Title: Shrinkage of pituitary adenomas with pasireotide – Authors' reply
Abstract: We thank Adrian F Daly and colleagues for their comments on our Correspondence1Coopmans EC van der Lely AJ Schneiders JJ Neggers S Potential antitumour activity of pasireotide on pituitary tumours in acromegaly.Lancet Diabetes Endocrinol. 2019; 7: 425-426Summary Full Text Full Text PDF PubMed Scopus (14) Google Scholar and appreciate the opportunity to further discuss our proposed antitumour activity of pasireotide long-acting release (PAS-LAR) on pituitary tumours in acromegaly. Daly and colleagues raise the point that although increased T2-weighted signal intensity (T2WSI) was associated with improved hormonal control, a significant decrease in tumour volume did not occur with nine months of PAS-LAR treatment. This could call into question the existence of the suggested antitumour effect of PAS-LAR. We agree with Daly and colleagues that besides T2WSI, there are more relevant ways to assess an antitumour effect of PAS-LAR. We believe, however, that it is necessary to differentiate tumour shrinkage from cystic degeneration or tumour cell necrosis. It has been reported that PAS-LAR shows similar inhibitory effects on the growth of cultured tumour specimens compared with first-generation somatostatin receptor ligands.2Ibanez-Costa A Rivero-Cortes E Vazquez-Borrego MC et al.Octreotide and pasireotide (dis)similarly inhibit pituitary tumor cells in vitro.J Endocrinol. 2016; 231: 135-145Crossref PubMed Scopus (53) Google Scholar Additionally, PAS-LAR seems to have an antitumour effect (cystic degeneration or tumour cell necrosis)1Coopmans EC van der Lely AJ Schneiders JJ Neggers S Potential antitumour activity of pasireotide on pituitary tumours in acromegaly.Lancet Diabetes Endocrinol. 2019; 7: 425-426Summary Full Text Full Text PDF PubMed Scopus (14) Google Scholar that has not been observed with first-generation somatostatin receptor ligands. The potential antitumour activity of PAS-LAR emerged when we observed a change in mean T2WSI ratio and a 3-fold higher incidence of T2-hyperintense adenomas in our cohort, compared with patients receiving first-generation somatostatin receptor ligands.1Coopmans EC van der Lely AJ Schneiders JJ Neggers S Potential antitumour activity of pasireotide on pituitary tumours in acromegaly.Lancet Diabetes Endocrinol. 2019; 7: 425-426Summary Full Text Full Text PDF PubMed Scopus (14) Google Scholar Of note, apart from hormonal control we did observe and report clinically significant (≥25%) tumour shrinkage in 5 of the 14 patients with adenomas in which we observed increased T2WSI during the first nine months of PAS-LAR treatment. Furthermore, not all patients with increased T2WSI adenomas during PAS-LAR treatment had a T2-hyperintense adenoma at baseline (of 14 adenomas, 7 adenomas had hyperintensity, 4 adenomas had T2-hypointensity, and 3 adenomas had T2-isointensity). In the two patients with acromegaly due to AIP germline mutations reported by Daly and colleagues,3Daly A Rostomyan L Betea D et al.AIP-mutated acromegaly resistant to first-generation somatostatin analogs: long-term control with pasireotide LAR in two patients.Endocr Connect. 2019; 8: 367-377Crossref PubMed Scopus (31) Google Scholar treatment with PAS-LAR induced clinically significant tumour shrinkage in the adenoma of one patient (after at least 24 months of treatment) and a regression of the tumour remnant in the other (after 60 months of treatment). We tested nine (19%) of the 47 patients in our cohort for germline AIP mutations, but none were detected. Therefore, the available data are insufficient to draw any firm conclusions about the relationship between the observed increased T2WSI and the potential antitumour activity of PAS-LAR. In other reports of treatment-naive patients,4Yamamoto R Robert Shima K Igawa H et al.Impact of preoperative pasireotide therapy on invasive octreotide-resistant acromegaly.Endocr J. 2018; 65: 1061-1067Crossref PubMed Scopus (7) Google Scholar, 5Chiloiro S Giampietro A Bianchi A et al.Acromegaly can be cured by first-line pasireotide treatment?.Endocrine. 