Introduction
Presentation, comorbidities, and mortality |
Although men present at a younger age than do women, women may show both increased incidence and mortality risk. (MQ, DR) Biochemical control remains the strongest predictor of patient outcomes, reflecting improvements in glucose metabolism, OSA, cardiovascular disease, and VFs. However, structural heart and joint changes are unlikely to resolve. (MQ, DR) The observed decline in reported mortality among acromegaly patients is likely due to more effective therapies, which, in turn, yield higher biochemical control rates and reduce the likelihood of developing respiratory and cardiovascular comorbidities that increase mortality. Rate of thyroid malignancies is not greater among acromegaly patients than among those without the condition. After screening colonoscopy at diagnosis, further testing should be performed similar to the general population, as per previous recommendations. (LQ, DR) |
Assays |
Reference GH nadir levels after OGTT using the IDS-iSYS assay accounting for BMI, sex, and ethinylestradiol-containing oral contraceptive use confirm the importance of these factors as confounders in GH measurements. (MQ, SR) IGF-I levels measured 6 weeks postoperatively can be used in most patients to assess remission, although patients with mildly elevated IGF-I may yet normalize by 3–6 months. (MQ, SR) |
Sex, age, and surgical outcomes |
Women, especially when postmenopausal, may exhibit lower surgical remission rates from TSS, as they tend to have larger and more invasive tumors that are less amenable to total resection. (LQ, DR) Patient age is likely not a predictor of surgical outcomes, nor does it impact the favorable effects of postsurgical remission on alleviating disease comorbidities. (LQ, DR) |
Radiotherapy outcomes |
Long-term follow-up of patients treated with SRS and FRT show that approximately half achieve and maintain biochemical control. However, up to one-third of patients with normal pituitary function develop hypopituitarism, confirming the need for ongoing monitoring. (LQ, SR) |
Injectable SRL |
Older age, female sex, lower IGF-I levels, and tumor T2 MRI hypointensity at baseline predict more favorable long-term biochemical responses to primary lanreotide 120 mg therapy every 4 weeks. (MQ, SR) Recent studies confirm that extended-dosing intervals (> 4 weeks) for 120 mg lanreotide may be effective among selected patients previously controlled with long-acting SRLs. (LQ, DR) Several studies confirm efficacy of pasireotide LAR for some patients uncontrolled on lanreotide or octreotide LAR. However, rates of treatment-induced hyperglycemia and DM are high, requiring careful monitoring for glycemic side effects. (HQ, SR) |
Pegvisomant |
Ten-year follow-up from ACROSTUDY shows a 73% biochemical control rate with very low rates of transient elevated transaminases and 6.8% exhibiting tumor growth visible on MRI. (HQ, SR) Pegvisomant use in patients with DM improves glucose metabolism independent of IGF-I control, but does not affect glycemic endpoints in patients without DM. (MQ, SR) Patients with DM and those with a higher BMI require higher doses of pegvisomant and more rapid up-titration to achieve IGF-I normalization. (MQ, SR) |
Combination therapy with SRL + pegvisomant |
Low-dose octreotide LAR or lanreotide plus weekly pegvisomant is a cost-effective and efficacious option for patients requiring combination therapy. (HQ, SR) Combination of pasireotide plus pegvisomant can yield biochemical control rates exceeding 70% even when pegvisomant doses are kept low. However, the addition of pegvisomant does not ameliorate the high rates of pasireotide-induced hyperglycemia. (MQ, SR) Patient selection for combination pasireotide plus pegvisomant should be carefully considered. (LQ, DR) |
How should OOC be integrated into the current treatment algorithm for medical management of acromegaly? |
OOC are suitable for patients who have demonstrated complete or partial biochemical response on injectable octreotide or lanreotide. (HQ, SR) Rationale: As octreotide and lanreotide have similar efficacy, patients who have responded to these injectable agents are candidates for OOC therapy, and results of the OPTIMAL study demonstrate that biochemically controlled patients (IGF-I ≤ 1.0 × ULN) on stable doses of injectable octreotide or lanreotide maintain response to OOC [4]. There are no data regarding efficacy of switching patients from pasireotide LAR to OOC.There are no data on the use of OOC as primary medical therapy in SRL-naïve patients. However, it is reasonable to expect that patients who respond to injectable octreotide LAR or lanreotide in this setting would also respond to OOC |
Due to a lack of available data, OOC is not currently recommended for patients who have tumor characteristics predictive of octreotide resistance. (MQ, SR) Rationale: Tumor characteristics associated with octreotide and lanreotide resistance (e.g., MRI T2 hyperintensity, sparsely granulated tumors) [5, 6] are presumed to also predict resistance to OOC |
How should OOC be initiated? |
OOC is initiated at a dose of 40 mg/day, given as 20 mg capsules twice per day taken 1 h before a meal or 2 h after a meal to maximize bioavailability. (MQ, SR) However, clinical study data suggest a starting dose of 60 mg/d may be optimal for most patients. Rationale: The 40 mg/day dose is the approved initiation dose [7]. Most responders in the OPTIMAL study up-titrated to 60 mg/d or 80 mg/d by study end, and all patients enrolling in the open label extension study were reinitiated at the 60 mg/d dose [4, 8] |
OOC should be initiated at the time of the previously scheduled SRL injection. (HQ, SR) Rationale: In clinical trials, OOC was initiated at the time of the next SRL injection, i.e., at the end of the once-monthly injection period [4, 9]. IGF-I levels may increase toward the end of the injection period with waning of injectable drug levels [10], and likely account for reported exacerbation of acromegaly symptoms [11‐13] |
How should OOC dose be escalated? |
OOC can be up-titrated by an increment of 20 mg every 2–4 weeks based on IGF-I and clinical symptoms. (MQ, SR) Rationale: The pharmacokinetics of OOC [14] enable a dose titration every 2–4 weeks. This is a more rapid escalation compared with injectable SRLs, which often are up-titrated every 3 months. Slower titration may risk re-emergence of disease signs and symptoms and loss of biochemical control |
Evidence | |
Very low quality (VLQ) | Expert opinion supported by one or few small uncontrolled studies |
Low quality (LQ) | Supported by large series of small uncontrolled studies |
Moderate quality (MQ) | Supported by one or few large uncontrolled studies or meta-analyses |
High quality (HQ) | Supported by controlled studies or large series of large uncontrolled studies with sufficiently long follow-up |
Recommendations | |
Discretionary recommendation (DR) | Based on VLQ or LQ evidence |
Strong recommendation (SR) | Based on MQ or HQ evidence |
Presentation, comorbidities, and mortality
What’s new
Summary points
-
Although men present at a younger age than do women, women may show both increased incidence and mortality risk.
