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Value of early postoperative random growth hormone levels and nadir growth hormone levels after oral glucose tolerance testing in acromegaly
Growth Hormone & IGF Research xxx (xxxx) xxx–xxx
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Value of early postoperative random growth hormone levels and nadir growth hormone levels after oral glucose tolerance testing in acromegaly ⁎
Roman Rotermunda, , Till Burkhardta, Zaina Rohanib, Roman Jungc, Jens Aberleb,1, Jörg Flitscha,1 a
Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany Department of Endocrinology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany c Department of laboratory medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany b
A R T I C LE I N FO
A B S T R A C T
Keywords: Acromegaly Early postoperative oral glucose tolerance testing Growth hormone IGF1
Objective: There is no ideal marker to identify residual tumor tissue after surgery in patients with acromegaly. The purpose was to elucidate if early postoperative hormone testing gives reliable information regarding complete resection of a GH-producing pituitary adenoma. Design: Fourty-eight patients undergoing surgery for acromegaly from 04/2013-05/2014 were prospectively examined for random GH, IGF1, and GH levels after oral glucose tolerance testing (OGTT) in the early postoperative phase and on follow-up. Criterion for inclusion was a minimum follow-up of one year for each patient with respect to remission. Results: Thirty-three patients showed GH suppression below 1 μg/l after OGTT in the early postoperative phase. Follow-up GH, IGF1 and OGTT tests confirmed the initial findings in 30 patients. The three remaining patients showed biochemical signs of persisting acromegaly. In the remaining 15 patients early postoperative GH suppression was above 1 μg/l. Of those, six patients went into remission during follow-up, nine patients without postoperative GH suppression < 1 μg/l remained acromegalic. Conclusions: GH suppression to < 1 μg/l as well as random GH levels below 1 μg/l in the early postoperative phase seem to be of good positive predictive value for long-term remission. However, several patients without suppression of GH to < 1 μg/l in the early postoperative OGTT went into delayed remission. These results have to be taken into account prior to initiation of further therapy.
1. Introduction Transsphenoidal surgery is the treatment of choice for acromegaly [1–3]. Completeness of tumor removal is crucial for avoiding or minimizing the use of adjuvant therapies including pharmacotherapy and radiotherapy. Persistent disease in the long run is associated with increased morbidity and the risk of premature mortality [3,4]. Therefore the aim was to evaluate if early postoperative endocrinological markers predict the extent of resection and may justify early reoperation as it is successfully performed in Cushing's disease [5–7]. The surgical concept of early reoperation is based on nearly no additional access morbidity since no scarring has happened. 2. Material and methods Fifty-four consecutive patients undergoing surgery for acromegaly ⁎
1
from April 2013 until June 2014 were included in the prospective analysis. Preoperative GH and IGF1 levels were collected. Preoperative tumor size was measured on a standard MRI (T1 with and without contrast enhancement, sagittal, coronal and transversal planes) and a possible invasive growth was estimated. The patients were classified into a primary surgery group and a group of patients who had previously undergone surgery. Somatostatin-analog pretreatment was noted. Intraoperatively the surgeon subjectively classified the operation as complete resection, questionable complete resection or partial resection. Postoperatively, GH and IGF-1 (Immulite® 2000 (GH) Siemens/ Liaison® (IGF1) DiaSorin) levels were measured on the morning of postoperative day one (07.00 a.m.). An early postoperative oral glucose tolerance test (epOGTT) with GH-sampling using 75 g glucose was performed within the postoperative days 2–4. The diagnosis of acromegaly was confirmed by standard neuropathological work-up whenever possible. Subsequently, the patients were followed for a minimum
Corresponding author. E-mail addresses: [email protected] (R. Rotermund), [email protected] (R. Jung), [email protected] (J. Aberle), fl[email protected] (J. Flitsch). Both authors contributed equally.
https://doi.org/10.1016/j.ghir.2018.03.002 Received 7 January 2018; Received in revised form 3 March 2018; Accepted 8 March 2018 1096-6374/ © 2018 Elsevier Ltd. All rights reserved.
Please cite this article as: Rotermund, R., Growth Hormone & IGF Research (2018), https://doi.org/10.1016/j.ghir.2018.03.002
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(median: 16 months, range: 12–22 months) were evaluated (Table 1). There were no missing data. The patients' age ranged from 22 years to 80 years with a median age of 46 years (male: 43 years, female: 49 years). 42 patients had the primary diagnosis of acromegaly, six patients were previously surgically treated for acromegaly. 31 adenomas were macroadenomas, the remaining 17 were microadenomas. Fourteen tumors were classified as invasive according to MRI studies. Five patients received either cabergoline, octreotide/lanreotide or pegvisomant pretreatment. Four other patients had undergone both previous surgery and SSTR- analog pretreatment in the past. Any pretreatment had been discontinued more than eight weeks prior to the current admission. Thirty of the 48 patients (63%) were classified as complete resection by the surgeon, in fourteen of 48 patients (29%) the surgeon was unsure regarding completeness of resection, and four patients (8%) underwent intended debulking/partial resection of large invasive adenomas (Table 2). None of the patients had pituitary insufficiencies before or after surgery. Immunohistochemical markers assessed can be seen in Table 3. The intra-assay variability for GH was 4.97% and the intra-assay variability for IGF1 was 6.47%, both calculated in a quality control over the six months previous. Of the 48 patients enrolled, 33 showed GH suppression below 1 μg/l after OGTT in the early postoperative phase. Follow-up by GH (Fig. 2), IGF1 (Fig. 3), OGTT and MRI confirmed the initial findings in thirty of 33 patients (91%). The three remaining of 33 patients had persisting biochemical signs of acromegaly (9%). In fifteen patients, GH suppression was above 1 μg/l in the early stage. Six of those 15 patients went into remission during follow-up (40%). The remaining nine of 15 patients without postoperative GH suppression showed persistent disease (60%). Based on the thesis that detection of residual tumor mass by epOGTT could be useful mainly in cases with surgically questionable complete resection, the collective was divided into groups according to surgeons' impression of resection grade (Table 4). However, these analyses also failed to show a significantly correct prediction. Correct
of one year. A postoperative MRI after 3 to 6 months was performed and visible residual tumor mass was documented. The patients were scheduled for routine follow-up every 6 months. Further follow-up data on GH and IGF1 were performed by the referring endocrinologists. In case of pathological IGF1 results, a follow-up OGTT was performed. For this study, the last follow-up is reported. Remission was defined by means of all collected values according to the current criteria (normalized IGF-1 plus either a random GH < 1 μg/l or a nadir GH < 0.4 μg/l after OGTT). Graphs were drawn using the Graph pad prism (GraphPad Software, Inc./USA). 3. Theory In 2000, the Cortina Consensus Conference established general criteria for the diagnosis and biochemical control of acromegaly, which have been revised in recent years and adapted to emerging clinical evidence as well as evolving assay techniques. According to those recent consensus statements, postoperative cure in the long-term is defined by age-normalized Insulin-like growth factor 1 (IGF1) levels, a random growth hormone (GH) < 1 μg/l, and nadir GH after oral glucose tolerance testing (OGTT) < 0.4 μg/l [2,3,8–10]. We prospectively investigated whether the early postoperative random GH or the GH after OGTT gives reliable information regarding the resection grade of a tumor and performed a follow-up of at least one year. 4. Results The fifty-four consecutive patients included 27 male and 27 female patients (Fig. 1). Due to the consecutive patient cohort this gender distribution happened by chance. Six patients were lost to follow-up (two of those patients were lost for complete follow-up due to missing epOGTT and additionally four patients did not provide their follow-up data). The remaining 48 patients with a minimum of one year follow-up
Fig. 1. Long-term remission in relation to epOGTT.
