This article presents management options for the patient with acromegaly after noncurative surgery. The current evidence for repeat surgery, adjuvant medical therapy with somatostatin analogues, dopamine agonists, the growth hormone receptor antagonist pegvisomant, combination medical therapy, and radiotherapy in the context of persistent postoperative disease are summarized. The relative advantages and disadvantages of each of these treatment modalities are explored, and a general treatment algorithm that integrates these modalities is proposed.
- •
Control of growth hormone (GH) and insulin-like growth factor I (IGF-I) levels is often not complete after surgery.
- •
Second surgery may be considered if an anatomic target is evident or to further reduce GH levels.
- •
Somatostatin analogues (SSAs) are the first line of medical therapy.
- •
Pegvisomant can be added or switched to if SSAs do not reach control.
- •
Radiation therapy has good tumor growth control, but hormonal control may require many years.
Introduction
Nearly one-third of patients with acromegaly will not be cured by initial surgery. This statistic is likely attributable to the fact that growth hormone (GH)-secreting tumors are often large by the time they are discovered, because of the delayed recognition of acromegalic features. Recently, the criteria for remission of acromegaly have become more stringent, meaning that an even larger number of individuals may be deemed not cured following surgery. To prevent the morbidity and early mortality associated with uncontrolled acromegaly, treatment options that provide prompt biochemical control while minimizing side effects are essential after unsuccessful surgery. Choosing the appropriate therapy is best done in a multidisciplinary fashion involving close communication between endocrinologists, neurosurgeons, neuro-ophthalmologists, and radiation therapists. This review presents treatment approaches to the patient with persistent or recurrent postoperative acromegaly.
Definitions
Persistent disease denotes unsuccessful initial treatment, whereas recurrent disease is a return to a state of GH excess following initial remission. Despite advancements in surgical techniques, the cure rate following first-time surgery for acromegaly has not improved significantly over the last 30 years. A recent meta-analysis of 32 surgical series found persistent disease in 39% of patients while the recurrence rate following initial cure was only approximately 3%. Thus, recurrence is much less likely than disease persistence to be encountered. From a management standpoint, the approach to persistent or recurrent disease is generally similar.
Factors Predictive of Tumor Aggressiveness
Tumor size, extrasellar extension, and GH levels are the most important predictors of initial surgical cure. Surprisingly, tumor size and invasiveness do not appear to predict the likelihood of tumor recurrence after remission. Lower recurrence rate is observed in patients with low postoperative and glucose-suppressed GH levels, while age and gender have no predictive value. The incidence of recurrences appears to peak around 1 to 5 years after surgery, although recurrences have been observed more than 10 years after initial cure.
Even with today’s multimodal therapy, which can provide adequate disease control for the majority of patients, there is a subset of individuals (fewer than 10% of those cured surgically) who exhibit treatment-resistant tumor growth. These factors have been associated with more aggressive tumor behavior :
- •
Younger age at diagnosis
- •
Larger or extensive and invasive tumors
- •
Higher pretreatment GH levels
- •
Molecular and genetic factors
- ○
gsp , PTTG, GADD45 gene mutations
- ○
FGF-4 expression
- ○
MEN-1, AIP gene mutations
- ○
- •
Tumor morphology
- ○
Sparsely granulated adenomas
- ○
Dotlike cytokeratin adenoma staining pattern
- ○
Higher Ki-67 index
- ○
Changing Biochemical Definition of Cure
A precise definition of cure has historically been challenging to reach in the absence of clear clinical parameters with which to monitor disease activity. Biochemical markers (insulin-like growth factor I [IGF-I] and GH) have therefore been relied on as the best indicators of disease burden. Higher GH and IGF-I are associated with increased mortality in acromegaly, often because of cardiovascular disease. Thus, goals of therapy include normalization of IGF-I according to age-specific and sex-specific reference ranges, and attainment of GH levels below specific random and oral glucose-suppressed cutoffs. Over the last 50 years, the GH cutoff has been progressively lowered as GH assays have become more sensitive and specific. In fact, the postoperative basal GH criterion for cure in the 1960s was 10 to 20 times less stringent compared with today. Up until the mid-1990s, GH was measured using polyclonal radioimmunoassay (RIA), and a GH treatment target of less than 2.5 μg/L was chosen as the criterion for cure based on data showing no incremental mortality risk below that level. In 1999, taking into consideration the improved sensitivity of newer monoclonal GH assays (chemiluminescence, immunofluorescence, immunoradiometric, and so forth), a consensus group met in Cortina, Italy to propose criteria for cure. According to these Cortina criteria, a normal IGF-I level and nadir GH level after oral glucose tolerance test (GH n ) of less than 1 μg/L suggested cure. That conference did not specifically mention a cutoff for random GH (GH r ), and several studies have used a cutoff of 2.5 μg/L as a definition of control.
