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Original Studies |
Departments of Endocrinology and Metabolism and Neurosurgery, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
Address all correspondence and requests for reprints to: Dr. Ferdinand Roelfsema, Department of Endocrinology, B4-P 15, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: roelfsema{at}rullf2.medfac.leidenuniv.nl
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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After unsuccessful surgery, adjuvant pituitary irradiation, and/or medical GH-suppressive treatment with depot preparations of long-acting somatostatin analogs additionally achieves clinical control in most patients. Secondary transsphenoidal surgery has a low success rate (13). Longer-term follow-up studies of transsphenoidal surgery clearly show that recurrences are seen in about 2–5% of patients within 5 yr (4, 5, 8) and provide a fairly good image of 5-yr results by now. Summarizing only studies using the generally accepted strict criteria for cure of a GH concentration below 2.5 µg/L, a suppressed GH concentration during glucose-suppressed GH [oral glucose tolerance test (GTT)] below 1 µg/L, and/or a normal IGF-I concentration, long-term surgical remission rates range from 42–62% (4, 6, 8, 14, 15), and multimodality remission rates vary between 52% and 83% (4, 8, 14, 16). The studies mentioned above included patients with even up to 20 yr of follow-up, but no study has been reported in which all patients were followed more than 10 yr postoperatively. We retrospectively analyzed data of all acromegalic patients who were operated before 1988 and were followed for at least 10 yr to investigate whether the effectiveness of surgery is maintained in the long-term in initially cured patients and whether multimodality therapy is able to achieve and maintain normalization in the noncured or in those with recurrence of disease.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Seventy-five patients underwent primary transsphenoidal microsurgery for acromegaly between 1977 and 1988. Diagnosis of acromegaly was based on clinical symptoms, an elevated GH day-profile, and insufficient GH suppression during the GTT. Sixteen patients with less than 10 yr of follow-up data were excluded from the study: nine patients died, four were lost to follow-up, and three patients had more than 10 yr of follow-up but failed to attend yearly follow-up visits. At the final follow-up visit (mean, 7.2 ± 1 yr after surgery), 88% of the excluded patients had a normal mean serum GH and 11 patients (70%) had normalized GH suppression and were considered in remission, 4 after radiotherapy and 7 without. The remaining 59 patients were studied: 34 males and 25 females with at least 10 yr of follow-up results. The mean age at surgery was 44.2 ± 1.4 yr (range, 21–67).
Treatment
All patients underwent transsphenoidal microsurgery performed by a single neurosurgeon (H.v.D.) as first line of therapy. Adjuvant radiotherapy (40 Gy) was given for elevated GH concentration, and, before 1985, it was also administered prophylactically to nine patients. Medical therapy, in the form of bromocriptine or octreotide was given instead of radiotherapy (on the patients’ or doctors’ preferences) or in combination with radiotherapy awaiting the effects of radiotherapy. Choice of adjuvant therapy for recurrence was made individually.
Hormonal evaluation
The preoperative, postoperative, and yearly assessments during a short hospital admission consisted of a GH day-profile (0800, 1130, 1600, and 2300 h), a 75-g oral GTT (serum GH and glucose measured at 0, 30, 60, 90, and 120 min), a 200-µg iv TRH test, and a serum IGF-I concentration from 1986 onward (17). Other pituitary hormone functions were evaluated by stimulation tests and measurements of serum levels of T4, cortisol or testosterone, and estradiol levels. In recent years, patients were evaluated in the outpatients’ clinic and a GTT, a random/fasting serum GH concentration, and IGF-I determination were measured yearly, followed by more extensive testing when a possible recurrence of disease activity or pituitary failure was suspected.
Tumor classification
Tumor classification was determined at surgical exploration by the neurosurgeon according to Hardy et al. (18). For this study, the classification was simplified to microadenoma (pI0), noninvasive macroadenoma (pII 0, A, B, C), and invasive macroadenomas (with suprasellar or parasellar invasive growth; i.e. pII D,E, pIII0-E, and pIV0-E).