2
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Table 1 Patient collective (48 patients). Relapse
Pretreatment
Tumor size (centimeter)
Radiologically invasive
Gh (μg/l)
IGF1 (μg/l)
Age- and sexrelated Ref. for IGF1 (μg/ l)
Followup (months)
Macroadenomas 1 Male 25 7 Female 40 9 Male 50 10 Male 49 11 Male 24 12 Male 41 13 Female 48 14 Female 52 15 Male 31 17 Male 29 20 Male 36 23 Male 39 24 Female 61 25 Female 40 26 Female 47 27 Male 70 29 Male 58 30 Female 47 31 Female 37 33 Female 50 34 Female 60 35 Female 25 36 Male 32 37 Male 53 38 Male 19 39 Female 50 40 Male 47 42 Male 39 Male 51 44 47 Female 55 48 Female 69
No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No
No No No No No No No No Octreotide No No No No No No Lanreotide No No no No No No No No Cabergoline (suspected prolactinoma) No No Lanreotide No No No
1.52 × 0.76 × 0.98 1.72 × 1.8 × 1.76 1.2 × 1.53 × 1.21 0.9 × 1.35 × 1.24 3.13 × 2.34 × 2.58 1.33 × 1.64 × 1.77 1.97 × 1.78 × 2.34 2.67 × 2.76 × 2.81 2.2 × 2.1 × 2.7 1.03 × 1.03 × 1.31 1.4 × 1.39 × 1.28 1.19 × 0.88 × 1.16 0.76 × 1.35 0.94 2.49 × 3.08 × 1.71 2.1 × 1.4 × 1.1 1.03 × 1.08 × 1.41 1.46 × 1.32 × 1.61 1.08 × 1.8 × 1.17 0.72 × 1.35 × 1.07 0.9 × 1.2 × 1.2 0.86 × 1.59 × 1.17 2.19 × 1.56 × 1.45 4.71 × 3.54 × 2.75 1.56 × 1.61 × 1.76 1.02 × 1.09 × 0.85 2.85 × 2.73 × 1.76 1.19 × 1.5 × 1.1 1.31 × 1.5 × 1.35 1.22 × 0.94 × 1.44 2.72 × 3.66 × 3.53 0.74 × 1.23 × 1.17
N = no Q = questionably N N Y = yes Q N Y Y N Y N N Y Q Y N Y N N Y Y Q N N Y N N N Y N
3.17 93.46 24.7 2.92 18.8 17.2 40.8 22.5 19.2 9.19 6.38 10.04 11.54 70.38 19.85 10.15 20.42 1.35 7.85 32.1 8.42 20.42 15.8 3.39 4.19 10.11 7.69 41.9 10.4 3.1 6.73
943 998.3 741.6 505 783.6 864.4 1003.9 691.7 867.8 1074.1 835.5 819.8 653.3 829.9 868.1 625.1 1274.7 504.1 827.6 1008.5 672.2 856.3 964.9 845.1 516.9 770 1165.7 1090.7 945.1 432.6 379.3
89–402 101–337 44–199 101–210 112–336 101–210 101–337 49–232 101–210 112–336 101–210 101–210 49–232 101–337 101–337 44–199 44–199 101–337 101–337 49–232 49–232 137–328 101–210 44–199 220–495 49–232 101–210 101–210 44–199 49–232 49–232
17 18 18 17 18 14 16 19 22 19 17 19 14 15 12 17 17 14 12 12 17 15 14 14 13 13 17 12 12 14 15
Microadenomas 2 Male 52 3 Male 57 4 Male 47 5 Male 44 6 Female 22 8 Female 56 16 Female 37 18 Female 80 19 Female 50 21 Female 61 22 Female 58 28 Female 31 32 Male 44 41 Female 50 43 Male 34 45 Female 67 46 Female 51
No No No No Yes No Yes No No No No Yes Yes No Yes No Yes
No No No Cabergoline TSS (transsphenoidal surgery) No TSS + Octreotide + Pegvisomant No No No No TSS TSS + Octreotide No TSS + Lanreotide + Cabergoline + Pegvisomant No TSS + Cabergoline + Octreotide
1 × 0.9 × 0.9 0.78 × 0.7 × 0.78 0.94 × 0.79 × 0.86 1.04 × 0.94 × 0.68 0.41 × 0.98 × 0.54 0.63 × 0.78 × 0.86 0.35 × 0.46 × 0.6 1 × 0.93 × 0.89 0.8 × 0.8 × 0.81 0.58 × 0.58 × 1 0.78 × 0.67 × 0.56 0.45 × 0.6 × 0.4 0.35 × 0.39 × 0.42 0.67 × 1.03 × 0.77 0.41 × 0.76 × 0.47 0.7 × 0.8 × 0.9 0.76 × 1.02 × 1.12
Q N N N Q N Q Y Y Y N N N N Y N Q
7.92 4.42 10.61 2.01 6.27 7.19 4.96
967 278.1 856.8 396.6 215.4 403.4 676.4 995.6 456.1 724.5 834 488.6 390.5 690.5 519.8 439.2 456.7
56–271 44–199 101–210 101–210 137–328 49–232 101–337 49–232 49–232 49–232 49–232 101–337 101–210 49–232 101–210 49–232 49–232
20 20 15 19 17 22 14 16 21 17 16 12 17 17 12 16 14
Pat.
Gender
Age
prediction by the surgeon for the patients with a suspected “complete resection” was 93% in this series. Correct positive prediction of the epOGTT in all patients who showed a GH suppression below 1 μg/l was 91%. Lowering the threshold of suppression to < 0.4 μg/l, none of the included patients relapsed during follow-up. With a threshold of < 2 μg/l, correct positive prediction was 81%. All patients relapsed when the border for suppression was set at > 3.5 μg/l. For the primarily operated patients who showed a GH suppression below 1 μg/l, the test had a positive predictive value of 97% (< 0.4 μg/l - 100%, < 2 μg/l 87%, > 3.5 μg/l - 0%). All patients with an early postoperative spontaneous GH below 1 μg/l stayed in remission also on follow-up. In addition, all patients with an early postoperative spontaneous GH above 4 μg/l remained acromegalic. For those in between, see Table 5. Total remission rate was 75% (36/48) on follow-up
3.75 12.2 9.54 2.85 0.86 6.35 0.9 8.58 3.31
[microadenomas 76% (13/17) macroadenomas 74% (23/31)] in this series after 12 months. Biochemical remission of all primarily operated patients was achieved in 81% (34/42) [microadenomas 100% (11/11)/ macroadenomas 74% (23/31)]. Two of the six patients undergoing recurrent surgery (33%) showed remission on follow-up. Age and gender did not affect the remission rate. However, cavernous sinus invasion and a history of prior surgery as shown above were associated with lower rates of disease control. IGF1 was not clinically useful within the first postoperative day. On follow-up, among the twelve patients not in remission, two patients (17%) have been treated with cabergoline, nine of twelve patients without remission (75%) have received somatostatin-analog therapy, and one of those twelve patients (8%) has undergone radiotherapy to date.