Current Consensus Criteria for Cure
In the years following the publication of the Cortina criteria, significant advancements have been made in the management of acromegaly, particularly with respect to adjunctive medical therapy for persistent disease. The complex, often multimodal treatment in acromegaly, and the development of even more sensitive (ultrasensitive) GH assays led to newer criteria for cure ( Table 1 ), published in 2010.
| Consensus Criteria | Random Fasting GH (GH r ) (μg/L) | Nadir GH After OGTT (GH n ) (μg/L) | IGF-I |
|---|---|---|---|
| 2000 Cortina criteria | (Not defined) | <1 | Age/sex normalized |
| Current 2010 criteria | <1 | <0.4 | Age/sex normalized |
Having only recently been implemented in practice, there are limited long-term outcome data to support the newer targets. The main evidence to date comes from 2 studies showing that mortality risk was similar to that in the reference population in patients whose GH r was less than 1 μg/L. There is a general consensus that using current ultrasensitive GH assays, a GH r less than 1 μg/L corresponds to the older RIA GH value of 2.5 μg/L, for which a clear mortality benefit has been demonstrated.
Discordant IGF-I and GH
Generally, GH and IGF-I results are concordant following surgery; however, an elevated IGF-I despite normal GH may be seen in up to 24% of surgically treated patients, while high GH despite normal IGF-I is seen in about 10% of patients. When there is discordance between IGF-I and GH results, determining the patient’s clinical status can be perplexing, and often repeated testing is needed.
The reasons for discordant hormonal results after treatment are not entirely certain, although several possible causes have been identified ( Fig. 1 ). The more common scenario of an elevated IGF-I with normal GH may result from inadequate GH sampling to detect elevated GH pulses, testing IGF-I levels too soon after surgery, low but uninterrupted GH secretion, and rare GH-receptor polymorphisms. The less common finding of a normal IGF-I with a high GH can result from any systemic condition that reduces hepatic IGF-I production. It is well known that medical treatment with somatostatin analogues (SSAs) is more likely to be associated with normal IGF-I despite elevated GH. This phenomenon has been attributed to pituitary-independent suppression of hepatic IGF-I production by SSAs. A problem common to both scenarios is the issue of GH and IGF-I interassay variability, which has been discussed extensively in the recent American Association of Clinical Endocrinologists guidelines and current consensus criteria.
Timing of Postoperative Biochemical Testing
Given the long biological half-life of IGF-I, accurate assessment of IGF-I status after surgery requires waiting at least 12 weeks for levels to stabilize. On the other hand, GH has a very short half-life, and elevated values are telling even in the immediate postoperative period. The role of early (1 week postoperative) GH n as a predictor of long-term remission has been examined in 2 studies. Using GH n cutoffs of 1.0 μg/L, these studies showed a high predictive value for cure based on early postoperative measurements. Although these cutoffs were higher than today’s current standard, both studies showed high correlation between early postoperative (1 week) and delayed GH n testing (12 weeks). This result suggests that an early GH n by today’s standard (<0.4 μg/L) probably predicts long-term remission. However, an early negative response to an oral glucose tolerance test requires follow-up testing at a later time point, because the inadequate sensitivity of this test may initially misclassify a patient in remission as having persistent disease.
Definitions
Persistent disease denotes unsuccessful initial treatment, whereas recurrent disease is a return to a state of GH excess following initial remission. Despite advancements in surgical techniques, the cure rate following first-time surgery for acromegaly has not improved significantly over the last 30 years. A recent meta-analysis of 32 surgical series found persistent disease in 39% of patients while the recurrence rate following initial cure was only approximately 3%. Thus, recurrence is much less likely than disease persistence to be encountered. From a management standpoint, the approach to persistent or recurrent disease is generally similar.