Assays and normal values
GH was measured by RIA up to 1993 and thereafter by immunofluorometric assay (IFMA). The RIA assay (Biolab/Serono, Coinsins Switzerland) was calibrated against WHO-IRP 66/21, with an interassay coefficient below 5% and a detection limit of 0.5 mU/L. The IFMA assay (Wallac,Turku Finland), specific for the 22-kDA GH protein, was calibrated against WHO-IRP 80–505, had an intra-assay coefficient of 1.6–8.4% between 0.25 and 40 mU/L, a detection limit of 0.03 mU/L, and used human biosynthetic GH (Pharmacia-Upjohn, Uppsala, Sweden) as a standard. GH concentrations originally expressed in mU/L, were converted into µg/L using the division factor 2 for the samples analyzed by RIA and a factor 2.6 for the samples analyzed by IFMA. Normal mean values for GH day-profile, fasting, or random GH measurements, as determined in healthy controls, were less than 5 mU/L for both assays, equal to less than 2.5 µg/L (RIA, before 1993) and 1.9 µg/L (IFMA, from 1993 onward) (6, 19, 20, 21). When a GH day-profile was not available, we used the mean of the basal values from the different dynamic tests usually obtained within a week. In recent years, we used a single GH measurement (random or fasting) for the GH concentration in most cases. Suppressed normal values during the GTT were less than 1.25 µg/L (RIA, before 1993) and less than 0.38 µg/L (IFMA, from 1993 onward (20, 21). A doubling of serum GH during TRH test was considered paradoxical.
The IGF-I concentration determination was performed by RIA (INCSTAR Corp., Stillwater, MN), with an interassay variation of less than 11% and a detection limit of 1.5 nmol/L. Normal values for IGF-I were calculated using in-house data obtained from 137 healthy controls in the same age range as our patients expressed as SD score, as used before (20, 21, 22, 23, 24, 25). A SD score of less than +2 SD was considered normal in this study. Other hormones were measured by commercially available RIA or enzyme-linked immunosorbent assay kits.
Statistics
Data analysis was performed using SSPS statistical package (8.0
for Windows; SPSS, Inc., Chicago, IL), JMP statistics
(SAS Institute, Inc., Cary, NC), and Sigma
Plot for Windows 4.0 (SPSS Inc., Chicago, IL). We
used Student’s t tests for paired and unpaired data,
2 tests, ANOVA, and logistic regression
analysis. A P value less than 0.05 was considered
significant. Descriptive data were expressed in mean ±
SEM, unless otherwise stated.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The mean preoperative GH concentration was 59 ± 8.7
µg/L (3–300 µg/L). The mean GH of a day-profile (60 ±
9.6 µg/L), and the mean of the basal value of tests (49 ±
8.6 µg/L) in 53 patients with both measured preoperatively were
highly correlated (r = 0.894, P < 0.001) (Fig. 1A
). Also, a single fasting GH
concentration and mean GH concentration (day-profile) correlated
significantly (r = 0.841, P < 0.001) (Fig. 1C).
The mean minimal GH concentration during the GTT was 35 ± 7.6
µg/L (range, 1–325).
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Postoperatively, the mean serum GH concentration (day-profile)
decreased to 5.6 ± 1.4 µg/L (range, 0.25–62) and 36
patients (61%) achieved a normal mean GH concentration. Correlation
between mean GH (day-profile) and mean GH (basal of tests) was high
(r = 0.972, P < 0.001) (Fig. 1B
). The correlation
of a single fasting sample with the postoperative mean GH day-profile
is plotted in Fig. 1D. When a mean GH of a day-profile below 2.5 µg/L
was used to exclude active disease, a random GH sample (both
preoperatively and postoperatively) had a sensitivity of 79% and a
specificity of 95%. Positive predictive value of a random serum GH
concentration was 88%, and the negative predictive value was 91%.
A postoperative GTT was performed in 58 patients (1 patient had overt
diabetes mellitus). The mean suppressed GH concentration during the GTT
was 2.6 ± 0.6 µg/L (range, 0.25–21.0), and normal GH
suppression was achieved in 39 patients (67%). Normalization of both
mean serum GH and glucose-suppressed GH concentrations occurred in 35
patients (60%), and 19 patients (33%) had both elevated serum GH and
suppressed GH concentrations. The patient with diabetes mellitus had
normal mean serum GH concentrations and was considered in remission.
Four patients had normalized suppression of GH concentration during GTT
early postoperative, but their mean serum GH concentration remained
(slightly) elevated, being 3.1, 3.2, 3.7, and 5.8 µg/L, respectively,
and they were considered not to be in remission. Remission rates
according to tumor class are shown in Table 1. The incidence of (partial)
hypopituitarism following transsphenoidal surgery was 5%.
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Patients were divided into four groups based on the early
postoperative evaluation and consequent treatment decisions, which are
detailed in the flow diagram (Fig. 2).