3
2.46 1.79 2.07 1.51 0.81 2.93 1.68
0.92 0.85 0.43
2.48 1.77
1
1 1 3 2 2 1 2 1 1 2 3 2 1
1 1 1 1 1 3 1
1 1
1 2 1
23 24 25 26 27 29 30 31 33 34 35 36 37
38 39 40 42 44 47 48
Microadenomas 2 1 3 1 4 1
1 2
20
5 6
8 16
4
18 19 21
0.23 1.32 0.99
2 4.5
1.78 1.2 12.35 1.87 1.27 0.4 2.6 0.46 1.67 5 1.94 1.74 0.29
2.31
1.02 2.99 0.63 1.25
2 3 = partial resection 1 1
13 14 15 17
0.8 0.46 1.74
2 3.89
0.14 1.15
0.3 0.16 0.31
0.35 0.94 0.65 0.08 0.35 1.87 0.27
0.12 0.28 6.54 1.97 0.29 0.57 0.6 0.08 0.19 3.61 0.72 0.91 0.49
0.49
1.05 2.38 0.47 0.27
0.37 1.28 3.37
0.69 2.33 3.33
Early postoperative OGTT (μg/l)
0.08 1.1 1.9
Early postoperative GH (μg)
0.94 1.41 0.78
Surgeons estimation of resection grade
Macroadenomas 1 1 = total resection 7 1 9 2 = questionably total resection 10 1 11 1 12 2
Pat.
Table 2 Results (48 patients).
190 140.9 238
104.3 215
230.8 206
157 144 218
264 287.1 164.1 165.2 164 243.4 131.6
246.7 143.1 352 139.2 155 162.1 178.3 198 132 319.3 157 132 230
360
180.8 461 180 350.4
113.2 248.6 340.2
237.4 257 103.3
IGF1 at timepoint of follow up (μg/l)
18–193 100–300 < 210
49–232 79–276
20–224 103–326
55–203 63–279 94–163
93–404 49–232 101–210 64–236 63–279 49–232 29–251
96–227 18–244 62–205 100–300 64–188 20–224 101–337 101–337 49–232 55–152 137–328 115–307 56–201
63–279
101–337 87–238 112–300 101–210
20–224 64–236 101–210
89–402 153–251 100–300
Age- and sex- related Reference for IGF1 (μg/l)
0.3 0.22 0.88
2.05 0.32
0.09 4.67
0.1 2.01 0.09
0.45 1.48 0.07 0.28 0.2 2.34 0.33
0.3
0.09 0.28 3 2.54 1.84 0.09 0.47 2.17 0.1 1.91 0.7
04
0.09 1.57 0.35 0.33
0.09 1.9 0.79
0.82 1.27 0.27
GH at timepoint of follow up (μg/l)
1 1 1
1 0
1 1
1 1 1
1 1 1 1 1 0 1
1 1 0 0 1 1 1 1 1 0 0 1 1
1
0 0 1 1
1 0 1
1 1 1
Remission 1 = yes 0 = no
16 21 17
22 14
19 17
20 20 15
13 13 17 12 12 14 15
19 14 15 12 17 17 14 12 12 17 15 14 14
17
16 19 22 19
17 18 14
17 18 18
Follow-up (months)
(continued on next page)
Invasive tumor growth. On follow up OGTTs: 2.39 and 18.5 μg/l, radiotherapy
Second surgery due to recurrence shown in MRI
Initial IGF-1: 856.8 μg/l, constantly decreasing, OGTT on follow up: 0.1 μg/l
Lanreotide
Initial IGF-1: 770 μg/l, decreasing
Initial IGF-1: 845.1 μg/l, decreasing, OGTT on follow up < 0.1 μg/l
Lanreotide
Cabergoline
Initial IGF-1: 1074.1 μg/l, const. decreasing, OGTTs on follow up 0.17 and 0.11 μg/l Initial IGF-1: 835.5, decreasing, follow up OGTT 0.1 μg/l
Octreotide Initial IGF-1: 864.4, constantly decreasing, follow up OGTT: 0.65 μg/l Octreotide
Comment on special cases
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Surgeons estimation of resection grade
1 2
2 1 2 1 2
Pat.
22 28
32 41 43 45 46
Table 2 (continued)
0.4 1.28 3.38 1.68 3.96
1.32 4.65
Early postoperative GH (μg)
0.15 0.28 0.86 0.41 0.98
0.53 1.82
Early postoperative OGTT (μg/l)
197 166.5 223 128.4 371
153 477
IGF1 at timepoint of follow up (μg/l)
94–252 40–231 109–324 109–324 55–235
49–232 109–324
Age- and sex- related Reference for IGF1 (μg/l)
0.01 1.26 17.9 2.6 0.77
6.15 5.24
GH at timepoint of follow up (μg/l)
1 1 0 1 0
1 0
Remission 1 = yes 0 = no
17 17 12 16 14
16 12
Follow-up (months)
Invasive tumor growth
Invasive tumor growth, Pegvisomant
Suprasellar extension, incomplete resection
Comment on special cases
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Table 3 Neuropathology/immunohistochemistry. STH STH + PRL STH + PRL + LH STH + Chondrosarcoma WHO °II No adenoma for histopathology available
Fig. 2. Spontaneous GH levels.