Factors Predictive of Tumor Aggressiveness
Tumor size, extrasellar extension, and GH levels are the most important predictors of initial surgical cure. Surprisingly, tumor size and invasiveness do not appear to predict the likelihood of tumor recurrence after remission. Lower recurrence rate is observed in patients with low postoperative and glucose-suppressed GH levels, while age and gender have no predictive value. The incidence of recurrences appears to peak around 1 to 5 years after surgery, although recurrences have been observed more than 10 years after initial cure.
Even with today’s multimodal therapy, which can provide adequate disease control for the majority of patients, there is a subset of individuals (fewer than 10% of those cured surgically) who exhibit treatment-resistant tumor growth. These factors have been associated with more aggressive tumor behavior :
- •
Younger age at diagnosis
- •
Larger or extensive and invasive tumors
- •
Higher pretreatment GH levels
- •
Molecular and genetic factors
- ○
gsp , PTTG, GADD45 gene mutations
- ○
FGF-4 expression
- ○
MEN-1, AIP gene mutations
- ○
- •
Tumor morphology
- ○
Sparsely granulated adenomas
- ○
Dotlike cytokeratin adenoma staining pattern
- ○
Higher Ki-67 index
- ○
Changing Biochemical Definition of Cure
A precise definition of cure has historically been challenging to reach in the absence of clear clinical parameters with which to monitor disease activity. Biochemical markers (insulin-like growth factor I [IGF-I] and GH) have therefore been relied on as the best indicators of disease burden. Higher GH and IGF-I are associated with increased mortality in acromegaly, often because of cardiovascular disease. Thus, goals of therapy include normalization of IGF-I according to age-specific and sex-specific reference ranges, and attainment of GH levels below specific random and oral glucose-suppressed cutoffs. Over the last 50 years, the GH cutoff has been progressively lowered as GH assays have become more sensitive and specific. In fact, the postoperative basal GH criterion for cure in the 1960s was 10 to 20 times less stringent compared with today. Up until the mid-1990s, GH was measured using polyclonal radioimmunoassay (RIA), and a GH treatment target of less than 2.5 μg/L was chosen as the criterion for cure based on data showing no incremental mortality risk below that level. In 1999, taking into consideration the improved sensitivity of newer monoclonal GH assays (chemiluminescence, immunofluorescence, immunoradiometric, and so forth), a consensus group met in Cortina, Italy to propose criteria for cure. According to these Cortina criteria, a normal IGF-I level and nadir GH level after oral glucose tolerance test (GH n ) of less than 1 μg/L suggested cure. That conference did not specifically mention a cutoff for random GH (GH r ), and several studies have used a cutoff of 2.5 μg/L as a definition of control.
Current Consensus Criteria for Cure
In the years following the publication of the Cortina criteria, significant advancements have been made in the management of acromegaly, particularly with respect to adjunctive medical therapy for persistent disease. The complex, often multimodal treatment in acromegaly, and the development of even more sensitive (ultrasensitive) GH assays led to newer criteria for cure ( Table 1 ), published in 2010.
| Consensus Criteria | Random Fasting GH (GH r ) (μg/L) | Nadir GH After OGTT (GH n ) (μg/L) | IGF-I |
|---|---|---|---|
| 2000 Cortina criteria | (Not defined) | <1 | Age/sex normalized |
| Current 2010 criteria | <1 | <0.4 | Age/sex normalized |
Having only recently been implemented in practice, there are limited long-term outcome data to support the newer targets. The main evidence to date comes from 2 studies showing that mortality risk was similar to that in the reference population in patients whose GH r was less than 1 μg/L. There is a general consensus that using current ultrasensitive GH assays, a GH r less than 1 μg/L corresponds to the older RIA GH value of 2.5 μg/L, for which a clear mortality benefit has been demonstrated.
Discordant IGF-I and GH
Generally, GH and IGF-I results are concordant following surgery; however, an elevated IGF-I despite normal GH may be seen in up to 24% of surgically treated patients, while high GH despite normal IGF-I is seen in about 10% of patients. When there is discordance between IGF-I and GH results, determining the patient’s clinical status can be perplexing, and often repeated testing is needed.
