 10 years121. Adenoma volume remains unchanged or even decreases in most patients122,137 after a decade of combination treatment121. The most frequent adverse events are injection-site reactions and transiently elevated levels of liver transaminases, which mainly occur within the first year of combination treatment121,136 (MQ). Combination treatment is beneficial for systemic metabolic and cardiovascular comorbidities (MQ). SRLs might increase risks of impaired glucose metabolism, whereas the addition of pegvisomant might mitigate this effect of SRL, leading to an overall neutral metabolic effect that is sustained over time121,128 (LQ). Combination treatment might also improve lipid profiles121,128 (VLQ). Moreover, long-term addition of pegvisomant to SRLs improves cardiac structure and performance in patients with partial resistance to SRLs121,138 (LQ).

Overall, this combination results in efficacious biochemical control, improved clinical outcomes, reduced risk of adenoma size increase, improved therapeutic adherence and reduced overall drug costs. These findings are supported by reported 10-year experience (HQ).

Cabergoline and pegvisomant

Cabergoline, a long-acting dopamine agonist, is orally administered and is less expensive than SRLs and pegvisomant (HQ). On the basis of observational studies, normalized IGF1 values with cabergoline monotherapy are attained in patients with mild disease (IGF1 levels less than two times ULN)139 (MQ). To date, there is a paucity of studies investigating the results of combining cabergoline and pegvisomant140,141,142 (VLQ).

A retrospective study reported that in 14 patients with resistance to SRLs and acromegaly that was not completely controlled after the switch to pegvisomant 10–30 mg per day, the addition of cabergoline at a final dose of 1.5 ± 0.7 mg per week normalized IGF1 levels in 4 (28%) patients140. In a single prospective study on the combination of pegvisomant and cabergoline in 24 patients141, the addition of pegvisomant led to disease control in 13 patients.

Results on effects on adenoma size are limited and not conclusive for long-term clinical outcomes and potential adverse effects (VLQ).

Pasireotide and pegvisomant

The combination of pasireotide plus pegvisomant has shown promising results in real-life studies and a single clinical trial137,143,144 (VLQ). A prospective, single-centre study included 61 patients considered to have biochemically controlled acromegaly who were treated with a dose-sparing strategy of pegvisomant in combination with SRLs144. After 12 months, biochemical control was achieved in 31 of 46 treated patients (67.4%)144. A subsequent extension study reported that control was sustained at 48 weeks137.

In a real-life monocentre experience, six patients treated with the combination of pasireotide plus pegvisomant after failure of other multiple therapeutics achieved normal IGF1 levels143,145. The pasireotide dose was 60 mg monthly, and the mean pegvisomant dosage was 25 mg per day.

However, the incidence of diabetes mellitus increased from 33% at baseline to 69% at 24 weeks of treatment144 and to 77% after 48 weeks of treatment137; these data include patients treated with pasireotide alone and in combination with pegvisomant. The combination of pasireotide plus pegvisomant was associated with a lower frequency of hyperglycaemia and HbA1c levels decreased compared with those treated with pasireotide alone145.

Medical treatment algorithm

Consensus statements:

  • The optimal therapeutic approach should include individualized management based on clinical, imaging and pathological features, in a shared decision-making process from diagnosis to long-term patient and disease management (SR).

A proposed algorithm for medical treatment of acromegaly when acromegaly is inadequately controlled after pituitary surgery is depicted in Fig. 1.

Fig. 1: A proposed updated algorithm for medical treatment in patients with acromegaly that is inadequately controlled after pituitary surgery.
figure 1

The proposed algorithm depicts recommended therapeutic approaches to acromegaly. The cornerstone of the approach is based on initially anticipated surgical resection of the growth hormone (GH)-secreting adenoma. After surgery, first-line, second-line and third-line medical approaches are proposed as determined by the characteristics of the patient and the disease. Somatostatin receptor ligand (SRL; injectable or oral) can be followed by combination approaches, increasing SRL monotherapy dose or frequency and/or switching to pegvisomant or pasireotide monotherapy. First-line treatment with cabergoline and pegvisomant monotherapy might be considered in selected patients. In the absence of achieving disease control, combination of pasireotide with pegvisomant could be considered. After these decision-supported approaches for medical therapies, for a specific group of patients, stereotactic surgery, repeated surgery and/or use of chemotherapies (such as temozolomide) could be considered. IGF1, insulin-like growth factor 1; OGTT, oral glucose tolerance test; OOC, oral octreotide capsule; SSTR2, somatostatin receptor subtype 2; SSTR5, somatostatin receptor subtype 5.