5 29 13 2 1 3
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24 h postoperatively had the highest predictive power for surgical remission and that if the nadir GH level was above 4 μg/l remission was highly unlikely [16]. This finding is confirmed by our results, as no patient with an early postoperative spontaneous GH above 4 μg/l achieved remission on follow-up. In order to find a reliable marker for the tumor resection grade and since nadir GH-measurement is not a sufficient negative predictive marker, postoperative OGTT was examined in the present study. Freda et al. showed in 2001 that glucosesuppressed GH levels in healthy subjects are < 1 μg/l, perhaps even < 0.2 μg/l [17]. Therefore, the cutoff for suppression in remission was determined to be 1 μg/l. In 2002 Kristof et al. published a retrospective series of 73 consecutive patients undergoing OGTT 2 weeks after surgery. The results showed that early postoperative OGTT had several false positive results and was more reliable three months after surgery [18,19]. Kim et al. assessed that postoperative OGTT was even more reliable after six months [16]. The false positive results could be confirmed in our prospective series including patients that initially showed suppression below 1 μg/l in the epOGTT and showed signs of active acromegaly on follow-up. In addition, some patients who initially failed suppression, went into remission during follow-up. In patients with no preoperative medical or operative pretreatment the results are better (correct positive prediction of epOGTT < 1 μg/l was 96% instead of 91% in all patients), however not good enough to sufficiently predict residual tumor mass. Setting the upper limit of normal for suppression at < 0.4 μg/l, none of the included patients relapsed during follow-up in our series. In the literature, others recommended a threshold of suppression at 0.5 μg/l [16,20]. Not surprisingly, these low limits might be best to predict the patients' long-term prognosis and define further control intervals. On the other hand, several publications were able to show that a threshold of > 4 μg/l in the early postoperative OGTT confirmed residual tumor [21], which corresponds to our results where the threshold > 3.5 μg/l correlated with residual tumor. Carmichael et al. stated that OGTT should not be performed in patients receiving somatostatin-analogs due to possible false results [22]. Our patients on somatostatin-analog therapy showed a correct positive prediction of the epOGTT of 100% (N = 5), which is in line with the results of Otani et al. who found no statistically significant difference for the intraoperative GH-measurements in medically pretreated patients [15]. In this article, we do not discuss the well-known problems of assay reliability, which are topic of several publications [2,17,23–25]. Due to the short inclusion period and consistency of one GH assay in one laboratory, we feel that the impact of potential assay errors could not have been further minimized.
Fig. 3. IGF1 levels.
Table 4 Remission in dependence of early postoperative OGTT (epOGTT) taking into account the surgeon's subjective intraoperative grading of resection. epOGTT Complete resection (30) Questionable complete resection (14) Partial resection (4)
< 1 μg/l > 1 μg/l < 1 μg/l > 1 μg/l < 1 μg/l > 1 μg/l
(25) (5) (7) (7) (1) (3)
Remission
Persistence
25 (100%) 3 (60%) 5 (71%) 3 (43%) – –
– 2 2 4 1 3
(40%) (29%) (57%) (100%) (100%)
Table 5 Early postoperative spontaneous GH (epGH) as predictor for remission. epGH
Remission (number of patients)
Persistence (number of patients)
< 0,4 μg/l < 1 μg/l 1–2 μg/l 2–3 μg/l 3–4 μg/l > 4 μg/l
4 (100%) 14 (100%) 15 (83%) 4 (50%) 3 (75%) –
– – 3 4 1 4
(17%) (50%) (25%) (100%)
6. Conclusions Our results show that spontaneous GH as well as OGTT in the early postoperative phase have some benefits as well as limitations, as previously shown by others. In patients showing a spontaneous GH or a GH suppression during OGTT below 1 μg/l, the tests have a high positive predictive value for remission, confirming the experienced surgeons' impression of a “complete resection”. The threshold of GH suppression during OGTT below 0.4 μg/l may even be better. However, several patients without suppression of GH < 1 μg/l in the early postoperative OGTT went into remission in the long-term. So far, we lack a safe marker for surgical failure unless GH > 3.5 μg/l (or if there is evidence of a visible remnant on postoperative MRI, if performed) which justifies early reoperation in acromegaly. These results also must be taken into account prior to initiation of pharmacotherapy, radiotherapy or reoperation, requiring careful monitoring of patients for up to 12 months after initial surgery.
5. Discussion There have been many efforts to optimize the prediction of resection grade after transsphenoidal adenomectomy in patients with acromegaly over the past few decades [8–14]. The surgeon's main concern is finding a reliable tool to extract the patients with resectable tumor remnants for early reoperation as it is successfully performed for patients with Cushing's disease [5–7]. Lüdecke et al. had good results with intraoperative GH-measurements, which could in some cases identify residual tumor tissue during surgery [11–13]. This is an elaborate, timely and costly procedure, which has not been established as a general clinical standard. A few years later, Valdemarsson et al. published data showing that the mean of a direct postoperative GH-series within the first postoperative week may lead to more reliable results predicting surgical outcome than the intraoperative measurement [14]. Otani et al. in 2012 presented a large series of intraoperative GH-measurements, questioning its use for identifying residual disease [15]. At the same time Kim et al. showed that immediate postoperative GH levels
Declarations of interest None. 6
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Acknowledgements [9]
The authors are indebted to Dieter K. Lüdecke, MD for his pioneering work on pituitary tumor research and therapy at UKE. We also thank all referring colleagues for their trust and cooperation.
[10]
Funding
[11]
This research used a data base which was financially supported by a grant from Novartis pharma (RSIG-053).
[12] [13]
Ethical approval
[14]
All procedures performed involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.
[15]
[16]
Informed consent
[17] [18]
Informed consent was obtained from all individual participants included in the study.
[19]