The reasons for discordant hormonal results after treatment are not entirely certain, although several possible causes have been identified ( Fig. 1 ). The more common scenario of an elevated IGF-I with normal GH may result from inadequate GH sampling to detect elevated GH pulses, testing IGF-I levels too soon after surgery, low but uninterrupted GH secretion, and rare GH-receptor polymorphisms. The less common finding of a normal IGF-I with a high GH can result from any systemic condition that reduces hepatic IGF-I production. It is well known that medical treatment with somatostatin analogues (SSAs) is more likely to be associated with normal IGF-I despite elevated GH. This phenomenon has been attributed to pituitary-independent suppression of hepatic IGF-I production by SSAs. A problem common to both scenarios is the issue of GH and IGF-I interassay variability, which has been discussed extensively in the recent American Association of Clinical Endocrinologists guidelines and current consensus criteria.
Timing of Postoperative Biochemical Testing
Given the long biological half-life of IGF-I, accurate assessment of IGF-I status after surgery requires waiting at least 12 weeks for levels to stabilize. On the other hand, GH has a very short half-life, and elevated values are telling even in the immediate postoperative period. The role of early (1 week postoperative) GH n as a predictor of long-term remission has been examined in 2 studies. Using GH n cutoffs of 1.0 μg/L, these studies showed a high predictive value for cure based on early postoperative measurements. Although these cutoffs were higher than today’s current standard, both studies showed high correlation between early postoperative (1 week) and delayed GH n testing (12 weeks). This result suggests that an early GH n by today’s standard (<0.4 μg/L) probably predicts long-term remission. However, an early negative response to an oral glucose tolerance test requires follow-up testing at a later time point, because the inadequate sensitivity of this test may initially misclassify a patient in remission as having persistent disease.
Clinical evaluation
In addition to targeting the source of the problem (excess GH), patients should be offered standard of care monitoring (ie, fasting lipid profile, blood pressure control, hemoglobin A 1C , and so forth), and treatments for their comorbidities (ie, blood sugar or lipid-lowering agents, osteoarthritis medications, bone-specific therapy, continuous positive airway pressure, and so forth). Worsening of a previously controlled symptom should prompt biochemical investigation for disease recurrence, and persistent symptoms might indicate the need for titration of medical therapy. Hypopituitarism is independently associated with reduced life expectancy, so anterior pituitary deficiencies resulting from the tumor or its treatment should be evaluated and appropriate hormone replacement started for any uncovered deficiencies.
Radiological Evaluation
All patients who are not cured by surgery require follow-up pituitary magnetic resonance imaging (MRI) to determine residual tumor anatomy. It is generally advisable to wait at least 3 months before assessing radiographic response, to avoid misinterpreting postoperative inflammation and edema as tumor remnant. The need for MRI in cured patients is less obvious. When residual tumor is identified, its size, location, invasiveness, and mass effect (optic chiasm compression) are key considerations in determining the next management step. If optic chiasm compression is still present, formal visual field testing is important in establishing a new baseline before other treatment attempts. Repeat surgery is reasonable if the tumor is accessible, regardless of size. Cavernous sinus invasion is associated with a very low likelihood of successful repeat surgery.
Treatment options
After failed pituitary surgery, treatment options include:
- •
Repeat surgery
- •
Medical therapy
- ○
SSA
- ○
Dopamine agonist (DA)
- ○
Growth hormone receptor antagonist (GHRA)
- ○
Combination medical therapy (SSA ± DA ± GHRA)
- ○
- •
Radiotherapy
- ○
Conventional radiotherapy
- ○
Stereotactic radiosurgery
- ○
A general treatment algorithm for persistent disease in proposed in Fig. 2 .
Repeat Surgery
While surgery is generally the best initial treatment choice for acromegaly, medical therapy affords the best chances of remission after failed surgery and is the favored approach for persistent disease. In practice, repeat surgery is usually reserved for debulking purposes to increase the likelihood of remission with adjuvant therapies or when relief of mass effect on the optic chiasm is needed.
