Acta Neurochir (Wien) (2005) 147: 485–493 DOI 10.1007/s00701-005-0511-9

Clinical Article Presurgical octreotide treatment in acromegaly: no improvement of final growth hormone (GH) concentration and pituitary function. A long-term case-control study U. Plo¨ckinger1 and H.-J. Quabbe2 1

Department of Hepatology and Gastroenterology, Interdisciplinary Centre of Metabolism: Endocrinology, Diabetes and Metabolism, Charit
e, Campus Virchow-Klinikum, Humboldt Universit€at zu Berlin, Berlin, Germany 2 Department of Endocrinology, Klinikum Benjamin Franklin, Freie Universit€at Berlin, Berlin, Germany Received July 20, 2004; accepted February 4, 2005; published online April 4, 2005 # Springer-Verlag 2005

Summary Background. The effect of presurgical long-acting somatostatin analogue (SSA) treatment on operative outcome in acromegaly is as yet uncertain and long-term observations are lacking. We evaluated in an acromegaly case-control study the effect of octreotide pre-treatment on short- and long-term postoperative GH concentrations, pituitary function and glucose tolerance. Methods. 48 patients with a pituitary macro-adenoma – micro- and giant adenomas excluded – were evaluated. 24 patients received presurgical octreotide treatment (secondary surgery, prospectively studied). Another 24 thoroughly matched patients had been operated on without prior octreotide therapy (primary surgery, retrospective evaluation). No patient had received any other treatment prior to operation=octreotide. Standardized testing was performed at diagnosis, following octreotide treatment, after surgery and then yearly for 10.3
0.9 yrs (mean
SE, primary surgery) and 4.1
0.6 yrs (secondary surgery). Immediate and 4-year postoperative results were compared. All work-up was strictly identical in both groups, except for imaging techniques. ‘‘Partial remission’’ was defined as mean GH profile (6-h=7-point) concentration <2.5 mg=L, and ‘‘complete remission’’ as GH nadir < 1 mg=L during OGTT plus normal IGF-I concentration (when available). Findings. The median profile GH (mg=L) values and the OGTT GH nadir values post-surgery (2.4=1.0 vs 1.8=0.7, primary and secondary surgery, resp.) as well as 4 yrs later (2.1=1.15 vs 2.3=0.8) were not significantly different between the groups. The 10-year results of the primary surgery group were not significantly different from its 4-year results. Subgroup analysis of pre-treated patients revealed no significant difference between those with and without tumour shrinkage, or between those with and without parasellar tumour extension. Postoperatively pituitary function was not significantly different between the groups. After 4-years the pituitary-adrenal axis was slightly more impaired in the secondary surgery group rather than following primary surgery, while the pituitary-gonadal axis was not different. Conclusion. Presurgical octreotide treatment has no significant short- or long-term beneficial effect on GH concentration or pituitary function.

Keywords: Acromegaly; surgery; octreotide pretreatment; pituitary function.

Introduction Results of transsphenoidal surgery for GH-secreting pituitary adenomas are negatively correlated with adenoma size, suprasellar extension and the preoperative GH concentration [2, 9, 11, 25, 28, 30, 32, 36, 37]. The SSA octreotide reduces GH concentration in most and induces tumour shrinkage in 50% or more of GHsecreting adenomas [5, 10, 21, 29, 35]. Hence preoperative octreotide therapy has been proposed to improve the surgical outcome in acromegalic patients. However, results are controversial. Improvement of surgical results has been reported from historical comparisons [5, 21] and from retrospective analyses [8, 35]. Other authors have seen no difference between pre-treated and untreated patients [1, 7, 19]. Comparison with historical experience, purely retrospective analysis, reliance on single GH values, a large range of octreotide doses and pre-treatment times and small patient numbers are some of the confounding factors in one or the other of these studies. Moreover, there is very little information on long-term GH results and pituitary function [2, 7]. While a purely prospective study of sufficient strength would be desirable to answer the question, such an investigation may be difficult to organize for various reasons, such as the necessary number of patients of a

