Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, phase 3 trial

Gadelha, Mônica R.; Bronstein, Marcello D.; Brue, Thierry; Coculescu, Mihail; Fleseriu, Maria; Guitelman, Mirtha; Pronin, Vyacheslav; Raverot, Gérald; Shimon, Ilan; Lievre, Kayo Kodama; Fleck, Juergen; Aout, Mounir; Pedroncelli, Alberto; Colao, Annamaria

doi:10.1016/s2213-8587(14)70169-x

Cited by 315 publications

(301 citation statements)

References 26 publications

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“…Responsiveness (random GH!1 ng/ml and normal age-matched IGF1), including partial responsiveness (O50% decrease of both GH and IGF1 levels), was assessed after 6 months of continuous treatment. Eleven patients resistant to first generation SSAs have been subsequently treated with pasireotide LAR (40-60 mg/4 weeks) in the setting of clinical trials (8,9) or compassionate use programme. These 11 patients (ten patients from the two clinical trials and one as compassionate use) were treated with pasireotide, while for the other 16 patients alternative treatment choice was made by the patient or the clinician.…”

Section: Patientsmentioning

confidence: 99%

“…Pasireotide is a multireceptor-targeted SSA that binds SSTR1, SSTR2, SSTR3 and SSTR5, with the highest affinity for SSTR5 (7). Pasireotide normalizes IGF1 in a higher proportion of patients compared to first-generation SSAs and in up to 20% of patients who are inadequately controlled on firstgeneration SSAs (8,9). Markers that could predict responsiveness to pasireotide would then be extremely valuable in clinical practice.…”

Section: Introductionmentioning

confidence: 99%

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Factors predicting pasireotide responsiveness in somatotroph pituitary adenomas resistant to first-generation somatostatin analogues: an immunohistochemical study

Iacovazzo

Carlsen²,

Lugli

et al. 2016

European Journal of Endocrinology

127

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Aim: To gather data regarding factors predicting responsiveness to pasireotide in acromegaly. Patients and methods: SSTR2a, SSTR3, SSTR5, AIP, Ki-67 and the adenoma subtype were evaluated in somatotroph adenomas from 39 patients treated post-operatively with somatostatin analogues (SSAs). A standardized SSTR scoring system was applied (scores 0-3). All patients received first-generation SSAs, and 11 resistant patients were subsequently treated with pasireotide LAR. Results: None of the patients with negative or cytoplasmic-only SSTR2a expression (scores 0-1) were responsive to firstgeneration SSAs, as opposed to 20% (score 2) and 50% of patients with a score of 3 (PZ0.04). None of the patients with an SSTR5 score of 0-1 were responsive to pasireotide, as opposed to 5/7 cases with a score of 2 or 3 (PZ0.02). SSTR3 expression did not influence first-generation SSAs or pasireotide responsiveness. Tumours with low AIP were resistant to first-generation SSAs (100 vs 60%; PZ0.02), while they had similar responsiveness to pasireotide compared to tumours with conserved AIP expression (50 vs 40%; PZ0.74). Tumours with low AIP displayed reduced SSTR2 (SSTR2a scores 0-1 44.4 vs 6.7%; PZ0.006) while no difference was seen in SSTR5 (SSTR5 scores 0-1 33.3 vs 23.3%; PZ0.55). Sparsely granulated adenomas responded better to pasireotide compared to densely granulated ones (80 vs 16.7%; PZ0.04). Conclusion: The expression of SSTR5 might predict responsiveness to pasireotide in acromegaly. AIP deficient and sparsely granulated adenomas may benefit from pasireotide treatment. These results need to be confirmed in larger series of pasireotide-treated patients.

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Section: Patientsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Factors predicting pasireotide responsiveness in somatotroph pituitary adenomas resistant to first-generation somatostatin analogues: an immunohistochemical study

Iacovazzo

Carlsen²,

Lugli

et al. 2016

European Journal of Endocrinology

127

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“…Pasireotide proved beneficial in a significant minority of patients uncontrolled by SSA: 15 and 20% of the cases treated with pasireotide LAR 40 and 60 mg, respectively, achieved biochemical control after 24 weeks in a large multicentric study (PAOLA; Gadelha et al 2014).…”

