The value of an acute octreotide suppression test in predicting response to long-term somatostatin analogue therapy in patients with acromegaly
TR Bandgar, V Sarathi, V Shivane, N Bansode, PS Menon, NS Shah
Department of Endocrinology, Seth G.S. Medical College and K.E.M. Hospital, Mumbai-400 012, India
T R Bandgar
Department of Endocrinology, Seth G.S. Medical College and K.E.M. Hospital, Mumbai-400 012
Context: The usefulness of the acute octreotide test in the selection of patients with acromegaly for chronic somatostatin depot analogues treatment is controversial. Aims: To determine the efficacy of acute octreotide suppression test (OST) in predicting response to long-term somatostatin analogue (Octreotide-long-acting repeatable, OCT-LAR) therapy in patients with acromegaly. Settings and Design: Prospective study (2006-2007) conducted at a tertiary healthcare centre in western India. Materials and Methods: Sixteen drug-naive patients with active acromegaly (postoperative±post radiotherapy) underwent 50 µg subcutaneous OST. Ten patients were treated with OCT-LAR for one year. Remission was defined as a nadir growth hormone (GH) <1 ng/ml during 75 g oral glucose tolerance test (OGTT) (0, 10, 30, 60, 120, 180 min) and normal age, sex-matched insulin-like growth factor 1 (IGF1) levels. Statistical Analysis: SPSS Software Version 11 was used for data analysis. Results: Using GH cutoff <1 ng/ml, four patients (40%) achieved control at 12 months, while five patients (50%) achieved normal IGF1 values. The mean basal GH levels in 10 responsive, four controlled and six uncontrolled patients were 34.7±61.14, 4.5±1.3 and 54.8±74.2 ng/ml respectively which suppressed to mean nadir GH of 3.75±4.03, 0.66±0.15 and 5.8±4 ng/ml respectively. Sensitivity, specificity, negative and positive predictive value for nadir GH <1 ng/ml reached after an OST was 100% each in predicting remission in our cohort. Odds for control increased if the baseline GH was low (<5 ng/ml in our cases). Conclusions: Nadir GH <1 ng/ml following an OST is a useful predictive marker of achieving disease remission with long-term OCT-LAR therapy.
|How to cite this article:|
Bandgar T R, Sarathi V, Shivane V, Bansode N, Menon P S, Shah N S. The value of an acute octreotide suppression test in predicting response to long-term somatostatin analogue therapy in patients with acromegaly.J Postgrad Med 2010;56:7-11
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Bandgar T R, Sarathi V, Shivane V, Bansode N, Menon P S, Shah N S. The value of an acute octreotide suppression test in predicting response to long-term somatostatin analogue therapy in patients with acromegaly. J Postgrad Med [serial online] 2010 [cited 2021 Apr 14 ];56:7-11
Available from: https://www.jpgmonline.com/text.asp?2010/56/1/7/62421
Acromegaly is a debilitating disorder that usually develops over many years due to long-term exposure to growth hormone (GH). Primary therapy of acromegaly is surgical in most cases. However, results are poor with only 12-70% GH normalization rates in macroadenomas.  Postoperative treatment consists of radiotherapy (RT) and/or medical therapy. Somatostatin analogues (SSA) are the mainstay of medical treatment. However, they are very expensive and hence prior identification of patients who will respond to and tolerate chronic therapy with SSA is important. Prior prediction of response and testing tolerability to chronic SSA therapy has gained more importance with the introduction of pegvisomant as a therapeutic agent for acromegaly. Role of acute octreotide suppression test (OST) in predicting response to chronic SSA therapy is controversial. This test was found useful by some authors, ,,, but not by others. ,, Some recommend restricting the use of OST to assess drug tolerance.  Moreover, there is no consensus regarding the criteria that predict response to long-term treatment with SSA. Hence, we undertook a study to assess the value of an acute OST in predicting response to long-term treatment with octreotide long acting repeatable (OCT-LAR) in acromegalic patients.
Materials and Methods
This prospective study was conducted at a tertiary care centre in western India. The study was approved by the institutional ethics committee and written informed consent was obtained from all participants. Drug-naïve patients with active acromegaly (post-surgery and/or post-RT) attending a single referral centre were included in the study. Definition of active acromegaly was based on non-suppression of GH below 1 ng/ml during 75 g oral glucose tolerance test (OGTT) (0, 10, 30, 60, 120, and180 min) and elevated age and sex-matched insulin-like growth factor 1 (IGF1) level.  Patients less than 18 years, pregnant or lactating women, those with deranged liver function tests or with visual field defects except postoperative stable residual defects and those having conditions or on drugs that may result in abnormal GH/IGF1 concentrations were excluded.