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consensus on the medical treatment of acromegaly, Nat. Rev. Endocrinol. 10 (4) (2014) 243–248, http://dx.doi.org/10.1038/nrendo.2014.21. A. Giustina, M.D. Bronstein, F.F. Casanueva, et al., Current management practices for acromegaly: an international survey, Pituitary 14 (2) (2011) 125–133, http:// dx.doi.org/10.1007/s11102-010-0269-9. S. Melmed, F.F. Casanueva, A. Klibanski, et al., A consensus on the diagnosis and treatment of acromegaly complications, Pituitary 16 (3) (2013) 294–302, http://dx. doi.org/10.1007/s11102-012-0420-x. D.K. Ludecke, T. Abe, Transsphenoidal microsurgery for newly diagnosed acromegaly: a personal view after more than 1,000 operations, Neuroendocrinology 83 (3–4) (2006) 230–239, http://dx.doi.org/10.1159/000095533. M. Kurosaki, D.K. Luedecke, T. Abe, Effectiveness of secondary transnasal surgery in GH-secreting pituitary macroadenomas, Endocr. J. 50 (5) (2003) 635–642. D.K. Lüdecke, Recent developments in the treatment of acromegaly, Neurosurg. Rev. 8 (3–4) (1985) 167–173. S. Valdemarsson, S. Ljunggren, A. Cervin, et al., Evaluation of surgery for acromegaly: role of intraoperative growth hormone measurement? Scand. J. Clin. Lab. Invest. 61 (6) (2001) 459–470. R. Otani, N. Fukuhara, T. Ochi, K. Oyama, S. Yamada, Rapid growth hormone measurement during transsphenoidal surgery: analysis of 252 acromegalic patients, Neurol. Med. Chir. (Tokyo) 52 (8) (2012) 558–562. E.H. Kim, M.C. Oh, E.J. Lee, S.H. Kim, Predicting long-term remission by measuring immediate postoperative growth hormone levels and oral glucose tolerance test in acromegaly, Neurosurgery 70 (5) (2012) 1106–1113 discussion 1113 https://doi. org/10.1227/NEU.0b013e31823f5c16. P.U. Freda, R.E. Landman, R.E. Sundeen, K.D. Post, Gender and age in the biochemical assessment of cure of acromegaly, Pituitary 4 (3) (2001) 163–171. R.A. Kristof, G. Neuloh, L. Redel, D. Klingmüller, J. Schramm, Reliability of the oral glucose tolerance test in the early postoperative assessment of acromegaly remission, J. Neurosurg. 97 (6) (2002) 1282–1286, http://dx.doi.org/10.3171/jns.2002. 97.6.1282. R.A. Kristof, A. Grote, L. Redel, G. Neuloh, D. Klingmüller, J. Schramm, The common consensus criteria have high predictive values for long-term postoperative acromegaly remission, Acta Neurochir. 153 (1) (2011) 19–25, http://dx.doi.org/10. 1007/s00701-010-0790-7. R.A. Feelders, M. Bidlingmaier, C.J. Strasburger, et al., Postoperative evaluation of patients with acromegaly: clinical significance and timing of oral glucose tolerance testing and measurement of (free) insulin-like growth factor I, acid-labile subunit, and growth hormone-binding protein levels, J. Clin. Endocrinol. Metab. 90 (12) (2005) 6480–6489, http://dx.doi.org/10.1210/jc.2005-0901. J.A. Takahashi, A. Shimatsu, K. Nakao, N. Hashimoto, Early postoperative indicators of late outcome in acromegalic patients, Clin. Endocrinol. 60 (3) (2004) 366–374. J.D. Carmichael, V.S. Bonert, J.M. Mirocha, S. Melmed, The utility of oral glucose tolerance testing for diagnosis and assessment of treatment outcomes in 166 patients with acromegaly, J. Clin. Endocrinol. Metab. 94 (2) (2009) 523–527, http:// dx.doi.org/10.1210/jc.2008-1371. R.K. Junnila, C.J. Strasburger, M. Bidlingmaier, Pitfalls of insulin-like growth factor-i and growth hormone assays, Endocrinol. Metab. Clin. N. Am. 44 (1) (2015) 27–34, http://dx.doi.org/10.1016/j.ecl.2014.10.003. P.U. Freda, Pitfalls in the biochemical assessment of acromegaly, Pituitary 6 (3) (2003) 135–140. P.U. Freda, Monitoring of acromegaly: what should be performed when GH and IGF-1 levels are discrepant? Clin. Endocrinol. 71 (2) (2009) 166–170, http://dx.doi. org/10.1111/j.1365-2265.2009.03556.x.
Contents lists available at ScienceDirect
Growth Hormone & IGF Research journal homepage: www.elsevier.com/locate/ghir
Value of early postoperative random growth hormone levels and nadir growth hormone levels after oral glucose tolerance testing in acromegaly ⁎
Roman Rotermunda, , Till Burkhardta, Zaina Rohanib, Roman Jungc, Jens Aberleb,1, Jörg Flitscha,1 a
Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany Department of Endocrinology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany c Department of laboratory medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany b
A R T I C LE I N FO
A B S T R A C T
Keywords: Acromegaly Early postoperative oral glucose tolerance testing Growth hormone IGF1
Objective: There is no ideal marker to identify residual tumor tissue after surgery in patients with acromegaly. The purpose was to elucidate if early postoperative hormone testing gives reliable information regarding complete resection of a GH-producing pituitary adenoma. Design: Fourty-eight patients undergoing surgery for acromegaly from 04/2013-05/2014 were prospectively examined for random GH, IGF1, and GH levels after oral glucose tolerance testing (OGTT) in the early postoperative phase and on follow-up. Criterion for inclusion was a minimum follow-up of one year for each patient with respect to remission. Results: Thirty-three patients showed GH suppression below 1 μg/l after OGTT in the early postoperative phase. Follow-up GH, IGF1 and OGTT tests confirmed the initial findings in 30 patients. The three remaining patients showed biochemical signs of persisting acromegaly. In the remaining 15 patients early postoperative GH suppression was above 1 μg/l. Of those, six patients went into remission during follow-up, nine patients without postoperative GH suppression < 1 μg/l remained acromegalic. Conclusions: GH suppression to < 1 μg/l as well as random GH levels below 1 μg/l in the early postoperative phase seem to be of good positive predictive value for long-term remission. However, several patients without suppression of GH to < 1 μg/l in the early postoperative OGTT went into delayed remission. These results have to be taken into account prior to initiation of further therapy.
1. Introduction Transsphenoidal surgery is the treatment of choice for acromegaly [1–3]. Completeness of tumor removal is crucial for avoiding or minimizing the use of adjuvant therapies including pharmacotherapy and radiotherapy. Persistent disease in the long run is associated with increased morbidity and the risk of premature mortality [3,4]. Therefore the aim was to evaluate if early postoperative endocrinological markers predict the extent of resection and may justify early reoperation as it is successfully performed in Cushing's disease [5–7]. The surgical concept of early reoperation is based on nearly no additional access morbidity since no scarring has happened. 2. Material and methods Fifty-four consecutive patients undergoing surgery for acromegaly ⁎
1
from April 2013 until June 2014 were included in the prospective analysis. Preoperative GH and IGF1 levels were collected. Preoperative tumor size was measured on a standard MRI (T1 with and without contrast enhancement, sagittal, coronal and transversal planes) and a possible invasive growth was estimated. The patients were classified into a primary surgery group and a group of patients who had previously undergone surgery. Somatostatin-analog pretreatment was noted. Intraoperatively the surgeon subjectively classified the operation as complete resection, questionable complete resection or partial resection. Postoperatively, GH and IGF-1 (Immulite® 2000 (GH) Siemens/ Liaison® (IGF1) DiaSorin) levels were measured on the morning of postoperative day one (07.00 a.m.). An early postoperative oral glucose tolerance test (epOGTT) with GH-sampling using 75 g glucose was performed within the postoperative days 2–4. The diagnosis of acromegaly was confirmed by standard neuropathological work-up whenever possible. Subsequently, the patients were followed for a minimum
Corresponding author. E-mail addresses: [email protected] (R. Rotermund), [email protected] (R. Jung), [email protected] (J. Aberle), fl[email protected] (J. Flitsch). Both authors contributed equally.
https://doi.org/10.1016/j.ghir.2018.03.002 Received 7 January 2018; Received in revised form 3 March 2018; Accepted 8 March 2018 1096-6374/ © 2018 Elsevier Ltd. All rights reserved.