The 36 patients in remission, according to both normal mean GH and
suppressed GH, were divided between groups A and B: 27 patients were
not adjuvantly treated (group A), and 9 patients received
prophylactical radiotherapy (group B) for persistent paradoxical
reaction to TRH (n = 7) and/or invasive tumor growth or suspected
incomplete tumor removal (n = 4). Patients with persistent disease
were divided between groups C and D: 18 patients underwent pituitary
irradiation for persistent disease postoperatively (group C), and 5
other patients not in remission early postoperatively were followed
without further treatment (group D). Group characteristics are
summarized in Table 2.
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Of the 27 patients early postoperatively in remission and not
adjuvantly treated, 5 patients (18.5%) were treated for recurrent
acromegaly in the course of follow-up. Two patients developed
recurrence within 6 months and after 3 yr, respectively, and received
radiotherapy. Two other patients developed recurrence with mild
elevations of GH concentration and insufficient suppression of GH after
glucose load after 3 yr and 4 yr, respectively, without clinical
activity, and were recently started on a long-acting formulation of
octreotide (Sandostatine LAR) (10 and 12 yr postoperatively). Another
patient underwent a second transsphenoidal operation 17 yr after
primary surgery for recurrent disease, becoming apparent 10 yr
postoperatively, and was treated with octreotide after unsuccessful
secondary surgery. Figure 3 details the
development of the five recurrences regarding serum mean GH
concentration (Fig. 3A) and GH suppression during the GTT (Fig. 3B).
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Ten years postoperatively, 2 patients were treated for recurrence, and of the other 25 patients, 21 (84%) had a normal serum GH, 17 of 24 (71%) had normal glucose- suppressed GH, and 20 of 24 patients (83%) had normal IGF-I concentration.
At the end of this study, a mean 16.0 ± 0.8 yr after surgery, 5 patients are treated for recurrence, and of the other patients, 21 of 22 have a normal serum GH, 19 of 21 have normal GH suppression (GTT), and 20 of 22 have normal IGF-I SD scores.
Remission at final follow-up in the 27 patients initially in remission (group A) was not significantly related to sex, tumor class, year of operation, or age of the patient. There was a significant relationship between the preoperative mean GH concentration (P = 0.04) and remission according to the most recent random GH concentration.
Follow-up results of multimodality therapy
Remission rates of multimodality therapy, applied as specified in
the flow diagram (Fig. 2), were 96% (serum GH, <2.5 µg/L) and 94%
(normal serum IGF-I). Figure 4 (A–D)
shows the follow-up data of the mean serum GH concentration of all
patients and patients of groups A, B, and C. All nine prophylactically
irradiated patients remained in remission. Two patients with early
postoperative persistent disease who were not treated further (group D)
showed spontaneous normalization of GH concentrations and GH dynamics
without additional treatment at the 6-month evaluation and remained in
remission according to all parameters in the long term. The remission
rates at the last visit of two criteria, a normal serum IGF-I and a
normal GH suppression, were compared. Both IGF-I and GH suppression
were normal in 43 of 51 patients with available data (84%). Discordant
results were present in two patients (normal GH suppression and
abnormal IGF-I) and six patients (insufficient GH-suppression and
normal IGF-I).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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There is still no consensus as to which criterion is best to use to define remission, some using suppressed GH concentration during the GTT (11, 15), others using mean serum GH concentration of day-profiles (5, 7, 28), and many using random or fasting GH samples or serum IGF-I concentrations (4, 8, 16, 29). The mean serum GH concentration indicating disease control has currently decreased in various studies from less than 10 µg/L to less than 2.5 µg/L.
In this study, mean GH concentrations and random GH samples correlated well, both in untreated and in treated acromegaly. Because both positive and negative predictive values of a random serum GH concentration were high (88% and 91%, respectively), we measured only random/fasting GH samples in recent years instead of the mean GH concentration of a day-profile as used in the first years postoperatively. Glucose-suppressed GH concentrations results are described separately, and they are concordant with random GH concentration in most cases, although there were some discrepancies. For instance, two patients had normal GH suppression after the GTT but elevated GH concentration, and two patients had normal GH levels but insufficient GH suppression after the GTT at the 10-yr follow-up visit.
Although in many studies biochemical cut-off levels for normalization of disease activity are arbitrarily set, all our normal values of GH concentration, glucose-suppressed GH concentration, and IGF-I concentration for all used assays are derived from normal controls measured in our laboratory. IGF-I and suppressed GH were both normal in most patients, although discordant results were present in 16% of patients at the end of follow-up. A similar discrepancy was also present in our recent data on radiotherapy results for acromegaly (25) in which both decline of IGF-I and GH was observed over time after irradiation, although there was a small percentage of discrepant data, which was also reported by others (30, 31).