Acute OST consisted of injection of octreotide, 50 µg subcutaneous (SC) with measurement of GH levels at 0, 1, 2, 3, 4, 5 and 6 h. After acute OST all patients were continued on 50 µg of octreotide SC tds. On seventh day of treatment, basal IGF1 levels were determined and 75 g OGTT for GH was performed. In patients with uncontrolled GH (nadir >1 ng/ml) and/or high IGF1 level, dose of octreotide was increased to 100 µg thrice daily. Therapy was continued for seven more days. At the end of 15 days similar evaluation (IGF1 and 75 g OGTT for GH) was performed. Mean GH was calculated by mean of one baseline and six OGTT GH levels. Patients with suppression of mean GH levels by more than 50% of the baseline (Day 0) at 15 days were termed responsive. Patients whose mean GH at 15 days did not suppress to > 50% of the basal value were excluded. Responsive patients were treated with OCT-LAR (Sun pharmaceutical industries) 20 mg IM per month for three months which was increased to 30 mg for total 12 months based on monthly OGTT for GH and IGF-1 level. Patients were defined to have remission if OGTT GH nadir was Statistics
Results are reported as the mean±SD. SPSS Software Version 11 was used for data analysis. Sensitivity, specificity, and positive predictive value (PPV) and negative predictive values (NPV) were calculated as follows: sensitivity = true positives/true positives + false negatives; specificity = true negatives/true negatives + false positives; PPV = true positives/true positives + false positives; NPV = true negatives/true negatives + false negatives. Various acute OST criteria were considered for prediction of GH and IGF1 control after 12 months of OCT-LAR therapy: 1) the percent GH suppression value from baseline during acute testing (50%, 60%, 70% and 80%); 2) Nadir GH below 1, 2 and 5 ng/ml.
The study cohort included 16 active acromegaly patients. Ten patients responded to acute OST and were treated with OCT-LAR. Only four treated patients achieved control. Summary of the study protocol is shown in [Figure 1]. Ten responsive patients included seven men and three women with mean age of 39±9.13 years. All patients had macroadenoma and were postoperative with mean duration of 46.3 months (8-118 months) of which three were post-RT with mean duration of 32 months (12-72 months). Other hormonal deficiencies (five-none; four-one; one-two) were replaced adequately. Patients were treated with OCT-LAR for 12 months. Using Nadir GH (OGTT) cutoff 50%, >60%, >70% and >80% suppression of GH was seen in 10, eight, seven and five patients respectively.
Using GH cutoff Efficacy of OST
Acute OST nadir GH  summarized four published series ,,, on acute OST and concluded that a poor response to an acute OST has excellent NPV, with none of the series reporting remission GH levels with SSA alone (without concurrent irradiation) in any patient with an acute OST GH nadir >10 mU/l (5 ng/ml). Among 61 patients from the four series, 87% with an acute OST nadir GH  Patients with high basal GH, who are less likely to achieve remission with SSA therapy alone, are also unlikely to achieve remission with RT in an acceptable timeframe. If debulking surgery is not feasible, combined RT and SSA therapy may be beneficial for them. Radiotherapy may also be considered at the beginning of SSA therapy for those who do not suppress to GHet al., used (300 µg) short-term therapy for one month while Halah et al., used the same dose for 21 days. , Both the studies concluded short-term therapy to be useful in predicting response as well as in testing tolerability. However, we used 150 µg for 15 days. Side-effects of the drug occur mostly during the beginning of therapy.  Hence 15 days of octreotide therapy may be enough to test tolerability. This assumption was also substantiated by our results in which all patients who tolerated the drug for 15 days, did so for the next 12 months. Moreover, in our study, side-effects of the drug lasted for only the initial one to two days of starting therapy. Although it is equally sensitive, GH suppression by ≥50% during an acute OST is less specific when compared to short-term therapy for one month.  Hence we used short-term therapy for 15 days to predict response rather than acute OST.
Recently, Harpin et al., reported a short 2-hr version of 100 µg acute OST to be fully informative for therapeutic decisions in acromegalic patients.  However, in our study nadir GH was achieved at mean duration of 3.4 hr. This discrepancy may be due to lower test dose of octreotide (50 µg) in our study. In our study mean GH at level 2-hr significantly differed from those at 3-4 and 5-hr with no significant difference between mean GH at the latter three time-points.