Please cite this article as: Rotermund, R., Growth Hormone & IGF Research (2018), https://doi.org/10.1016/j.ghir.2018.03.002
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(median: 16 months, range: 12–22 months) were evaluated (Table 1). There were no missing data. The patients' age ranged from 22 years to 80 years with a median age of 46 years (male: 43 years, female: 49 years). 42 patients had the primary diagnosis of acromegaly, six patients were previously surgically treated for acromegaly. 31 adenomas were macroadenomas, the remaining 17 were microadenomas. Fourteen tumors were classified as invasive according to MRI studies. Five patients received either cabergoline, octreotide/lanreotide or pegvisomant pretreatment. Four other patients had undergone both previous surgery and SSTR- analog pretreatment in the past. Any pretreatment had been discontinued more than eight weeks prior to the current admission. Thirty of the 48 patients (63%) were classified as complete resection by the surgeon, in fourteen of 48 patients (29%) the surgeon was unsure regarding completeness of resection, and four patients (8%) underwent intended debulking/partial resection of large invasive adenomas (Table 2). None of the patients had pituitary insufficiencies before or after surgery. Immunohistochemical markers assessed can be seen in Table 3. The intra-assay variability for GH was 4.97% and the intra-assay variability for IGF1 was 6.47%, both calculated in a quality control over the six months previous. Of the 48 patients enrolled, 33 showed GH suppression below 1 μg/l after OGTT in the early postoperative phase. Follow-up by GH (Fig. 2), IGF1 (Fig. 3), OGTT and MRI confirmed the initial findings in thirty of 33 patients (91%). The three remaining of 33 patients had persisting biochemical signs of acromegaly (9%). In fifteen patients, GH suppression was above 1 μg/l in the early stage. Six of those 15 patients went into remission during follow-up (40%). The remaining nine of 15 patients without postoperative GH suppression showed persistent disease (60%). Based on the thesis that detection of residual tumor mass by epOGTT could be useful mainly in cases with surgically questionable complete resection, the collective was divided into groups according to surgeons' impression of resection grade (Table 4). However, these analyses also failed to show a significantly correct prediction. Correct
of one year. A postoperative MRI after 3 to 6 months was performed and visible residual tumor mass was documented. The patients were scheduled for routine follow-up every 6 months. Further follow-up data on GH and IGF1 were performed by the referring endocrinologists. In case of pathological IGF1 results, a follow-up OGTT was performed. For this study, the last follow-up is reported. Remission was defined by means of all collected values according to the current criteria (normalized IGF-1 plus either a random GH < 1 μg/l or a nadir GH < 0.4 μg/l after OGTT). Graphs were drawn using the Graph pad prism (GraphPad Software, Inc./USA). 3. Theory In 2000, the Cortina Consensus Conference established general criteria for the diagnosis and biochemical control of acromegaly, which have been revised in recent years and adapted to emerging clinical evidence as well as evolving assay techniques. According to those recent consensus statements, postoperative cure in the long-term is defined by age-normalized Insulin-like growth factor 1 (IGF1) levels, a random growth hormone (GH) < 1 μg/l, and nadir GH after oral glucose tolerance testing (OGTT) < 0.4 μg/l [2,3,8–10]. We prospectively investigated whether the early postoperative random GH or the GH after OGTT gives reliable information regarding the resection grade of a tumor and performed a follow-up of at least one year. 4. Results The fifty-four consecutive patients included 27 male and 27 female patients (Fig. 1). Due to the consecutive patient cohort this gender distribution happened by chance. Six patients were lost to follow-up (two of those patients were lost for complete follow-up due to missing epOGTT and additionally four patients did not provide their follow-up data). The remaining 48 patients with a minimum of one year follow-up
Fig. 1. Long-term remission in relation to epOGTT.
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Table 1 Patient collective (48 patients). Relapse
Pretreatment
Tumor size (centimeter)
Radiologically invasive
Gh (μg/l)
IGF1 (μg/l)
Age- and sexrelated Ref. for IGF1 (μg/ l)
Followup (months)
Macroadenomas 1 Male 25 7 Female 40 9 Male 50 10 Male 49 11 Male 24 12 Male 41 13 Female 48 14 Female 52 15 Male 31 17 Male 29 20 Male 36 23 Male 39 24 Female 61 25 Female 40 26 Female 47 27 Male 70 29 Male 58 30 Female 47 31 Female 37 33 Female 50 34 Female 60 35 Female 25 36 Male 32 37 Male 53 38 Male 19 39 Female 50 40 Male 47 42 Male 39 Male 51 44 47 Female 55 48 Female 69
No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No No
No No No No No No No No Octreotide No No No No No No Lanreotide No No no No No No No No Cabergoline (suspected prolactinoma) No No Lanreotide No No No
1.52 × 0.76 × 0.98 1.72 × 1.8 × 1.76 1.2 × 1.53 × 1.21 0.9 × 1.35 × 1.24 3.13 × 2.34 × 2.58 1.33 × 1.64 × 1.77 1.97 × 1.78 × 2.34 2.67 × 2.76 × 2.81 2.2 × 2.1 × 2.7 1.03 × 1.03 × 1.31 1.4 × 1.39 × 1.28 1.19 × 0.88 × 1.16 0.76 × 1.35 0.94 2.49 × 3.08 × 1.71 2.1 × 1.4 × 1.1 1.03 × 1.08 × 1.41 1.46 × 1.32 × 1.61 1.08 × 1.8 × 1.17 0.72 × 1.35 × 1.07 0.9 × 1.2 × 1.2 0.86 × 1.59 × 1.17 2.19 × 1.56 × 1.45 4.71 × 3.54 × 2.75 1.56 × 1.61 × 1.76 1.02 × 1.09 × 0.85 2.85 × 2.73 × 1.76 1.19 × 1.5 × 1.1 1.31 × 1.5 × 1.35 1.22 × 0.94 × 1.44 2.72 × 3.66 × 3.53 0.74 × 1.23 × 1.17
N = no Q = questionably N N Y = yes Q N Y Y N Y N N Y Q Y N Y N N Y Y Q N N Y N N N Y N
3.17 93.46 24.7 2.92 18.8 17.2 40.8 22.5 19.2 9.19 6.38 10.04 11.54 70.38 19.85 10.15 20.42 1.35 7.85 32.1 8.42 20.42 15.8 3.39 4.19 10.11 7.69 41.9 10.4 3.1 6.73
943 998.3 741.6 505 783.6 864.4 1003.9 691.7 867.8 1074.1 835.5 819.8 653.3 829.9 868.1 625.1 1274.7 504.1 827.6 1008.5 672.2 856.3 964.9 845.1 516.9 770 1165.7 1090.7 945.1 432.6 379.3
89–402 101–337 44–199 101–210 112–336 101–210 101–337 49–232 101–210 112–336 101–210 101–210 49–232 101–337 101–337 44–199 44–199 101–337 101–337 49–232 49–232 137–328 101–210 44–199 220–495 49–232 101–210 101–210 44–199 49–232 49–232
17 18 18 17 18 14 16 19 22 19 17 19 14 15 12 17 17 14 12 12 17 15 14 14 13 13 17 12 12 14 15
Microadenomas 2 Male 52 3 Male 57 4 Male 47 5 Male 44 6 Female 22 8 Female 56 16 Female 37 18 Female 80 19 Female 50 21 Female 61 22 Female 58 28 Female 31 32 Male 44 41 Female 50 43 Male 34 45 Female 67 46 Female 51
No No No No Yes No Yes No No No No Yes Yes No Yes No Yes
No No No Cabergoline TSS (transsphenoidal surgery) No TSS + Octreotide + Pegvisomant No No No No TSS TSS + Octreotide No TSS + Lanreotide + Cabergoline + Pegvisomant No TSS + Cabergoline + Octreotide
1 × 0.9 × 0.9 0.78 × 0.7 × 0.78 0.94 × 0.79 × 0.86 1.04 × 0.94 × 0.68 0.41 × 0.98 × 0.54 0.63 × 0.78 × 0.86 0.35 × 0.46 × 0.6 1 × 0.93 × 0.89 0.8 × 0.8 × 0.81 0.58 × 0.58 × 1 0.78 × 0.67 × 0.56 0.45 × 0.6 × 0.4 0.35 × 0.39 × 0.42 0.67 × 1.03 × 0.77 0.41 × 0.76 × 0.47 0.7 × 0.8 × 0.9 0.76 × 1.02 × 1.12
Q N N N Q N Q Y Y Y N N N N Y N Q
7.92 4.42 10.61 2.01 6.27 7.19 4.96
967 278.1 856.8 396.6 215.4 403.4 676.4 995.6 456.1 724.5 834 488.6 390.5 690.5 519.8 439.2 456.7
56–271 44–199 101–210 101–210 137–328 49–232 101–337 49–232 49–232 49–232 49–232 101–337 101–210 49–232 101–210 49–232 49–232
20 20 15 19 17 22 14 16 21 17 16 12 17 17 12 16 14
Pat.