-
Biochemical control remains the strongest predictor of patient outcomes, reflecting improvements in glucose metabolism, OSA, cardiovascular disease, and VFs. However, structural heart and joint changes are unlikely to resolve.
-
The observed decline in reported mortality among acromegaly patients is likely due to more effective therapies, which, in turn, yield higher biochemical control rates and reduce the likelihood of developing respiratory and cardiovascular comorbidities that increase mortality. The rate of thyroid malignancies is not greater among acromegaly patients than among those without the condition. After screening colonoscopy at diagnosis, further testing should be performed similar to the general population, as per previous recommendations.
Assays
What’s new
Summary points
-
Reference GH nadir levels after OGTT using the IDS-iSYS assay accounting for BMI, sex, and estradiol-containing oral contraceptive use confirm the importance of these factors as confounders in GH measurements.
-
IGF-I levels measured 6 weeks postoperatively can be used in most patients to assess remission, although patients with mildly elevated IGF-I may yet normalize by 3–6 months.
Sex, age, and surgical outcomes
What’s new
Summary points
-
Women, especially when postmenopausal, may exhibit lower surgical remission rates from TSS, as they tend to have larger and more invasive tumors that are less amenable to total resection.
-
Patient age is likely not a predictor of surgical outcomes, nor does it impact the favorable effects of postsurgical remission on alleviating disease comorbidities.
Injectable SRL
What’s new
Summary points
-
Older age, female sex, lower IGF-I levels, and tumor T2 MRI hypointensity at baseline predict more favorable long-term biochemical responses to primary lanreotide 120 mg therapy every 4 weeks.
-
Recent studies confirm that extended-dosing intervals (> 4 weeks) for 120 mg lanreotide may be effective among selected patients previously controlled with long-acting SRLs.
-
Several studies confirm efficacy of pasireotide LAR for some patients uncontrolled on lanreotide or octreotide LAR. However, rates of treatment-induced hyperglycemia and DM are high, requiring careful monitoring for glycemic side effects.
Oral octreotide capsules
What’s new
Recommendations
-
OOC are suitable for patients who have demonstrated complete or partial biochemical response on injectable octreotide or lanreotide.
-
Due to a lack of available data, OOC is not currently recommended for patients who have tumor characteristics predictive of octreotide resistance.
-
OOC is initiated at a dose of 40 mg/day, given as 20 mg capsules twice per day taken 1 h before a meal or 2 h after a meal to maximize bioavailability. However, clinical study results suggest a starting dose of 60 mg/day may be the optimal starting dose for most patients.
-
OOC should be initiated at the time of the previously scheduled SRL injection.
-
OOC can be up-titrated by an increment of 20 mg every 2–4 weeks based on IGF-I and clinical symptoms. This is a more rapid escalation than is used with injectable SRLs, which often are up-titrated every 3 months.
Pegvisomant
What’s new
Summary points
-
Ten-year follow-up from ACROSTUDY shows a 73% biochemical control rate with very low rates of transient elevated transaminases and 6.8% exhibiting tumor growth visible on MRI.
-
Pegvisomant use in patients with DM improves glucose metabolism independent of IGF-I control, but does not affect glycemic endpoints in patients without DM.
-
Patients with DM and those with a higher BMI require higher doses of pegvisomant and more rapid up-titration to achieve IGF-I normalization.
Combination therapy with SRL + pegvisomant
What’s new
Summary points
-
Low-dose octreotide LAR or lanreotide plus weekly pegvisomant is a cost-effective and efficacious option for patients requiring combination therapy.
-
Combination of pasireotide plus pegvisomant can yield biochemical control rates exceeding 70% even when pegvisomant doses are kept low. However, the addition of pegvisomant does not ameliorate the high rates of pasireotide-induced hyperglycemia.
-
Patient selection for combination pasireotide plus pegvisomant should be carefully considered.
Radiotherapy
What’s new
Summary points
-
Long-term follow-up of patients treated with SRS and FRT show that approximately half achieve and maintain biochemical control. However, up to one-third of patients with normal pituitary function develop hypopituitarism, confirming the need for ongoing monitoring.