Pasireotide and Pegvisomant Combination Treatment in Acromegaly Resistant to Second-Line Therapies

A Longitudinal Study

Sabrina Chiloiro; Chiara Bima; Tommaso Tartaglione; Antonella Giampietro; Marco Gessi; Liverana Lauretti; Carmelo Anile; Cesare Colosimo; Guido Rindi; Alfredo Pontecorvi; Laura De Marinis; Antonio Bianchi

Disclosures

J Clin Endocrinol Metab. 2019;104(11):5478-5482. 

In This Article

Results

The clinical features of the six patients of the study population are summarized in Table 2. The patient data were collected from October 2004 to November 2018. Most of the patients had undergone first-line treatment with pituitary neurosurgery (Figure 1). For patient d, after a multidisciplinary evaluation, pituitary neurosurgery was considered contraindicated owing to technical difficulties with intubation and the induction of anesthesia, because the patient was affected by severe scoliosis. Pituitary neurosurgery had resulted in a subtotal resection in all six patients, because the pituitary adenoma had invaded the cavernous sinus. In patients c and d, the tumors had also extended to the third ventricle.

Figure 1.

Trend of IGF-I stratified by the treatment of each patient. The transparent gray area represents the range of physiological values of IGF-I adjusted for age. Acromegaly was defined as controlled if the IGF-I values were in the reference range for age and, in patients receiving somatostatin receptor ligands, the random GH level was <1.0 ng/mL.

The histological examinations of the pituitary adenomas showed positive immunohistochemistry forGHin all six cases and also for prolactin in patients b, c, and e. Positive p53 expression was found in patients a, b, and f. The Ki-67 labeling index reached 2% in patients b and c, 3% in patients a and e, and 7% in patient f.

Because of the subtotal resection of the pituitary adenomas and the persistence of GH and IGF-1 hypersecretion, all the patients had received medical treatment with conventional SSAs. Complete resistance to conventional SSAs had developed in all six patients. Consequently, the patients were treated with second-line drugs, including combination therapy with conventional SSAs and pegvisomant for patients b, c and d) and pasireotide for patients a, c, e, and f. When possible, the expression of the somatostatin receptors (SSTRs) was evaluated according to the system reported by Volante et al..[7] In patients a and f, the SSTR subtypes 2A and 5 were detected (SSTR2A and SSTR5, respectively). In patients c and e, only SSTR5 was identified.

A second pituitary surgery was performed when tumor debulking was possible, such as in patients a, c, and e. After failure of all other treatments, biochemical control of acromegaly was reached in all six patients through combination therapy with pasireotide and pegvisomant. This therapeutic approach was efficacious and safe. Regrowth of the residual pituitary adenoma never occurred, and a reduction of the residual lesion was detected in one patient (Figure 2). Moreover, a worsening of the glucidic metabolism occurred in one patient with diabetes mellitus (patient b), and new-onset impaired glucose tolerance occurred in patient f. These events improved with the adjustment of previous insulin therapy for patient b and the prescription of a hypocaloric hypoglucidic diet for patient f (Figure 1). A significantly greater percentage of the patients in the study group had had a giant somatotropic pituitary adenoma that had invaded the cavernous sinus and other neighboring structures, such as the third ventricle, clivus, and prepontine cistern.

Figure 2.

Magnetic resonance images of pituitary adenoma in patient a (a) before and (b) 2 y after the start of the combined pasireotide plus pegvisomant treatment showing a substantial reduction in the tumor mass.

The tumor dimensions and invasive nature of the somatotropic pituitary adenomas represent the main determinants of the benefit of the combination therapy with pasireotide and pegvisomant compared with the other treatments. Although not statistically significant (statistical power of the tests was <0.8), greater GH expression at the diagnosis of acromegaly and more elevated Ki-67 were detected in the study population (Table 2). Moreover, we found greater expression of SSTR2 in the pituitary adenoma of patients with acromegaly responsive to conventional SSAs and greater expression of SSTR5 in the pituitary adenoma of patients with acromegaly responsive to pasireotide alone or combined with pegvisomant.

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