Gender
Age
prediction by the surgeon for the patients with a suspected “complete resection” was 93% in this series. Correct positive prediction of the epOGTT in all patients who showed a GH suppression below 1 μg/l was 91%. Lowering the threshold of suppression to < 0.4 μg/l, none of the included patients relapsed during follow-up. With a threshold of < 2 μg/l, correct positive prediction was 81%. All patients relapsed when the border for suppression was set at > 3.5 μg/l. For the primarily operated patients who showed a GH suppression below 1 μg/l, the test had a positive predictive value of 97% (< 0.4 μg/l - 100%, < 2 μg/l 87%, > 3.5 μg/l - 0%). All patients with an early postoperative spontaneous GH below 1 μg/l stayed in remission also on follow-up. In addition, all patients with an early postoperative spontaneous GH above 4 μg/l remained acromegalic. For those in between, see Table 5. Total remission rate was 75% (36/48) on follow-up
3.75 12.2 9.54 2.85 0.86 6.35 0.9 8.58 3.31
[microadenomas 76% (13/17) macroadenomas 74% (23/31)] in this series after 12 months. Biochemical remission of all primarily operated patients was achieved in 81% (34/42) [microadenomas 100% (11/11)/ macroadenomas 74% (23/31)]. Two of the six patients undergoing recurrent surgery (33%) showed remission on follow-up. Age and gender did not affect the remission rate. However, cavernous sinus invasion and a history of prior surgery as shown above were associated with lower rates of disease control. IGF1 was not clinically useful within the first postoperative day. On follow-up, among the twelve patients not in remission, two patients (17%) have been treated with cabergoline, nine of twelve patients without remission (75%) have received somatostatin-analog therapy, and one of those twelve patients (8%) has undergone radiotherapy to date.
3
2.46 1.79 2.07 1.51 0.81 2.93 1.68
0.92 0.85 0.43
2.48 1.77
1
1 1 3 2 2 1 2 1 1 2 3 2 1
1 1 1 1 1 3 1
1 1
1 2 1
23 24 25 26 27 29 30 31 33 34 35 36 37
38 39 40 42 44 47 48
Microadenomas 2 1 3 1 4 1
1 2
20
5 6
8 16
4
18 19 21
0.23 1.32 0.99
2 4.5
1.78 1.2 12.35 1.87 1.27 0.4 2.6 0.46 1.67 5 1.94 1.74 0.29
2.31
1.02 2.99 0.63 1.25
2 3 = partial resection 1 1
13 14 15 17
0.8 0.46 1.74
2 3.89
0.14 1.15
0.3 0.16 0.31
0.35 0.94 0.65 0.08 0.35 1.87 0.27
0.12 0.28 6.54 1.97 0.29 0.57 0.6 0.08 0.19 3.61 0.72 0.91 0.49
0.49
1.05 2.38 0.47 0.27
0.37 1.28 3.37
0.69 2.33 3.33
Early postoperative OGTT (μg/l)
0.08 1.1 1.9
Early postoperative GH (μg)
0.94 1.41 0.78
Surgeons estimation of resection grade
Macroadenomas 1 1 = total resection 7 1 9 2 = questionably total resection 10 1 11 1 12 2
Pat.
Table 2 Results (48 patients).
190 140.9 238
104.3 215
230.8 206
157 144 218
264 287.1 164.1 165.2 164 243.4 131.6
246.7 143.1 352 139.2 155 162.1 178.3 198 132 319.3 157 132 230
360
180.8 461 180 350.4
113.2 248.6 340.2
237.4 257 103.3
IGF1 at timepoint of follow up (μg/l)
18–193 100–300 < 210
49–232 79–276
20–224 103–326
55–203 63–279 94–163
93–404 49–232 101–210 64–236 63–279 49–232 29–251
96–227 18–244 62–205 100–300 64–188 20–224 101–337 101–337 49–232 55–152 137–328 115–307 56–201
63–279
101–337 87–238 112–300 101–210
20–224 64–236 101–210
89–402 153–251 100–300
Age- and sex- related Reference for IGF1 (μg/l)
0.3 0.22 0.88
2.05 0.32
0.09 4.67
0.1 2.01 0.09
0.45 1.48 0.07 0.28 0.2 2.34 0.33
0.3
0.09 0.28 3 2.54 1.84 0.09 0.47 2.17 0.1 1.91 0.7
04
0.09 1.57 0.35 0.33
0.09 1.9 0.79
0.82 1.27 0.27
GH at timepoint of follow up (μg/l)
1 1 1
1 0
1 1
1 1 1
1 1 1 1 1 0 1
1 1 0 0 1 1 1 1 1 0 0 1 1
1
0 0 1 1
1 0 1
1 1 1
Remission 1 = yes 0 = no
16 21 17
22 14
19 17
20 20 15
13 13 17 12 12 14 15
19 14 15 12 17 17 14 12 12 17 15 14 14
17
16 19 22 19
17 18 14
17 18 18
Follow-up (months)
(continued on next page)
Invasive tumor growth. On follow up OGTTs: 2.39 and 18.5 μg/l, radiotherapy
Second surgery due to recurrence shown in MRI
Initial IGF-1: 856.8 μg/l, constantly decreasing, OGTT on follow up: 0.1 μg/l
Lanreotide
Initial IGF-1: 770 μg/l, decreasing
Initial IGF-1: 845.1 μg/l, decreasing, OGTT on follow up < 0.1 μg/l
Lanreotide
Cabergoline
Initial IGF-1: 1074.1 μg/l, const. decreasing, OGTTs on follow up 0.17 and 0.11 μg/l Initial IGF-1: 835.5, decreasing, follow up OGTT 0.1 μg/l
Octreotide Initial IGF-1: 864.4, constantly decreasing, follow up OGTT: 0.65 μg/l Octreotide
Comment on special cases
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Surgeons estimation of resection grade
1 2
2 1 2 1 2
Pat.