Effectiveness of Secondary (Repeat) Surgery
There is scant evidence on the effectiveness of repeat surgery. Among the handful of surgical series that have published outcomes of reoperations, only 5 used Cortina remission criteria ( Table 2 ). The mean remission rate for reoperations in these contemporary series is 37%, but there is wide variation among the individual studies (8%–59%). When data from all the studies is combined, 117 of 345 reoperated patients achieved remission (34%), with the same remission rate seen when including only studies that used the Cortina criteria. As a reference, the mean remission rates from primary surgery using Cortina criteria in microadenomas, macroadenomas, and adenomas overall are 80%, 57%, and 64%, respectively.
| Authors, Ref. Year | Remission Criteria: Normal IGF-I and | Total No. of Patients | No. of Reoperated Patients | No. of Persistent/Recurrent Patients (% of Each) | Remission Rate (%) | Remission Rate Among Resectable Tumors Only (%) | |
|---|---|---|---|---|---|---|---|
| GH n (μg/L) | GH r (μg/L) | ||||||
| Long et al, 1996 | <2 | <5 | 212 | 16 | 12/1 a (75/6) | 5/16 (31) | NR |
| Freda et al, 1998 | <2 | <2 | 115 | 12 | 2/10 (17/83) | 4/12 (33) | NR |
| Abe and Lüdecke, 1998 | <2 | <4.5 | 270 | 28 | 26/2 (93/7) | 16/28 (57) | 16/18 (89) |
| Shimon et al, 2001 | <2 | <2 | 103 | 12 | 12/0 (100/0) | 1/12 (8) | NR |
| Kurosaki et al, 2003 | <1 | <2.5 | NR | 22 | 18/4 (82/18) | 13/22 (59) | 13/16 (81) |
| Nomikos et al, 2005 | <1 | <2.5 | 688 | 140 | 98/42 (70/30) | 38/140 (27) | 38/97 (39) |
| Espinosa de los Monteros, 2009 | <1 | – | NR | 53 | 53/0 (100/0) | 5/53 (9) | NR |
| Yamada et al, 2010 | <1 | NR | 482 | 53 | NR | 31/53 (58) | NR |
| Alahmadi et al, 2012 | <1 | <2.5 | 350 | 9 | NR | 4/9 (44) | 4/5 (80) |
| All studies combined | 345 | 221/59 (79/21) | 117/345 (34) | 71/136 (52) | |||
| Combined studies that used Cortina criteria | 277 | 169/46 (79/21) | 91/267 (34) | 55/118 (47) | |||
a Indication for surgery was visual impairment for 4 tumors, not specified as persistent or recurrent.
One of the major limitations in appraising the value of repeat surgery is the lack of clear inclusion criteria in the studies. When the investigators excluded tumors deemed unresectable on the basis of MRI appearance, the mean remission rate increased in individual studies by 12% to 36%, with an overall increase of 13% among pooled studies using the Cortina criteria. For example, in a recent study by Alahmadi and colleagues, when only noninvasive tumors were included in the calculations, 80% of persistent tumors (4 of 5 patients) were successfully cured. By contrast, in a much larger series of 140 reoperated patients by Nomikos and colleagues, the remission rate only increased from 27% to 39% when invasive tumors with very high GH levels before first surgery were excluded.
In pooled data of all resectable tumors using the Cortina criteria, a remission rate of 47% is seen (55 out of 118 reoperations). While this efficacy rate is not significantly inferior to medical therapy (50%–60%), one must be cautious about directly comparing repeat surgery with medical therapy, given the much lower number of reoperated compared with medically treated patients described in the literature, the lack of consistently defined inclusion criteria, and varying durations of follow-up among these studies. Selection bias may actually overestimate the true remission rate if surgeons only choose to reoperate on those cases they believe have a high likelihood of being cured.
As is the case with primary surgery, the following were found to be predictors of unsuccessful repeat surgery:
- •
Extradural or large suprasellar component
- •
Cavernous sinus invasion or carotid artery encasement
- •
Tumor segmentation
- •
GH level greater than 40 μg/L before first surgery
- •
Younger age (<40 years)
Among the combined patients in these series, 79% were persistent tumors while 21% were recurrences. It can therefore be assumed that most invasive tumors at repeat surgery had invasive features before the initial surgery. With the increasing specialization of pituitary surgery, failed initial surgery can more often than not be attributed to larger tumor size and invasiveness rather than lack of surgical expertise; however, if a patient has a residual tumor that appears completely resectable and lacks the aforementioned negative prognostic features (especially if the first surgery was performed by an inexperienced neurosurgeon), it is reasonable to consider repeat surgery by a more experienced pituitary surgeon. The surgeon’s experience certainly should weigh heavily in the decision to consider repeat surgery, because several studies have demonstrated higher remission and lower complication rates when surgery is performed by a single experienced surgeon.