486

U. Plo¨ckinger and H.-J. Quabbe lowed prospectively. These patients were carefully matched for age, sex, initial GH concentration and tumour volume with 24 patients who had been operated on without any pre-treatment (primary surgery, retrospective evaluation). Patient characteristics are given in Table 1. No patient had received any other treatment for acromegaly before entering the study (octreotide pre-treatment group) or before being operated on (primary surgery). Follow-up was 10.3
0.9 yrs (mean
SE) after primary surgery and 4.1
0.6 yrs after secondary surgery. At the time of inclusion tumour volume was evaluated by MRI in 5 patients of the primary surgery group and by contrast-enhanced cranial computed tomography in 19 patients, while all secondary surgery patients had MRI evaluation. Patients were operated on by a dedicated neurosurgeon with experience in pituitary surgery in 54% (13=24) and 79% (19=24), for the primary and secondary surgery group, respectively (p ¼ ns). Eight patients with primary surgery and four patients with secondary surgery received single or multiple additional therapies following incomplete tumour removal. Acromegaly was diagnosed according to clinical criteria, nonsuppressibility of the plasma GH concentration to below 1 mg=L during an oral glucose tolerance test (OGTT, 100 g of glucose, samples at baseline and at 30, 60, 90, 120 and 180 min for the determination of GH, glucose and insulin) and an elevated, age- and sex-adjusted IGF-I concentration (IGF-I values were not available in patients of the primary surgery group at the time of their initial evaluation, see Table 2). Surgical success was

rare disease and requirements for equal surgical expertise in participating centres. We therefore performed a case-control study of 48 acromegalic patients. Twenty-four patients were studied prospectively and received standardized preoperative octreotide therapy. They were carefully matched for their GH concentration and tumour size with 24 patients without pre-treatment who were evaluated retrospectively, but had undergone exactly the same work-up and follow-up. All patients had a macro-adenoma, but none had a giant adenoma. We report results of immediate postoperative, as well as long-term results for GH values and pituitary function. Glucose tolerance was also studied.

Patients and methods Twenty-four acromegalic patients with a pituitary macro-adenoma were preoperatively treated with octreotide (secondary surgery) and folTable 1. Patient characteristics Age (years) mean and range

Follow-up (years) mean and range

Sex m=f

Clinic1 A=B

Primary surgery 46 (20–66)

10.3 (7–17)

13=11

13=11

11=13

19=5

Secondary surgery (preoperative therapy) 45 (29–70) 4.1 (0.6–11) 1 2

Tumour imaging CT=MRI2

Postoperative residual tumor

Diag

Post-Op-2

19=5

5=19

6

0=24

6

0=24

Clinic-A, specialized in pituitary surgery, Clinic-B, group of neurosurgeons not specialized in pituitary surgery. Method of radiological investigation: CCT, cranial computer-tomography and MRI, magnetic resonance imaging.

Table 2. GH concentration (mg=L) during GH profile (6-h, 7 samples), GH nadir during OGTT and IGF-I concentration at diagnosis (Diag), after surgery (Post-Op-1), 4-years post-operatively (Post-Op-2) and at the last investigation of the primary surgery group (last invest) Primary surgery

Secondary surgery

Diag

Post-Op-1

Post-Op-2

Profile N Median GH % of pts <2.5 mg=L

24 29.3 –

24 2.4 50%

24 2.1 58%

24 1.7 63%

OGTT Nadir N Median GH % of pts <1.0 mg=L

23 14.0 –

23 1.0

22 1.15

23 1.2

48%

50%

48%

14 221.3 71%

21 189.7 71%

20 218.2 70%

14 43%

20 45%

20 35%

IGF-I N Median IGF-I % of pts normal

n.a.3 –

OGTT-Nadir plus IGF-I N 24 % of pts normal – 1 2 3

Last invest

Diag

24 29.6

Post-Op-1

Post-Op-22

Difference between groups1 (p)

24 1.8 63%

24 2.3 50%

21 0.7 62%

22 0.8 59%

ns, ns, ns

24 1007.5 –

24 256.4 71%

24 226.9 83%

ns, ns, ns

24

21 57%

21 59%

ns, ns, ns

– 19 23.6 –

–

ns, ns, ns

Significance of difference between groups (Diag=Diag, Post-Op-1=Post-Op-1, Post-Op-2=Post-Op-2, Mann-Whitney U-test). Synonymous with ‘‘last investigation’’ for this group. n.a. Not available,  p < 0.01 versus value at diagnosis within each group (Wilcoxon’s signed rank test).

