W M Drake, A B Grossman and R K Hutson
V J Moyes, K A Metcalfe and W M Drake
Cabergoline is a dopamine agonist that may be used as primary or adjunctive therapy for acromegaly. Although one study suggested biochemical control may be achieved in a substantial proportion of patients, it is still commonly perceived to be a relatively ineffective treatment.
Design and method
A prospective audit was performed of 15 consecutive acromegalic patients (eight males, seven females, median age 55, range 31–92 at presentation) treated with cabergoline to determine the effective dose and tolerability. All had normal anterior pituitary function; two patients had hyperprolactinaemia. Magnetic resonance imaging revealed nine adenomata, two partially empty sellae and four structurally normal pituitary glands. Nine patients had undergone transsphenoidal surgery 1–12 months, and one patient had received pituitary radiotherapy 18 years, prior to commencement of cabergoline. All patients had biochemical GH excess; median serum IGF1 471 ng/ml, range 239–746 ng/ml. The calculated mean of a series of GH measurements ranged from 2.7–45.8 mIU/l, median 9.7 mIU/l.
On a median weekly dose of cabergoline of 1.75 mg (range 0.5–7 mg) normalisation of both IGF1 and GH occurred in 4 out of the 15 patients (27%). Out of the 15 patients (33%), 5 achieved a serum IGF1 within the reference range with notable reductions seen in a further five patients. Nine patients (60%) achieved a mean serum GH level of less than 5 mIU/l. Duration of treatment was 2–52 months and was well tolerated in 14 patients.
Cabergoline can be an effective and well tolerated primary or adjunctive therapy for acromegaly and useful clinical responses are noted even with modest doses.
C E Higham, J D J Thomas, M Bidlingmaier, W M Drake and P J Trainer
Clinical trials using 80 mg once weekly pegvisomant (pegV) in active acromegaly led to a 30% fall in serum IGF1. Subsequent studies demonstrated that daily administration of up to 40 mg/day achieved an IGF1 within reference range in 97% of patients. PegV has a half-life of >70 h suggesting weekly dosing may be possible but using higher doses than in the initial trials.
To determine the efficacy of weekly dosing of pegV.
A two center, open-label prospective study in patients with acromegaly converted from a stable daily dose of pegV (median dose 15 mg daily (range 10–20 mg od), IGF1 normal for 3 months prior to inclusion) to twice-weekly (week 0–16) followed by once-weekly (week 16–32) administration.
Seven patients (4M, age 57±7 years, 6/7 prior transsphenoidal surgery, 7/7 prior radiotherapy) were recruited. Six patients completed the twice-weekly and five patients both the twice-weekly and once-weekly administration. Headaches led to two patient withdrawals at 0+24 weeks. Mean pre-dose serum IGF1 levels remained stable with the different administration regimens (IGF1 baseline 145±39 ng/ml, twice-weekly 124±39 ng/ml and once-weekly 127±22 ng/ml) and all values were within age adjusted IGF1 reference range. PegV dose was reduced in two patients and five opted to continue weekly administration at trial termination. Safety and quality of life parameters remained stable.
Twice and once-weekly administration of pegV is effective in controlling serum IGF1 levels in acromegaly and although not formally assessed, continuation of weekly dosing in five patients at study conclusion suggests patient preference for this regimen.
W M Drake, D M Berney, K Kovacs and J P Monson
We report our findings on markers of cell proliferation (Ki-67 labelling index and topoisomerase-α expression) in a somatotroph pituitary tumour before and after exposure to pegvisomant, a GH receptor antagonist developed for the treatment of acromegaly. Specimens from two separate pituitary operations, separated by a period of 17 years that included 4 years of pegvisomant treatment, were stained for markers of cellular proliferation. Ki-67 labelling index and topoisomerase-α expression were both markedly greater (1–3% compared with 0–0.5% and 15–80% compared with 2–10% respectively) in the pegvisomant-exposed tumour compared with the earlier specimen. Clearly, caution must be exercised when interpreting findings from a single case, particularly one sufficiently refractory to conventional therapies to require treatment with pegvisomant. However, our data reinforce the requirement for careful radiological surveillance of the pituitary in the context of a drug that does not target the tumour responsible and where serum GH cannot serve as a marker of disease activity or tumour size.
W M Drake, R A Loureiro, C Parkinson, J P Monson, G M Besser and P J Trainer
Objective: Pegvisomant, a modified growth hormone (GH) molecule, is a novel medical therapy for acromegaly that functions as a GH receptor antagonist. Serum GH cannot be used as a marker of disease activity in patients taking this form of therapy, partly because GH levels rise on pegvisomant and partly because the drug cross-reacts with many routine GH assays. The purpose of this study was to assess the time for which it is necessary to discontinue pegvisomant prior to biochemical reassessment of acromegaly.
Design and methods: This was a retrospective study of 13 patients (seven male, median age 61 years, range 43–77) enrolled in two separate, open-label studies of the efficacy and tolerability of pegvisomant in the treatment of acromegaly. All had been taking a stable dose of pegvisomant (median dose 15 mg daily, range 10–30) as monotherapy for at least 3 months before discontinuing the drug. After discontinuation of pegvisomant, serum IGF-I was measured at 0, 2, 4, 6 and 8 weeks in all patients. Serum GH (single sample) was measured in nine patients at 2, 4, 6 and 8 weeks, but not at baseline on account of the cross-reactivity of pegvisomant with the GH assay.