Role of Debulking Surgery
Despite a low prospect of cure, repeated surgery can be used for the purposes of tumor debulking to increase the effectiveness of adjuvant medical therapy. In a study of 86 patients poorly responsive to medical treatment with SSAs, partial primary surgical removal improved success rate from 12.8% to 55.5%. Another study of 24 patients taking SSAs found that primary surgery increased the proportion of patients having normal GH and IGF-I from 29% to 54% and 46% to 78%, respectively. Regarding the debulking benefit of secondary surgery, in a recent study of 53 patients whose preoperative GH was greater than 10 μg/L, partial tumor resection resulted in GH reduction below 10, 5, and 2.5 μg/L in 50%, 35%, and 21% of patients, respectively. With respect to IGF-I, 17% of patients had a 30% reduction from preoperative levels while 9% achieved normalization.
Risks of Repeat Surgery
Studies have reported varying incidences of new anterior pituitary hormone deficiencies after repeat transsphenoidal surgery. Yamada and colleagues showed that among 31 reoperated patients almost all hormone deficiencies were acquired after the first surgery, with an incidence of new hormone deficiencies of only 1.9% after the second surgery. Recovery of pituitary function was seen in over one-third of patients after second surgery in another study. By contrast, in their study of 53 reoperated patients, Espinosa de los Monteros and colleagues showed nearly the same incidence of individual anterior pituitary hormone deficiencies after primary and secondary surgery. Because the mortality from untreated acromegaly exceeds that of hypopituitarism, and because hormone deficiencies can easily be replaced, the fear of worsening pituitary function should not bear heavily on the decision to consider repeat surgery.
Regarding operative morbidity, in the large study by Nomikos and colleagues of 140 reoperated patients, the complication rates were comparable between primary and secondary surgery. However, the major complication rates from other surgical series ( Table 3 ) were higher than expected based on data from first-time surgeries, likely because of the smaller sample size in these studies. For example, meningitis, cerebrospinal fluid (CSF) leak, vascular injury, and ophthalmopathy are reported to occur in 0.7%, 2.2%, 0.6%, and 0.5% of major endoscopic series, respectively. By comparison, in reoperated cases the incidence of meningitis was 1.8% to 6%, CSF leak/fistula 2% to 9%, vascular injury 0.1% to 6%, and ophthalmopathy 6%. There was no reoperative mortality in these series.
| Authors, Ref. Year | Operative Mortality Rate, % | Overall Complication Rate, % | Major Complications (Rate, %) |
|---|---|---|---|
| Long et al, 1996 | 0 | 19 | SAH, intrasellar hemorrhage (6) New bitemporal hemianopsia (resolved) (6) Bacterial meningitis (6) CN III, IV, VI palsies (6) |
| Abe and Lüdecke, 1998 | 0 | 0 | |
| Kurosaki et al, 2002 | 0 | 0 | |
| Nomikos et al, 2005 | NR | Similar to primary surgery | Overall complications (primary and secondary surgery): Meningitis (1.8) CSF leak (0.8) Carotid artery injury (0.1) |
| Espinosa de los Monteros et al, 2009 | 0 | 21 | Arachnoid tear (8) CSF fistula (9) Meningitis (2) CSF fistula + meningitis (2) |
| Yamada et al, 2010 | 0 | 13 | CSF leak (3) CN VI palsy (3) Severe nasal bleeding (3) Pituitary abscess (3) |
Related posts:
Imaging the Pituitary and Parasellar Region
Management of Incidentally Found Nonfunctional Pituitary Tumors
Clinical Management of Pituitary Carcinomas
Neurosurgical Treatment of Cushing Disease
Visual Outcomes After Treatment of Pituitary Adenomas
Medical Management of Persistent and Recurrent Cushing Disease
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