487

Presurgical octreotide in acromegaly: long-term study classified as ‘‘partial remission’’ when the mean GH concentration was <2.5 mg=L during a 6-h=7-point GH profile [16, 20] or as ‘‘complete remission’’ when the GH nadir was <1 mg=L during OGTT [13] and the age- and sex-adjusted IGF-I concentration was normal (a few patients had no OGTT at one or another investigation due to diabetes mellitus at that time point). Preoperative octreotide therapy consisted of 3  100 mg=d sc at 0800, 1600, 2400 h for three months. Fourteen of these patients received 3  500 mg=d for an additional three months in an attempt to further reduce their GH concentration and=or tumour volume. The last octreotide dose was given on the evening before operation. During the first three days on octreotide all patients had mild gastrointestinal discomfort. One patient newly developed gallstones. Thereafter all patients received prophylactic chendeoxy- plus ursodeoxy cholic acid treatment and no further gallstones developed, although gallbladder sludge was seen in 3 patients. The octreotide effect on tumour volume was examined by MRI (see below) after three (M3) and 6 months (M6) of treatment. Pituitary function was evaluated at diagnosis, after 1 week (W1), 3 months (M3), and 6 months (M6, N ¼ 14) on octreotide treatment, and again 6 weeks after surgery as follows: Insulin induced hypoglycemia (IHG) for cortisol response; LH-releasing hormone (LHRH) test (Relefact+ LHRH, Aventis, Bad Soden, Germany, 100 mg, iv) and thyrotropin releasing hormone (TRH) test (Relefact+ TRH, Aventis, Bad Soden, Germany, 200 mg, iv) for the LH=FSH and the TSH and PRL responses, respectively. The evaluation scheme was identical for both groups. During IHG plasma glucose and cortisol were determined at 30, 0, 30, 45, 60 and 90 min. The test result was accepted when the glucose nadir was <2.2 mmol=L and hypoglycemic symptoms had occurred. Secondary adrenal insufficiency was defined as a basal and stimulated cortisol <200 nmol=L and <550 nmol=L, respectively. Patients with a contra-indication for the IHG received an overnight metyrapone test (30 mg=kg body weight; normal: 11-desoxycortisol concentration >200 nmol=L at 0800 h the next morning). During the LHRH-TRH test blood was drawn at 0, 15, 30, 45 and 60 min. Complete LH insufficiency was defined as basal and stimulated LH <2 and <20 IU=L in females and <2 and <10 IU=L in males. Postmenopausal women were excluded from later LH analysis. Normal PRL concentration was 5–25 mg=L in female and 5–15 mg=L in male patients for basal values and a 4-fold or greater increase after TRH stimulation. Complete TSH insufficiency was defined as a basal TSH concentration <0.3 mIU=L and an increase of less than 5 mIU=L, plus a subnormal thyroid hormone concentration. Patients received routine hormone substitution therapy as needed. Glucose tolerance was determined from the results of the OGTT according to WHO criteria [38]. After surgery, all patients were seen within 6 weeks, after 6 and 12 months and then at yearly intervals for complete re-evaluation of GH secretion, pituitary function, glucose tolerance and pituitary imaging (imaging as clinically needed, but always at the last investigation). Results of the first postoperative testing (post-Op-1) and at a mean of approximately 4 years postoperatively (post-Op-2) were compared (corresponding to the last investigation in the pre-treated group and almost half-way to the last investigation in the primary surgery group). Results of the last investigation (Last invest) of the primary surgery group were also compared with its post-Op-2 values. The following assays were used in all patients: GH (RIA, Sorin, Sallugia, Italy, IRP 80=505), acid-ethanol extracted IGF-I (RIA, Nichols, San Juan Capistrano, CA, IRP 87=518), PRL (IRMA, Sorin, Sallugia, Italy, MRC 75=504), LH (MAIA-Clone, Serono, Freiburg, Germany, IRP 68=40), FSH (MAIA-Clone, Serono, Freiburg, Germany, IRP 80=552), TSH (IRMA-MP, Biermann, Bad Nauheim, Germany, IRP 87=558), insulin (RIA, Sorin, Sallugia, Italy, IRP 66=304), cortisol (RIA, Incstar, Stillwater, Minnesota, USA). 11-Desoxycortisol was determined by an in-house RIA [3]. Typical intra- and interassay coefficients of variation were as follows: GH 4.9% and 3.8%, IGF-I 1.6% and 11.0%, PRL 2.8% and 4.3%, LH 2.8% and 3.2%, FSH 1.7% and 4.6%, TSH 1.9% and 5.1%, insulin 4.7% and 2.8%, cortisol 3.6% and 6.0%,