2019; 64: 196-199Crossref PubMed Scopus (7) Google Scholar clinically significant tumour shrinkage was observed in one patient after about 12 months of PAS-LAR treatment, and substantial tumour shrinkage in the other after 3 months of PAS-LAR treatment. However, comparison of patients in previous reports3Daly A Rostomyan L Betea D et al.AIP-mutated acromegaly resistant to first-generation somatostatin analogs: long-term control with pasireotide LAR in two patients.Endocr Connect. 2019; 8: 367-377Crossref PubMed Scopus (31) Google Scholar, 4Yamamoto R Robert Shima K Igawa H et al.Impact of preoperative pasireotide therapy on invasive octreotide-resistant acromegaly.Endocr J. 2018; 65: 1061-1067Crossref PubMed Scopus (7) Google Scholar, 5Chiloiro S Giampietro A Bianchi A et al.Acromegaly can be cured by first-line pasireotide treatment?.Endocrine. 2019; 64: 196-199Crossref PubMed Scopus (7) Google Scholar with our cohort might be challenging; no T2WSI data was collected or observed and the two patients reported by Yamamoto and colleagues4Yamamoto R Robert Shima K Igawa H et al.Impact of preoperative pasireotide therapy on invasive octreotide-resistant acromegaly.Endocr J. 2018; 65: 1061-1067Crossref PubMed Scopus (7) Google Scholar and Chiloiro and colleagues5Chiloiro S Giampietro A Bianchi A et al.Acromegaly can be cured by first-line pasireotide treatment?.Endocrine. 2019; 64: 196-199Crossref PubMed Scopus (7) Google Scholar are treatment-naive patients, while our cohort as well as the patients reported by Daly and colleagues3Daly A Rostomyan L Betea D et al.AIP-mutated acromegaly resistant to first-generation somatostatin analogs: long-term control with pasireotide LAR in two patients.Endocr Connect. 2019; 8: 367-377Crossref PubMed Scopus (31) Google Scholar partially responded to first-generation somatostatin receptor ligands. The patient with maintained regression of tumour remnant3Daly A Rostomyan L Betea D et al.AIP-mutated acromegaly resistant to first-generation somatostatin analogs: long-term control with pasireotide LAR in two patients.Endocr Connect. 2019; 8: 367-377Crossref PubMed Scopus (31) Google Scholar after 18 months off PAS-LAR treatment might provide some evidence to support PAS-LAR antitumour activity. We have not yet published data on tumour shrinkage after long-term PAS-LAR treatment in our cohort. Post-study MRIs were assessed in 10 of the 14 patients; interestingly, an additional decrease in tumour volume was observed in the adenomas of five patients (mean tumour volume was 2·9 cm3 [SD 3·0] at baseline, 2·3 cm3 [2·2] after 9 months of PAS-LAR, and 1·9 cm3 [10·0] after 30·3 months of PAS-LAR). We will obtain more conclusive data in the next few years. We agree with Daly and colleagues that additional pituitary histology is needed to confirm whether cystic degeneration, tumour cell necrosis, or both leads to increased T2WSI. Moreover, the identification of genetic, molecular, and clinical characteristics associated with the effects of PAS-LAR will improve clinical practice. AJvdL is a consultant for Pfizer, and has received speaker fees from Novartis, Ipsen, and Pfizer. SJCMMN has received research grants and speaker fees from Ipsen, Novartis, and Pfizer, and consulting fees from Ipsen. ECC and JJS have nothing to disclose. Shrinkage of pituitary adenomas with pasireotideThe value of T2-weighted signal intensity (T2WSI) of pituitary tumours on MRI in predicting tumour characteristics and response to somatostatin analogues is receiving increasing attention.1,2 We read with interest the recent Correspondence in The Lancet Diabetes & Endocrinology by Eva C Coopmans and colleagues3 regarding pasireotide long-acting release (PAS-LAR) treatment in patients with acromegaly and the relationship between increased T2WSI on MRI and stronger reductions in insulin-like growth factor-1 (IGF-1) concentrations. Full-Text PDF Potential antitumour activity of pasireotide on pituitary tumours in acromegalyPasireotide long-acting release (PAS-LAR) is a second-generation somatostatin multireceptor ligand for the treatment of acromegaly. Previous studies indicate that PAS-LAR can achieve control of growth hormone (somatotropin) and insulin-like growth factor I (IGF-1) concentrations, and might reduce tumour size in patients uncontrolled with first-generation somatostatin receptor ligands.1,2 Full-Text PDF