Full size image

Presurgical approach

Consensus statements:

  • The effects of preoperative SRL treatment in improving surgical outcomes are as yet unclear, and more studies are needed to determine whether to widely recommend this approach (DR).

Surgery is potentially curative but, even with modern techniques, might be associated with modest remission rates, especially in patients with macroadenomas (particularly with cavernous sinus invasiveness), potentially requiring lifelong postoperative medical treatments146,147 (HQ). SRL efficacy in postoperative control has been hypothesized to also be useful in a preoperative setting148 (LQ). In a meta-analysis, a significant benefit of preoperative medical treatment was observed when only prospective randomized controlled trials were evaluated149 (MQ). Meta-analyses and reviews based on prospective randomized controlled trials on resected GH-secreting macroadenomas showed improved short-term remission rates compared with no preoperative medical therapy150,151 (LQ). However, previously published studies reported conflicting results on effects of preoperative medical treatment on surgical outcomes, achieving and sustaining normalization of IGF1 levels, with some studies reporting improved remission rates whereas others did not (VLQ). In a retrospective study including 110 consecutive newly diagnosed patients, long-term remission rates were higher in the cohort receiving presurgical SRL treatment than in those who did not receive this treatment152.

First-line medical treatment

Consensus statements:

  • SRLs represent the first-line option for medical therapy, and new therapeutic formulations have led to new opportunities for personalized approaches (SR).

  • Cabergoline should only be considered as a first-line medical therapy in patients with IGF1 levels <2.0–2.5 times the ULN or in patients with mixed GH-prolactin-secreting adenomas (DR).

  • Pegvisomant monotherapy is a valuable first-line medical option, particularly in patients with severely impaired glucose metabolism and no adenoma mass concern with potential non-responsiveness to SRLs; that is, T2 MRI hyperintensity signal and very high IGF1 concentrations (DR).

First-line medical treatment of acromegaly is used in patients in whom surgery is contraindicated or declined, as well as in patients not expected to be cured by surgical resection of the adenoma8 (HQ). SRLs are still the mainstay treatment for biochemical control and adenoma size reduction, although with very variable efficacy rates among series8 (HQ). However, despite overall improved disease outcomes and QoL, patients treated with SRLs often experience a considerable therapy-related burden101,102,103 (LQ). New oral and subcutaneous-depot SRL formulations have been developed to avoid discomfort of parenteral administration and potentially improving both patients’ QoL and therapeutic adherence153. These compounds show promising results in disease control with adequate safety profiles and non-inferiority compared with injectable formulations154,155 (MQ). The development of new therapeutic formulations has opened new opportunities to increase personalized approaches, which might be considered of value in emergency situations, such as the COVID-19 pandemic, that limit patient access to care156,157 (VLQ).

Cabergoline has the advantages of reduced costs and an oral route of administration (LQ). However, its positioning as a first-line medical approach is limited by modest efficacy and should be restricted to addressing mild postoperative increases in levels of IGF1 and/or GH158,159 (VLQ).

It is recommended to monitor the potential risk of cardiac valvulopathy and development of impulse control disorders that might occur with long-term use of very high cabergoline doses160,161,162,163.

Second-line medical treatment

Consensus statements:

  • For patients with acromegaly inadequately controlled with first-line medical approaches, second-line treatment options should be considered (SR)164,165.

  • Increasing the SRL dose and/or dose frequency to improve biochemical control in patients sensitive to SRLs but with acromegaly inadequately controlled on standard doses can be considered for off-label second-line treatment (DR).