11-desoxycortisol 8.3% and 9.2%. Assay sensitivity was 0.5 mg=L for GH, 11.6 mg=L for IGF-I, 0.7 mg=L for PRL, 0.15 IU=L for LH, 0.25 IU=L for FSH, 0.02 mIU=L for TSH, 2.5 mIU=L for insulin, 14 nmol=L for cortisol and 20 nmol=L for 11-desoxycortisol. Serum glucose was measured by a glucose oxidase method (Glucose analyzer II, Beckmann Instruments, Brea, CA). All determinations were performed in the same laboratory. MRI (T1 weighted S1 sequences, 3 mm slices in coronal and sagittal planes, native and with Gd-DTPA [0.1 mmol=kg BW] enhancement 1.5 Tesla, Magnetom, Siemens, Erlangen, Germany) was standardized for the individual patient. Contrast enhanced CT images (sagittal, coronal and planar) were obtained using Somatom DR2 (Siemens, Erlangen, Germany). Tumour volume was calculated according to the formula of Di Chiro and Nelson: volume ¼ height  length  width 
=6. A volume decline of at least 20% was considered significant [22]. For the comparison of tumours from the primary and secondary surgery groups, the Wilson classification was used [39].

Statistics When data distribution was normal, means
SE were used, otherwise median values were calculated. Normal distribution was tested by the Shapiro-Wilks W-test. Median group values were calculated using the individual values, means or areas under the curves (AUCs). Between-group comparisons were analyzed by Mann-Whitney U-test. Comparison of paired values was done using Wilcoxon’s signed rank test. For multiple comparisons the p value was corrected according to Holm-Bonferroni and the level of significance defined as p < 0.05 for the first, p < 0.025 for the second comparison. All data were compiled in a databank on the basis of MS Access, statistical evaluation was performed with Statistica software (Statsoft Inc, Tulsa, OK, USA). Informed written consent was obtained from the patients of the preoperative treatment group. The study was performed in agreement with the Declaration of Helsinki as revised in 1983 and the general outlines of good clinical practice (GCP). The study protocol was approved by the hospital Ethical Committee.

Results Octreotide treatment At diagnosis the GH concentration was similar in both treatment groups (Table 2). Octreotide induced partial or complete remission in 17% and 35% of the patients respectively (Fig. 1). Tumour volume determination was possible for 23 of the 24 pre-treated patients. The volume was significantly reduced in 11 patients at month 3 (from a mean of 8393 mm3 to 4246 mm3, reduction 49.4%). Four volume responders and 7 nonresponders received 1500 mg=d for an additional 3 months. In 3 of the 4 responders tumour volume continued to decrease and one nonresponder now attained a more than 20% volume reduction. Individual tumour volume changes are indicated in Fig. 2. Octreotide reduced TRH stimulated TSH and basal PRL concentrations (to 55% and 58% of their initial values, p< 0.01), but had no effect on basal TSH, stimulated PRL, the pituitary-adrenal and the pituitary-gonadal axis. At diagnosis 7 and 3 patients had diabetes mellitus and impaired glucose tolerance

