The value of an acute octreotide suppression test in predicting response to long-term somatostatin analogue therapy in patients with acromegalyTR 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
Correspondence Address: Source of Support: Sun Pharmaceuticals Industries Private Limited provided Octreotide-LAR,, Conflict of Interest: None DOI: 10.4103/0022-3859.62421
Source of Support: Sun Pharmaceuticals Industries Private Limited provided Octreotide-LAR,, Conflict of Interest: None
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.
Keywords: Acromegaly, octreotide suppression test, octreotide test dose, remission prediction, somatostatin analogue
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.
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 <1 ng/ml
Growth hormone was measured by Immulite 2500 which is a solid-phase, two-site chemiluminescent immunometric assay. Standards were calibrated against the World Health Organization (WHO) reference (98/574). Analytical sensitivity was 0.01 ng/ml with inter and intraassay coefficient of variation (CV) of 5.5% and 3.4% respectively. IGF1 was measured with Immulite 1000 solid-phase, enzyme-labeled chemiluminescent immunometric assay. Standards were calibrated against the WHO reference (87/512). Analytical sensitivity was 20 ng/ml with inter and intraassay CV of 6.4% and 3.7% respectively.
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 <1 ng/ml and normal IGF1 for age and sex, four patients (40 %) achieved control at the end of 12 months. Data of 10 responsive and baseline characteristics of controlled and uncontrolled patients are compared in [Table 1] and [Table 2] respectively.
Acute OST results of six unresponsive, four controlled and six uncontrolled patients are shown in [Figure 2],[Figure 3],[Figure 4] respectively. The mean basal GH levels of 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. Nadir GH was achieved in 3-4 h (mean 3.5 h) of OST. Nadir GH <1, <2 and <5 ng/ml was achieved in four, six and seven patients respectively. Mean percentage suppression of GH during OST in 10 responsive, four controlled and six uncontrolled patients was 77.8±15.1, 85±1.9 and 73±18.5ng/ml respectively. During acute OST >50%, >60%, >70% and >80% suppression of GH was seen in 10, eight, seven and five patients respectively.
Using GH cutoff <1 ng/ml, 40% of subjects achieved control at 12 months, while 50% achieved normal IGF1 values. IGF1 and OGTT GH nadir levels at baseline and three-monthly intervals are shown in [Figure 5] and [Figure 6] respectively. All patients reported improvement of symptoms (headache, hyperhidrosis, joint pain and fatigue) with mean 61.48% reduction in symptom score from baseline. Mild abdominal discomfort was reported in 60% of patients which started during the first day of injection and disappeared in the next two to three days.
Baseline, three, six, nine and 12 months nadir GH (OGTT) in 10 responsive patients were 27.7±48.6, 12.7±21.6, 13.3±27.4, 5.0±4.8 and 6.3±7.7 ng/ml respectively while in four controlled patients the corresponding levels were 3.8±2.5, 2.14±0.26, 1.25±0.10, 0.82±0.49 and 0.73±0.28 ng/ml respectively, and in six uncontrolled patients they were 4.6±59.2, 19.8±26.3, 21.5±34.0, 7.9±4.3, 10.1±8.1ng/ml, respectively. At the end of 12 months mean nadir GH showed 77.1±9.4, 81.7±1.94 and 76.8±13.2% suppression from baseline in 10 responsive, four controlled and six uncontrolled patients, respectively [Figure 5].
Baseline, three, six, nine and 12 months IGF1 was 608.4±189.4, 428.6±177.7, 372.7±174.1, 326.5±217.7 and 314.9±160.7 ng/ml respectively in 10 responsive patients while it was 563.±178.6, 402.2±15.6, 303.2±80.7, 167.5±49.71 and 84.2±84.1 ng/ml respectively in four controlled patients and 638.6±206.7, 446.1±236.2, 419.0±210.3, 432.5±223.9 and 402.±139.6 ng/ml respectively in six uncontrolled patients.
Efficacy of OST
Acute OST nadir GH<1 ng/ml had sensitivity, specificity, PPV and NPV of 100% for predicting remission (GH normalization) in our cohort of patients [Table 3]. Nadir GH<1 ng/ml after OST had sensitivity, specificity, positive and negative predictive values of 80, 100, 100 and 83.3% respectively for predicting IGF1 normalization [Table 4]. Basal GH level of acute OST correlated significantly with nadir GH following acute OST (r=0.76, P=0.011), 12-month basal GH (r:0.892, P:0.001) and 12-month IGF1 level (r:0.821, P:0.021). Similarly, percentage GH suppression following OST correlated significantly with GH (r:0.76, P:0.011) and IGF1 level (r:0.95, P:0.00) at 12 months while nadir GH following OST also had significant correlation with GH (r:0.837; P:0.021 and IGF1 level (r:0.961; P:0.00) at 12 months.
We prospectively evaluated the efficacy of an acute OST to predict response to long term OCT-LAR therapy.
The study gives us an insight into the basal GH, percentage GH suppression from baseline and nadir GH level following an acute OST which can effectively predict control or remission with stricter criteria (OGTT nadir GH <1 ng/ml at the end of one year) on long-term treatment in patients who are responsive to short-term octreotide treatment.
Aylwin S  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 < 5 mU/l (2.5 ng/ml) achieved remission.
Basal GH was high in uncontrolled patients in comparison with controlled patients (54.8±74.2 vs. 4.5±1.3 ng/ml). Though the suppression of GH after OST was comparable in both the groups (85±1.9% vs. 73±18.5%), only those with low baseline GH achieved control, stating thereby that the odds for control increase if the baseline GH is low (<5 ng/ml in our cases). Nevertheless all 10 patients in our group showed significant clinical response in the symptom score and GH and IGF1 suppression at the end of 12 months of therapy.
We compared various cutoffs of GH suppression after OST for prediction of remission (GH and/or IGF1 normalization) and found that the specificity and positive predictive value were low. Nadir GH <1 ng/ml following an OST was the most useful predictive marker of achieving disease remission with 100% accuracy.
Prior to therapy with octreotide-LAR, half the patients in the uncontrolled group received RT while none received it in the controlled group. This observation suggests that the biochemical remission was due to octreotide-LAR treatment rather than due to the effect of RT. External RT has been used extensively in the treatment of acromegaly, and most of the studies have documented a predictable but slow reduction in GH excess, which is at its maximum in the first year after treatment (30-50%) and continues at an average rate of 10-15% thereafter in the long term. Therefore, achievement of 'safe' GH concentrations in an acceptable time interval after RT will be achieved only in those patients who have lower GH concentrations prior to irradiation.  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 GH<1 ng/ml after an OST.
With the advent of various newer medical therapies (pegvisomant and somatostatin-dopamine chimeric molecules) for management of acromegaly, we speculate that OST could give us predictive information and those who do not suppress to GH <1 ng/ml after an OST may require early introduction of combination treatment for achieving remission with the stricter GH criteria.
Short-term octreotide therapy has been used to predict response and test tolerability to chronic therapy with SSA. Colao et 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.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3], [Table 4]