Some studies have confirmed the logical idea that surgical results improve with time, and with experience of the neurosurgeon and improvement of neurosurgical techniques (4, 7, 11). Although the generally accepted criteria for remission were less strict 1 or 2 decades ago, the criteria of a mean serum GH concentration of less than 2.5 µg/L (as measured by RIA) was already used in all our patients to define postoperative remission, and adjuvant treatment decisions also were based on this criterion, as has been described before (6). Whether the early postoperative evaluation at 7–10 days after surgery provides an adequate view of surgical results can be challenged by data of the two patients of group D, who showed persistent GH hypersecretion at the first evaluation and met both all used criteria for remission at the 6-month evaluation and required no further treatment. This interesting observation is probably due to late tumor necrosis induced by surgery, which was also reported by others (14, 32).
Nine patients underwent prophylactic radiotherapy for invasive tumor growth and/or paradoxical reaction to TRH. None of these patients, formerly believed to be at high-risk for development of recurrence, developed biochemical recurrent disease at follow-up. Prophylactic radiotherapy is no longer used in our institution, because the value of the TRH test in predicting recurrences is questioned and also because of the high incidence of hypopituitarism following irradiation.
Follow-up of the 27 patients, not adjuvantly treated patients in
remission, revealed five recurrences (19%), and although four recurred
within the first 5 postoperative years, 1 patient showed the first
signs of recurrence of acromegaly as evidenced by slightly elevated GH
concentration and insufficient suppression more than 10 yr
postoperatively. The incidence of recurrences might have been higher
had no prophylactic radiotherapy been applied. This question can,
however, only be addressed when follow-up results of more recently
surgically treated patients with invasive tumor growth and/or
paradoxical reaction to TRH, who did not receive prophylactical
radiotherapy, become available. At the most recent assessments ranging
from 10–22 yr, some patients have repeatedly or incidentally abnormal
serum GH or IGF-I concentrations or insufficiently suppressed serum GH
concentrations. Whether the elevated concentrations of one or more
parameters indicate variation within the normal range of control of
treated acromegaly or are the first signs of biochemical recurrence is
not known and requires even longer follow-up to become clear. In all
recurrences, the minor elevation of GH concentration and inadequate GH
suppression during the GTT, as shown in Fig. 3, preceded the
development of clinical disease activity. In the three well-documented
recurrences in this report, we observed mild biochemical disturbances
several years before clinical symptoms developed. From this clinical
observation, we suggest that the process of recurrence can take up to
10 yr and abnormal and normal biochemical results may be present for
many years, making the diagnosis of recurrence difficult. Repeated
follow-up assessments are, therefore, required to establish with
certainty the diagnosis of recurrence.
The incidence of recurrence of acromegaly of 19% in patients with at least 10 yr of follow-up and a mean follow-up of 16 yr we report here is higher than the 4 of 38 recurrences within 5 yr of follow-up described by Truong et al. (33) in an abstract on separate 10 yr outcome of surgery. All other long-term follow-up studies of transsphenoidal surgery in acromegaly also included patients with a shorter duration of follow-up, making the evaluation of long-term results difficult. Swearingen et al. (4) reported a recurrence rate of 6% at 10 yr of follow-up and 10% at 15 yr of follow-up and a mean follow-up duration of 7.8 yr (1–19 yr). Freda et al. (8) found a recurrence rate of 5.4% after a mean follow-up of 5.4 yr (1 week to 15.7 yr).
In accordance with previous reports, both early postoperative outcome for all patients and latest outcome for patients of group A (remission, not further treated) were significantly related to preoperative mean GH concentration using logistic regression analysis (5, 15). Consistent with a former publication of transsphenoidal surgery in our hospital (6), we could not demonstrate a significant relationship between outcome and tumor class, which was reported by many others (5, 8, 15).
In summary, 24 of 59 patients (41%) are still in remission following only transsphenoidal surgery, without need for adjuvant therapy after a mean follow-up period of 15.9 yr (range, 10–22). Multimodality therapy, in the form of primary surgery, followed by radiotherapy and/or medical therapy, achieved normalization of serum GH concentration in 57 of 59 patients (97%) and normalization of serum IGF-I concentration in 56 of 59 patients (95%) at long-term follow-up.
Received March 3, 2000.
Accepted August 30, 2000.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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