488

U. Plo¨ckinger and H.-J. Quabbe

Fig. 1. GH concentration at diagnosis, during octreotide treatment (month 3), after secondary and after primary surgery. GH values are the mean of the 6-h=7-point profile (logarithmic scale). The dotted line at 2.5 mg=L indicates the limit for partial remission

Fig. 2. Change of tumour volume in individual patient after A) 3 months of octreotide 300 mg=d and B) 3 months of 300 mg=d followed by 3 months of 1500 mg=d. Tumour volume after 3 months and 6 months is given as percent of basal volume. Tumour volume reduction of more than 20% is considered significant. No tumour volume data were available for one patient in group B. Numerical values for the individual tumour volumes are in cm3. Basal, months 3 (A) and basal, months 3 and 6 (B) values are indicated

(IGT), respectively. During octreotide treatment glucose tolerance deteriorated in 5 additional patients. Surgical results GH and IGF-I Both, primary and secondary surgery reduced the GH concentration more than octreotide (Fig. 1). Postoperatively (post-Op-1), the median GH profile concentration, the median OGTT GH nadir and the median IGF-I concentration was similar in both groups (Table 2). The partial (GH profile) and complete (OGTT GH nadir plus IGF-I) remission rates (expressed as percentage of patients fulfilling the respective criteria) following primary surgery were somewhat lower than those following secondary surgery, but the differences were not significant. At post-Op-2, GH and IGF-I values were again similar in both groups. The remission rates were now essentially unaltered and similar in both groups. Post-

operatively 6 patients in each group had residual tumour documented by imaging technique. Five of these in the primary surgery group and 4 in the secondary surgery group received follow-up treatment, while the others were left untreated for various reasons (absence of clinical activity, refusal). At the last investigation of the primary surgery group (median 10.3 years postoperatively) the median GH and IGF-I values were not significantly different from those at the post-Op-1 or post-Op-2 investigations. A subgroup analysis of the secondary surgery patients revealed no significant postoperative difference between volume-responders and nonresponders, nor between those with and without parasellar tumour extension, or those who received 300 mg octreotide for 3 months and those with an additional 3 months of 1500 mg=d. Moreover, comparison of the octreotide volume-responders (N ¼ 12) and their individually matched controls of the primary surgery group also showed no significant differ-

489

Presurgical octreotide in acromegaly: long-term study

the median stimulated cortisol value became slightly subnormal at post-Op-1 and post-Op-2. Stimulated LH concentrations were lower postoperatively in both groups and not significantly different (postmenopausal patients were excluded from the LH analysis). Basal and stimulated PRL concentrations also decreased slightly after surgery with no significant difference between the groups. Individual evaluation showed that in the primary surgery group one patient each developed ACTH- and LHinsufficiency postoperatively. In the secondary surgery

ence of their postoperative GH and IGF-I values (data not shown). Pituitary function At diagnosis the median basal and stimulated cortisol, LH and PRL concentrations were normal and not significantly different between treatment groups (Table 3). Basal and stimulated cortisol remained normal in the primary surgery group at post-Op-1, post-Op-2 and at the last investigation. In the secondary surgery group,

Table 3. Anterior pituitary function at diagnosis (Diag), after surgery (Post-Op-1), 4-years post-operatively (Post-Op-2) and at the last investigation of the primary surgery group (last invest). Cortisol values (nmol=L) are from insulin-induced hypoglycemia test, LH (IU=L) and PRL (mg=L) values are from LHRH-TRH test (for details see text). Ranges omitted for the sake of clarity Primary surgery