Results: Mean serum IGF-I rose from 210±105 ng/ml (s.d.) at baseline to 392±175 ng/ml at 2 weeks after discontinuation of pegvisomant (P < 0.0001). Although there was no statistically significant change in mean serum IGF-I beyond 2 weeks (412±181, 392±152 and 399±150 ng/ml at 4, 6 and 8 weeks respectively; P = 0.13 (2 vs 4 weeks), 0.31 (4 vs 6 weeks) and 0.46 (6 vs 8 weeks), serum IGF-I rose by more than twice the interassay coefficient of variation (CV) in two of the 13 patients between weeks 2 and 4. The standard deviation of the difference in serum IGF-I between time points was calculated. The values declined from 118% (weeks 0–2) 17%, 19.7% and 10% (weeks 2–4, 4–6 and 6–8 respectively). The expected measure if there was no systematic change in base would be 15% (1.4 ×interassay CV). Mean serum GH was virtually unchanged at 2–8 weeks after cessation of pegvisomant therapy.
Conclusions: These results suggest that the activity of acromegaly may be assessed by serum IGF-I levels 6 weeks after the discontinuation of pegvisomant.
K Nadarasa, A Theodoraki, T R Kurzawinski, R Carpenter, J Bull, T T Chung and W M Drake
F M Swords, J P Monson, G M Besser, S L Chew, W M Drake, A B Grossman and P N Plowman
We report the use of ‘gamma knife’ (GK) radiosurgery in 25 patients with pituitary adenomas not cured despite conventional therapy, including external beam radiotherapy.
Patients and methods
All patients had previously received conventional radiotherapy for a mean of 11.8 years prior to receiving GK; 23 out of 25 had also undergone pituitary surgery on at least one occasion. Seventeen had hyperfunctioning adenomas that still required medical therapy without an adequate biochemical control – ten somatotroph adenomas, six corticotroph adenomas and one prolactinoma, while eight patients had non-functioning pituitary adenomas (NFPAs).
Following GK, mean GH fell by 49% at 1 year in patients with somatotroph tumours. Serum IGF1 fell by 32% at 1 year and by 38% at 2 years. To date, 80% of the patients with acromegaly have achieved normalisation of IGF1, and 30% have also achieved a mean GH level of <1.8 ng/ml correlating with normalised mortality. A total of 75% NFPAs showed disease stabilisation or shrinkage post GK. The patient with a prolactinoma showed a dramatic response: 75% reduction in prolactin at 2 years, with a marked shrinkage on magnetic resonance imaging. The results in corticotroph adenomas were variable. Prior to GK, 72% of the patients were panhypopituitary, and 42% of the remainder have developed new anterior pituitary hormone deficiencies to date. No other adverse events have been detected at a mean follow-up of 36.4 months.
These data indicate that GK is a safe and effective adjunctive treatment for patients with NFPAs and acromegaly not satisfactorily controlled with surgery and radiotherapy.
V J Moyes, G Alusi, H I Sabin, J Evanson, D M Berney, K Kovacs, J P Monson, P N Plowman and W M Drake
A 64-year-old woman was previously treated for Cushing's disease with trans-sphenoidal surgery, external beam radiotherapy and bilateral adrenalectomy. Progression of an aggressive corticotroph adenoma was evident 3 years post-adrenalectomy; involvement of the clivus was treated with surgery and gamma knife radiosurgery. Tumour spread through the skull base, occiput and left ear with persistent facial pain and left ear discharge; progression continued despite second gamma knife treatment. ACTH levels peaked at 2472 and 2265 pmol/l pre- and post-hydrocortisone respectively. Treatment with temozolomide resulted in a significant improvement in symptoms, a reduction of plasma ACTH to 389 pmol/l and regression of tumour on magnetic resonance imaging scan after four cycles of treatment. We propose that temozolomide is an effective and well-tolerated therapeutic tool for the treatment of Nelson's syndrome and a useful addition to the range of therapies available to treat this condition.
T T L L Chung, W M Drake, P N Plowman, K Metcalfe, A B Grossman, S A Akker, S L Chew, G M Besser, D M Walker, M Koltowska-Haggstrom, P Wilton, A F Mattsson and J P Monson
D Dworakowska, M Gueorguiev, P Kelly, J P Monson, G M Besser, S L Chew, S A Akker, W M Drake, P D Fairclough, A B Grossman and P J Jenkins
It is suggested that patients with acromegaly have an increased risk of colorectal cancer and pre-malignant adenomatous polyps. However, the optimum frequency with which colonoscopic screening should be offered remains unclear.
To determine the optimum frequency for repeated colonoscopic surveillance of acromegalic patients.
We retrospectively reviewed the case records of all patients with acromegaly seen in our centre since 1992: 254 patients had at least one surveillance colonoscopy, 156 patients had a second surveillance colonoscopy, 60 patients had a third surveillance colonoscopy and 15 patients had a fourth surveillance colonoscopy.
The presence of hyperplastic or adenomatous polyps was assessed in all patients, while one cancer was detected at the second surveillance. At the third surveillance, mean (±s.d.) serum IGF1 levels (ng/ml) in patients with hyperplastic polyps were significantly higher than those with normal colons (P<0.05). The presence of an adenoma rather than a normal colon at the first colonoscopy was associated with a significantly increased risk of adenoma at the second (odds ratio (OR) 4.4, 95% confidence interval (CI) 1.9–10.4) and at the third (OR 8.8, 95% CI 2.9–26.5) screens. Conversely, a normal colon at the first surveillance gave a high chance of normal findings at the second (78%) or third surveillance (78%), and a normal colon at the second colonoscopy was associated with normality at the third colonoscopy (81%).
Repeated colonoscopic screening of patients with acromegaly demonstrated a high prevalence of new adenomatous and hyperplastic colonic polyps, dependent on both the occurrence of previous polyps and elevated IGF1 levels.