Section: Medical Treatmentmentioning

confidence: 99%

60 YEARS OF NEUROENDOCRINOLOGY: Acromegaly

Căpățînă¹,

Wass²

2015

Journal of Endocrinology

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Acromegaly (ACM) is a chronic, progressive disorder caused by the persistent hypersecretion of GH, in the vast majority of cases secreted by a pituitary adenoma. The consequent increase in IGF1 (a GH-induced liver protein) is responsible for most clinical features and for the systemic complications associated with increased mortality. The clinical diagnosis, based on symptoms related to GH excess or the presence of a pituitary mass, is often delayed many years because of the slow progression of the disease. Initial testing relies on measuring the serum IGF1 concentration. The oral glucose tolerance test with concomitant GH measurement is the gold-standard diagnostic test. The therapeutic options for ACM are surgery, medical treatment, and radiotherapy (RT). The outcome of surgery is very good for microadenomas (80-90% cure rate), but at least half of the macroadenomas (most frequently encountered in ACM patients) are not cured surgically. Somatostatin analogs are mainly indicated after surgical failure. Currently their routine use as primary therapy is not recommended. Dopamine agonists are useful in a minority of cases. Pegvisomant is indicated for patients refractory to surgery and other medical treatments. RT is employed sparingly, in cases of persistent disease activity despite other treatments, due to its long-term side effects. With complex, combined treatment, at least three-quarters of the cases are controlled according to current criteria. With proper control of the disease, the specific complications are partially improved and the mortality rate is close to that of the background population.

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“…Somatostatin analogues are considered the first option of medical treatment in the majority of patients, but prospective randomized studies show control rates of 20-40% for patients with first-generation SA (4,(7)(8)(9)(10)(11). Pasireotide LAR, a next-generation SA (not yet approved for acromegaly treatment in Brazil), allows disease control in a higher percentage of patients and is effective in approximately 15% of those patients not controlled by first-generation SA with the dose of 40 mg and in 20% of the patients with the dose of 60 mg (12,13). The efficacy of cabergoline as monotherapy has not been evaluated in prospective studies, but normalization of IGF-I was reported in 34% of the patients in a meta-analysis of the literature, but can be as low as 10% in more recent studies, therefore, it is reserved for those patients with mildly elevated GH and IGF-I levels (4,(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

Experience with pegvisomant treatment in acromegaly in a single Brazilian tertiary reference center: efficacy, safety and predictors of response

Kasuki

Machado

Ogino

et al. 2016

Arch. Endocrinol. Metab.

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Objective: To describe the safety and efficacy of pegvisomant therapy and the predictors of treatment response in acromegaly patients at a single tertiary reference center in Brazil. Materials and methods: We retrospectively reviewed the clinical, hormonal and radiological data of acromegaly patients treated with pegvisomant in our center. We also evaluated the presence of the d3 isoform of the growth hormone receptor (d3GHR). Results: Twenty-seven patients were included (17 women). Pegvisomant was used in combination with octreotide LAR in 20 patients (74%), in combination with cabergoline in one (4%) and as monotherapy in six (22%). IGF-I normalization was achieved in 23 patients (85%). Mild and transitory elevation of liver enzymes was observed in two patients (7.4%), tumor growth in one (3.4%) and lipodystrophy in two (7.4%). One patient stopped the drug due to headaches. The GHR isoforms were evaluated in 14 patients, and the presence of at least one d3GHR allele was observed in 43% of them, but it was not a predictor of treatment response. Only pretreatment IGF-I level was a predictor of treatment response. Conclusion: Pegvisomant treatment was highly effective and safe in our series of Brazilian patients. A better chance of disease control can be expected in those with lower pre-pegvisomant IGF-I levels. Arch Endocrinol Metab. 2016;60(5):479-85

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Pasireotide versus continued treatment with octreotide or lanreotide in patients with inadequately controlled acromegaly (PAOLA): a randomised, phase 3 trial

Cited by 315 publications

References 26 publications

Factors predicting pasireotide responsiveness in somatotroph pituitary adenomas resistant to first-generation somatostatin analogues: an immunohistochemical study

Factors predicting pasireotide responsiveness in somatotroph pituitary adenomas resistant to first-generation somatostatin analogues: an immunohistochemical study

60 YEARS OF NEUROENDOCRINOLOGY: Acromegaly

Experience with pegvisomant treatment in acromegaly in a single Brazilian tertiary reference center: efficacy, safety and predictors of response

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