22 28
32 41 43 45 46
Table 2 (continued)
0.4 1.28 3.38 1.68 3.96
1.32 4.65
Early postoperative GH (μg)
0.15 0.28 0.86 0.41 0.98
0.53 1.82
Early postoperative OGTT (μg/l)
197 166.5 223 128.4 371
153 477
IGF1 at timepoint of follow up (μg/l)
94–252 40–231 109–324 109–324 55–235
49–232 109–324
Age- and sex- related Reference for IGF1 (μg/l)
0.01 1.26 17.9 2.6 0.77
6.15 5.24
GH at timepoint of follow up (μg/l)
1 1 0 1 0
1 0
Remission 1 = yes 0 = no
17 17 12 16 14
16 12
Follow-up (months)
Invasive tumor growth
Invasive tumor growth, Pegvisomant
Suprasellar extension, incomplete resection
Comment on special cases
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Table 3 Neuropathology/immunohistochemistry. STH STH + PRL STH + PRL + LH STH + Chondrosarcoma WHO °II No adenoma for histopathology available
Fig. 2. Spontaneous GH levels.
5 29 13 2 1 3
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24 h postoperatively had the highest predictive power for surgical remission and that if the nadir GH level was above 4 μg/l remission was highly unlikely [16]. This finding is confirmed by our results, as no patient with an early postoperative spontaneous GH above 4 μg/l achieved remission on follow-up. In order to find a reliable marker for the tumor resection grade and since nadir GH-measurement is not a sufficient negative predictive marker, postoperative OGTT was examined in the present study. Freda et al. showed in 2001 that glucosesuppressed GH levels in healthy subjects are < 1 μg/l, perhaps even < 0.2 μg/l [17]. Therefore, the cutoff for suppression in remission was determined to be 1 μg/l. In 2002 Kristof et al. published a retrospective series of 73 consecutive patients undergoing OGTT 2 weeks after surgery. The results showed that early postoperative OGTT had several false positive results and was more reliable three months after surgery [18,19]. Kim et al. assessed that postoperative OGTT was even more reliable after six months [16]. The false positive results could be confirmed in our prospective series including patients that initially showed suppression below 1 μg/l in the epOGTT and showed signs of active acromegaly on follow-up. In addition, some patients who initially failed suppression, went into remission during follow-up. In patients with no preoperative medical or operative pretreatment the results are better (correct positive prediction of epOGTT < 1 μg/l was 96% instead of 91% in all patients), however not good enough to sufficiently predict residual tumor mass. Setting the upper limit of normal for suppression at < 0.4 μg/l, none of the included patients relapsed during follow-up in our series. In the literature, others recommended a threshold of suppression at 0.5 μg/l [16,20]. Not surprisingly, these low limits might be best to predict the patients' long-term prognosis and define further control intervals. On the other hand, several publications were able to show that a threshold of > 4 μg/l in the early postoperative OGTT confirmed residual tumor [21], which corresponds to our results where the threshold > 3.5 μg/l correlated with residual tumor. Carmichael et al. stated that OGTT should not be performed in patients receiving somatostatin-analogs due to possible false results [22]. Our patients on somatostatin-analog therapy showed a correct positive prediction of the epOGTT of 100% (N = 5), which is in line with the results of Otani et al. who found no statistically significant difference for the intraoperative GH-measurements in medically pretreated patients [15]. In this article, we do not discuss the well-known problems of assay reliability, which are topic of several publications [2,17,23–25]. Due to the short inclusion period and consistency of one GH assay in one laboratory, we feel that the impact of potential assay errors could not have been further minimized.
Fig. 3. IGF1 levels.
Table 4 Remission in dependence of early postoperative OGTT (epOGTT) taking into account the surgeon's subjective intraoperative grading of resection. epOGTT Complete resection (30) Questionable complete resection (14) Partial resection (4)
< 1 μg/l > 1 μg/l < 1 μg/l > 1 μg/l < 1 μg/l > 1 μg/l
(25) (5) (7) (7) (1) (3)
Remission
Persistence
25 (100%) 3 (60%) 5 (71%) 3 (43%) – –
– 2 2 4 1 3
(40%) (29%) (57%) (100%) (100%)
Table 5 Early postoperative spontaneous GH (epGH) as predictor for remission. epGH
Remission (number of patients)
Persistence (number of patients)
< 0,4 μg/l < 1 μg/l 1–2 μg/l 2–3 μg/l 3–4 μg/l > 4 μg/l
4 (100%) 14 (100%) 15 (83%) 4 (50%) 3 (75%) –
– – 3 4 1 4
(17%) (50%) (25%) (100%)
6. Conclusions Our results show that spontaneous GH as well as OGTT in the early postoperative phase have some benefits as well as limitations, as previously shown by others. In patients showing a spontaneous GH or a GH suppression during OGTT below 1 μg/l, the tests have a high positive predictive value for remission, confirming the experienced surgeons' impression of a “complete resection”. The threshold of GH suppression during OGTT below 0.4 μg/l may even be better. However, several patients without suppression of GH < 1 μg/l in the early postoperative OGTT went into remission in the long-term. So far, we lack a safe marker for surgical failure unless GH > 3.5 μg/l (or if there is evidence of a visible remnant on postoperative MRI, if performed) which justifies early reoperation in acromegaly. These results also must be taken into account prior to initiation of pharmacotherapy, radiotherapy or reoperation, requiring careful monitoring of patients for up to 12 months after initial surgery.
5. Discussion There have been many efforts to optimize the prediction of resection grade after transsphenoidal adenomectomy in patients with acromegaly over the past few decades [8–14]. The surgeon's main concern is finding a reliable tool to extract the patients with resectable tumor remnants for early reoperation as it is successfully performed for patients with Cushing's disease [5–7]. Lüdecke et al. had good results with intraoperative GH-measurements, which could in some cases identify residual tumor tissue during surgery [11–13]. This is an elaborate, timely and costly procedure, which has not been established as a general clinical standard. A few years later, Valdemarsson et al. published data showing that the mean of a direct postoperative GH-series within the first postoperative week may lead to more reliable results predicting surgical outcome than the intraoperative measurement [14]. Otani et al. in 2012 presented a large series of intraoperative GH-measurements, questioning its use for identifying residual disease [15]. At the same time Kim et al. showed that immediate postoperative GH levels
Declarations of interest None. 6
Growth Hormone & IGF Research xxx (xxxx) xxx–xxx
R. Rotermund et al.
Acknowledgements [9]
The authors are indebted to Dieter K. Lüdecke, MD for his pioneering work on pituitary tumor research and therapy at UKE. We also thank all referring colleagues for their trust and cooperation.
[10]
Funding
[11]
This research used a data base which was financially supported by a grant from Novartis pharma (RSIG-053).
[12] [13]
Ethical approval
[14]
All procedures performed involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.
[15]
[16]
Informed consent
[17] [18]
Informed consent was obtained from all individual participants included in the study.
[19]
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