Our study had three limitations. Firstly, nonresponsive patients were exempted from treatment with SSA and all of them were treated with RT. Hence prediction of response to long-term therapy with SSA by an acute OST was restricted to only responsive patients (>50% OGTT GH suppression) and role of acute OST in nonresponsive patients could not be assessed from the present study. Assessment of acute OST would have been more powerful if all patients had been treated chronically, independent of their response after 15 days of treatment. Secondly, all patients in our study were postoperative and hence our results may not be valid for primary medical treatment with SSA. Thirdly, we used mean of one baseline and six OGTT GH levels as mean GH while standard mean GH is the mean of five basal GH levels (GH day curve).  Since OGTT was a must as per our protocol and due to the inconvenience of doing extra GH levels to calculate mean GH, we assumed mean GH of our study cohort to correlate well with standard mean GH.
Acute OST is a useful test for predicting response to long-term octreotide therapy in acromegalic patients. Acute OST may help in identifying patients who may benefit from early RT or pegvisomant therapy.
|1||Erturk E, Tuncel E, Kiyici S, Ersoy C, Duran C, Imamoglu S. Outcome of surgery for acromegaly performed by different surgeons: Importance of surgical experience. Pituitary 2005;8:93-7.|
|2||Gilbert JA, Miell JP, Chambers SM, McGregor AM, Aylwin SJ. The nadir growth hormone after an octreotide test dose predicts the long-term efficacy of somatostatin analogue therapy in acromegaly. Clin Endocrinol (Oxf) 2005;62:742-7. |
|3||Lindsay JR, McConnell EM, Hunter SJ, McCance DR, Sheridan B, Atkinson AB. Poor responses to a test dose of subcutaneous octreotide predict the need for adjuvant therapy to achieve 'safe' growth hormone levels. Pituitary 2004;7:139-44.|
|4||Biermasz NR, Pereira AM, Smit JW, Romijn JA, Roelfsema F. Intravenous octreotide test predicts the long term outcome of treatment with octreotide-long-acting repeatable in active acromegaly. Growth Horm IGF Res 2005;15:200-6.|
|5||Halperin I, Nicolau J, Casamitjana R, Sesmilo G, Serra-Prat M, Palomera E, et al. A short acute octreotide test for response prediction of long-term treatment with somatostatin analogues in acromegalic patients. Horm Metab Res 2008;40:422-6.|
|6||Colao A, Ferone D, Lastoria S, Marzullo P, Cerbone G, Di Sarno A, et al. Prediction of efficacy of octreotide therapy in patients with acromegaly. J Clin Endocrinol Metab 1996;81:2356-62.|
|7||de Herder WW, Taal HR, Uitterlinden P, Feelders RA, Janssen JA, van der Lely AJ. Limited predictive value of an acute test with subcutaneous octreotide for long-term IGF-I normalization with Sandostatin LAR in acromegaly. Eur J Endocrinol 2005;153:67-71.|
|8||Pokrajac A, Claridge AG, Shakoor SK, Trainer PJ. The octreotide test dose is not a reliable predictor of subsequent response to somatostatin analogue therapy in patients with acromegaly. Eur J Endocrinol 2006;154:267-74.|
|9||Melmed S, Casanueva FF, Cavagnini F, Chanson P, Frohman L, Grossman A, et al. Acromegaly Treatment Consensus Workshop Participants: Guidelines for acromegaly management. J Clin Endocrinol Metab 2002;87:4054-8.|
|10||Aylwin S. Inadequate growth hormone (GH) suppression following an octreotide test dose predicts the need for adjuvant therapy to achieve 'safe' GH levels. Clin Endocrinol (Oxf) 2006;65:133.|
|11||Karavitaki N, Botusan I, Radian S, Coculescu M, Turner HE, Wass JA. The value of an octreotide suppression test in predicting long-term responses to depot somatostatin analogues in patients with active acromegaly. Clin Endocrinol (Oxf) 2005;62:282-8.|
|12||Monson JP. Is there still a role for radiotherapy in acromegaly? Neuroendocrinology 2006;83:269-73.|
|13||Halah FP, Elias LL, Martinelli CE Jr, Castro M, Moreira AC. Usefulness of subcutaneous or long-acting octreotide as a predictive test and in the treatment of acromegaly. Arq Bras Endocrinol Metabol 2004;48:245-52.|
|14||Kaltsas GA, Isidori AM, Florakis D, Trainer PJ, Camacho-Hubner C, Afshar F, et al. Predictors of the outcome of surgical treatment in acromegaly and the value of the mean growth hormone day curve in assessing postoperative disease activity. J Clin Endocrinol Metab 2001;86:1645-52.|