Cortisol N Basal Peak

Secondary surgery

Diag

Post-Op-1

Post-Op-2

Last invest

Diag

Post-Op-1

Post-Op-2

15 326 632

20 346 598

22 400 534

23 394 606

7 337 505

19 276 467

16 313 436

Difference between groups1 (p)

ns, ns, <0.05 <0.01, ns, <0.05

LH N Basal Peak

17 4.2 19.4

17 3.4 14.8

17 4.0 12.5

15 4.0 11.9

19 2.8 21.0

19 2.2 11.2

18 3.0 14.5

ns, ns, ns ns, ns, ns

PRL N Basal Peak

20 8.7 23.4

20 5.0 18.5

23 4.5 11.9

24 3.6 13.1

22 10.5 21.0

24 5.9 17.4

24 7.2 23.0

ns, ns, ns ns, ns, ns

Values are the median of the individual concentrations, N; number of patients. Patients without adequate hypoglycemia during IHG were excluded from the analysis of cortisol values. Postmenopausal female patients were excluded from the analysis of LH insufficiency.  p < 0.05 and  p < 0.01 versus diagnosis (Wilcoxon’s signed rank test). 1 Significance between groups for Diagnosis, Post-Op-1 and Post-Op-2 (Mann-Whitney U-test).

Table 4. Median fasting and 2-h glucose concentration (mmol=L), insulin AUC (mIU=L=180 min) during OGTT, insulin=glucose ratio (mIU=mmol) and percentage of patients with impaired glucose tolerance (IGT) or diabetes mellitus (DM) at diagnosis (Diag), after surgery (Post-Op-1), at post-Op2 and at the last investigation of the primary surgery group (last invest) Primary surgery Diag N

23

Glucose Fasting 2-h

5.0 7.8

Insulin AUC

17601 2

Insulin=Glucose

Pts with IGT or DM

12.0 15=24

Secondary surgery

Post-Op-1

Post-Op-2

23

23

4.4 5.4 10155 9.0 7=24

4.5 6.1 11084 7.5 6=24

Last invest 23 4.5 7.8 6510 7.2 11=24

Diag

Post-Op-1

19 5.7 8.4 22653 10.5 10=24

21

Post-Op-2 22

4.7 6.3 8154

4.9 6.7 8223

6.0 4=24

Difference between groups1 (p)

5.8 6=24

 p < 0.05,  p < 0.01 versus diagnosis (Wilcoxon’s signed rank test). 1 Significance of difference between the groups for Diagnosis, Post-Op-1 and Post-Op-2 (Mann-Whitney U-test). 2 Insulin=glucose ratio for AUC values.

ns, ns, ns ns, ns, ns ns, ns, ns ns, ns, ns <0.01, <0.01, ns

490

group 5 patients developed ACTH-, 2 patients LH- and 3 patients TSH-insufficiency. No patient developed lasting diabetes insipidus. At post-Op-2 two patients of the primary surgery group had recovered from ACTH-insufficiency and one patient had newly developed TSHinsufficiency. In the secondary surgery group 4 patients had recovered from LH-insufficiency. Thus postoperative impairment of pituitary function occurred more often in the secondary than in the primary surgery group and this difference persisted at post-Op-2. Glucose tolerance Glucose data are shown in Table 4. The median fasting glucose concentration, the glucose- and insulin responses during OGTT, as well as the insulin=glucose ratio were all significantly reduced postoperatively in both groups, as was the number of patients with impaired glucose tolerance or diabetes mellitus (IGT=Dm). The number of patients with IGT=Dm was higher in the primary than the secondary surgery group both at diagnosis and at post-Op-1. At post-Op-2 it was similar in both groups. At the last investigation of the primary surgery group, the 2-h glucose concentration and the number of patients with IGT=Dm had increased and the insulin AUC decreased, probably due to the advanced age of these patients. Discussion The benefit of prior SSA treatment for the operative outcome in acromegaly is controversial. The major series and our own results are summarized in Table 5. No beneficial effect [1, 7, 19] and improvement of surgical results were both reported [5, 8, 21, 35]. Inclusion of patients with a micro-adenoma, of patients who had previously received medical, surgical or irradiation treatment, lack of match for invasiveness or IGF-I concentrations, reliance on single GH values rather than day profiles, variable octreotide doses and treatment times, as well as liberal criteria for cure [1, 5, 7, 8, 21], were all factors that make it difficult to definitively prove or disprove a positive effect. Our study was designed to avoid these pitfalls. Cure rates are close to 90% in experienced centres in patients with a micro-adenoma [11, 15, 34] and giant adenomas are not operated on curatively even by the most experienced neurosurgeons. Such patients were therefore excluded. The octreotide dose and treatment time were standardized. Both groups had a strictly identical shortand long-term workup. Patients were carefully matched,