  • The addition of cabergoline to SRLs could be considered in patients responsive to SRLs and not reaching IGF1 normalization independently of serum levels of prolactin or adenoma prolactin immunostaining (DR).

  • Pegvisomant monotherapy might be the first choice as a second-line treatment in patients with pre-existing hyperglycaemia or diabetes mellitus (DR).

  • Pegvisomant combined with SRLs could be considered as a second-line treatment in those with limited adherence to daily injections, when costs of therapy are a determinant and in patients with impaired glucose tolerance and/or with adenoma shrinkage during lanreotide and octreotide treatment (DR).

  • When SRLs cannot be tolerated, pegvisomant combined with cabergoline might be considered (DR).

  • Pasireotide LAR might be used in patients with acromegaly that is inadequately controlled, especially in patients with relevant or growing adenomas and with a low risk of hyperglycaemia (SR).

Increasing the SRL dose and/or frequency showed biochemical control in 18–36% of patients81,82. With adequate dose titration, the efficacy of pegvisomant monotherapy is favourable, and it might be the first choice as a second-line treatment in patients with pre-existing hyperglycaemia or diabetes mellitus9,165 (Box 2). Pasireotide LAR might be used in patients with acromegaly inadequately controlled with octreotide85 as the first choice for second-line treatment, especially in patients with relevant or growing adenomas, sparsely granulated histopathological characteristics, germline AIP mutations and with a low risk of hyperglycaemia165 (Fig. 1). Combined treatment with SRL and pegvisomant achieved control in 80–96% (refs. 135,165) of patients, possibly enabling a reduction of doses or frequencies of pegvisomant administration (Box 2).

As there are limited reports on long-term efficacy and safety139,140, combined pegvisomant and cabergoline treatment might be considered when therapy with SRLs and pegvisomant is not feasible owing to intolerance to SRLs (VLQ).

Oral oestrogens and selective oestrogen receptor modulators might reduce IGF1 levels. Therefore, when used for other indications alone or in combination with SRLs or cabergoline, they improve biochemical control in selected female patients (LQ)166,167,168,169.

Third-line medical treatment

Consensus statements:

  • When monotherapy does not achieve biochemical control, pasireotide plus pegvisomant might be considered (DR).

  • Combination of cabergoline and pegvisomant cannot be recommended as no prospective results are available (DR).

  • Stereotactic radiosurgery or surgical intervention or reintervention should be considered if control is not achieved with medical therapies (SR).

  • Chemotherapies should be considered, limited to aggressive or malignant lesions (SR).

Interpretation of efficacy reports on third-line medical treatment and use of different combinations is hampered by the paucity of prospective data (VLQ). Limited but promising results on combining pasireotide with pegvisomant have been reported in the PAPE study and real-life cohort experiences, mostly with poorly responsive disease136,142,143 (LQ). When monotherapy does not achieve biochemical control, pasireotide plus pegvisomant might be considered if no contraindications are present136,142,143. Although combining cabergoline with pasireotide could have a similar additive effect, there are no published prospective studies on the efficacy of this approach.

If biochemical control is not achieved with medical therapies, stereotactic radiosurgery or surgical intervention or reintervention should be considered7. Temozolomide and other chemotherapies should be limited to aggressive or malignant lesions and be used under neuro-oncological supervision8,9,170,171.

Conclusions

Our recommendations for management of acromegaly have been updated and extended since the previous 2018 Consensus Statement8. Given the increased usage of combinations of drug classes, and with the promising results on novel oral formulations, patients now have more treatment options that are likely to achieve disease control specifically based on each patient’s unique needs and characteristics. Increased knowledge on predictive factors and response outcomes to medical therapy has opened opportunities for enhanced personalization of treatments. A rigorous guide for clinicians to predict and to choose optimal tailored therapeutic approaches still requires further research. A comprehensive classification of pituitary adenoma outcomes incorporating molecular, pathological, imaging, biochemical and clinical information should prove helpful in this regard172. This approach would enable the evaluation of treatment responsiveness and outcomes using comprehensive phenotypes not based solely on biochemical parameters but also on clinical features and concomitant comorbidities.