U. Plo¨ckinger and H.-J. Quabbe

including initial GH concentration and tumour size. None had received any prior treatment. A GH concentration <1.0 mg=L in an OGTT [13] was a criterion of cure in our department since 1966. We could therefore reliably compare complete remission rates between the two groups. Definition of partial remission was based on a 7-point standardized day profile, which is more reliable than a random GH value [17]. IGF-I determination was not yet available at the time of diagnosis for most patients with primary surgery, but IGF-I values were included in the post-Op-1 and post-Op-2 evaluations. Despite – or because of – our rigorous study protocol, we were unable to document a significant effect of octreotide pre-treatment on surgical outcome. There are a number of potential biases that may have arisen from our study design. The comparison of groups diagnosed and treated at different time periods potentially favours the pre-treated group, due to better diagnostic tools and surgical techniques. Moreover, slightly more patients in the pre-treated group were operated on by a specialized neurosurgeon. Surgical expertise is an important factor for success in pituitary surgery [4, 20]. Another bias may arise from the difference of tumour volume determination: Most patients in the primary surgery group were initially evaluated by CCT and only later by MRI. However, images of the patient groups were individually matched according to the criteria of Wilson [39], that allow for good determination of suprasellar and parasellar extensions (which predominantly affect surgical results) in both, CCT and MRI images. More importantly, all these potential biases should have benefited the pre-treated group and no such effect was apparent from our data analysis. Insufficient treatment in terms of dose or duration cannot be responsible for our negative results. An octreotide dose of 300 mg=d given for a period of 3 months has previously been shown to provide a maximal or near maximal effect on both GH concentration and tumour volume in most patients [5, 14, 26]. Moreover, we found no significant difference between the patients on the lower and the higher dose=treatment time schedule. The long-acting octreotide LAR has now mostly replaced the short-acting preparation. In one report, GH=IGF-I suppression and tumour volume reduction was larger, when patients were switched after 24 weeks from short-acting to LAR treatment [6]. However, for de novo treatment there is at present no evidence for a significantly better effect on GH secretion, IGF-I concentration or tumour shrinkage [12, 23, 26]. It therefore

–

3 or 6

1–17

470 (150–300)

713 (300=1500)

529 (150–1500)

– 9 (300–1500) 314 (150–600) 221 (100–1500)

535 (150–1000) 300 –

Oct dose3 (mg=d) mean (range)

norm

norm

norm norm norm

norm

IGF-1

<2.5

<2.5

þ<2.0 þ<5.012 þ<2.5

<4.67 þ<5.0

Profile

GH

Remission criteria4

þ<1.0

<1.0

<1.25

<1.0

þ<1.0

<2.0 þ<2.0

OGTT

52

–

2410 2313 3115

80 608

Volume reduction % of pts5

69

79 74 74 50 48

5011 30 77

– –

C

1

55

53 79 63 63 62

7211 55 69

80 60

Pre-Tx

Remission % of pts

ns ns

<0.0516

<0.00514

– –

p6

[19]

this study17

[7]17

[35] [8] [1]

[5] [21]

Reference

1 C, Control group, 2 Mean time of preoperative octreotide therapy in months, 3 Mean octreotide dose per day, 4 IFG-I normal, mean GH concentration of a GH profile, nadir GH concentration during OGTT; therapy was accepted as successful when one of the three criteria was achieved or IGF-I was normalized and an additional (‘‘ þ ’’) criterion for GH was fulfilled, 5 Percent of patients in whom a tumour volume reduction of at least 20% had occurred during preoperative octreotide therapy, 6 Controls vs. preoperative octreotide therapy, 7 Mean of 24-h profile, 8 Volume reduction ranged from 9–78% in these patients, 9 Different therapy groups with variable treatment times and octreotide dose, 10 Criterion of tumour volume reduction in this study: >25% shrinkage. Another 34% of patients had tumour shrinkage <25%, 11 Calculated from percentages for 3 different tumour sizes, 12 Single GH determination, 13 Criterion of tumour volume reduction in this study: 30% reduction of the maximum diameter, 14 p < 0.005 for the comparison of surgical outcome, but not for remission criteria, since GH and IGF-I concentration were similar in both groups, 15 Criterion of tumour volume reduction in this study: 30% reduction of the maximum diameter, 16 p < 0.05 only for the comparison of the mean IGF-I concentration, 17 Data of reference #7 and our own study are separately given for each remission criterion.

Prospective Study 13 11

4.1

4.2

24

24

5.2

Case Control Study 19 19

0.8–39 3–6 3–21

Retrospective Comparison 108 64 –9 37 22 – 57 90 8.0

Tx-range

0.8–7.5 –

Tx time

Historical Comparison – 10 2.9 – 10 1.5

Pre-Tx

2

1

C

(months)

N

Table 5. Published results of pre-operative octreotide therapy (Pre-Tx)

Presurgical octreotide in acromegaly: long-term study

491

492

seems unlikely, that use of the LAR preparation will significantly improve the effect – if any – of presurgical octreotide treatment. It has been suggested that only smaller macro-adenomas – estimated by the surgeon to be ‘‘resectable’’ – may benefit from octreotide pre-treatment [1]. This may indeed be expected in view of the significance of dural invasion for the postoperative recurrence of pituitary tumours [18, 24]. However, a subgroup analysis of our pre-treated patients revealed no difference between tumours with and without parasellar extension, nor was there a difference between volume responsive and unresponsive patients. Although the biochemical cure rate of acromegalic patients does not seem to be improved by presurgical SSA treatment, it may be useful to diminish perioperative risk factors. Acromegalic patients have been shown to have more anaesthetic complications, such as airway difficulties, fluid imbalance or glucose intolerance [31]. These as well as ECG abnormalities and hypertension may be diminished by presurgical SSA treatment [8]. Thus, SSA use may be warranted preoperatively in patients, in whom such factors are expected to pose a peri-operative problem. There is very little information on the long-term effect of presurgical SSA treatment [1, 7]. Improved operative results should diminish the necessity for secondary treatment, which – in turn – would minimize the risk of pituitary insufficiency or persistence of impaired glucose tolerance. With increasing time elapsed since the operation, factors other than a possible influence of presurgical SSA treatment on the operative results become important, secondary therapy and advancing age being among them. Nevertheless, our failure to detect a higher cure rate or a better pituitary function in the pre-treated group, both immediately after the operation and 4 years later, does not support an indication for presurgical SSA treatment. Conclusions We conclude that octreotide pre-treatment does not significantly improve the immediate or long-term surgical outcome in patients with acromegaly.

Acknowledgments We thank Ms M. Ro¨sick for the determination of hormone concentrations. Ms M. Mahlcke performed most of the endocrinological tests and cared for the patients. W. Oelkers kindly performed the 11-desoxycortisol assays.

U. Plo¨ckinger and H.-J. Quabbe

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Comment This detailed manuscript describes a case-control study of surgical outcome in acromegaly by comparing 24 patients who received pre-operative octreotide therapy and who were studied prospectively, with 24 carefullymatched patients who received primary surgery without medical pretreatment, and who were reviewed retrospectively. The matching process is crucial and has been done well. The paper contains much detail but is very clearly written. The authors show good insight into the difficulties of such studies and present a nice critique of other papers in the field. The tables and figures are well-constructed. J. S. Bevan Aberdeen

Correspondence: Ursula Plo¨ckinger, Department of Hepatology and Gastroenterology, Interdisciplinary Centre of Metabolism: Endocrinology, Diabetes and Metabolism, Charit
e, Campus Virchow-Klinikum, Humboldt Universit€at zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. e-mail: [email protected]