O R I G I N A L A R T I C L E
ACROSTUDY: the Italian experience
S. Grottoli• P. Maffei•F. Bogazzi•S. Cannavo` •A. Colao• E. Ghigo•R. Gomez• E. Graziano•
M. Monterubbianesi•P. Jonsson •L. De Marinis
Received: 3 March 2014 / Accepted: 11 August 2014 / Published online: 23 August 2014 Ó Springer Science+Business Media New York 2014
Abstract ACROSTUDY is a world-wide non-interven-tional, post marketing surveillance study performed to monitor the safety and outcomes of pegvisomant (PEG) in clinical practice. We report data from acromegaly patients who have been included in the Italian ACROSTUDY registry. The data of 341 acromegaly patients (171 males) were available for analysis using data freeze (12/9/2012). Patients were enrolled in 25 Italian endocrine centres. Before and during PEG treatment IGF-I, liver enzymes, metabolic parameters, and pituitary MRI were assessed. Before PEG, 54.3 % patients had been treated with medical therapy and surgery, 22.9 % medical therapy only, and 15.8 % medical plus radiation and surgical therapy. 199 adverse events were reported in 98 patients (28.7 %).
Serious adverse events were documented in 29 patients (8.5 %). 71.1 % of patients had no significant change in tumor volume. Central MRI reading was performed in 34 patients; in 7 patients, an increase in tumor volume was found. Hormonal efficacy progressively increased since the start of PEG. After 6 years, normal IGF-I levels were found in 70.9 % of patients (mean daily dose 18.1 mg). 87.1 % of patients were treated with daily PEG although in 8.8 % of patients, it was administered 2–6 times per week and in 3.8 % with weekly injections. 74.8 % received a PEG dose 10–15 mg/daily. PEG is a drug with a favorable safety profile which is efficacious also considering that in Italy it is currently available as third-line therapy.
Keywords Acromegaly Italy Pegvisomant Efficacy Safety
On behalf of Italian ACROSTUDY Group. The members of Italian ACROSTUDY Group are given inAppendix.
Dr. Grottoli and Dr. Maffei equally contributed to this work. S. Grottoli (&) E. Ghigo
Divisione di Endocrinologia, Diabetologia e Metabolismo, Dipartimento di Scienze Mediche, AO Citta` della Salute e della Scienza di Torino, Universita` di Torino, C.so AM Dogliotti 14, 10126 Turin, Italy
e-mail: ninagro@yahoo.it P. Maffei
Dipartimento di Medicina, Azienda Ospedaliera di Padova, Padova, Italy
F. Bogazzi
Sezione di Endocrinologia, Dipartimento di Medicina Clinica e Sperimentale, Universita` di Pisa, Pisa, Italy
S. Cannavo`
Dipartimento di Medicina Clinica e Sperimentale, Universita` di Messina, Messina, Italy
A. Colao
Sezione di Endocrinologia, Dipartimento di Medicina Clinica e Chirurgia, Universita` Federico II di Napoli, Napoli, Italy R. Gomez
Pfizer European Medical Affairs, Puurs, Belgium E. Graziano M. Monterubbianesi
Department Endocrinology, Pfizer Italia Medical, Rome, Italy P. Jonsson
Pfizer Endocrine Care, Pfizer Inc, Sollentuna, Sweden L. De Marinis
UOS Patologia ipofisaria Istituto di Patologia Medica, Policlinico Universitario A. Gemelli, Roma, Italy DOI 10.1007/s12020-014-0393-9
Introduction
Acromegaly patients’ morbidity and mortality can be restored to normal with adequate therapy and normaliza-tion of GH and IGF-I levels [1]. Many acromegaly patients have to be treated with a combination of medical, surgical, and radiation treatments before achieving the disease control and amelioration of systemic complications [2,3]. Pegvisomant (PEG) is a recombinant-derived analog of human GH that acts as a GH antagonist of liver GH receptors and induces a dose-dependent reduction of IGF-I levels [4,5]. Pegvisomant is actually considered among the most effective therapies for acromegaly also for those patients who have not achieved a biochemical control of the disease or are resistant to somatostatin analogs (SSA) [6–8]. Efficacy was demonstrated in clinical trials which reported that approximately 90 % of patients with acro-megaly treated with optimally titrated levels of pegviso-mant normalized their IGF-I levels and ameliorated quality of life (QoL) without significant adverse events [9, 10]. Pegvisomant does not seem to have a direct effect on pituitary mass [11–13].
Pegvisomant was approved in Europe in 2004. At that time, considering the limited information on the effects of pegvisomant used in clinical practice, a long-term sur-veillance study on safety and treatment outcomes was established namely the German Pegvisomant Observational Study (GPOS).The objective of this study was to monitor long-term effects of pegvisomant in clinical practice; results from different interim analyses were reassuring both in terms of safety and treatment outcomes [11, 14]. In 2004, ACROSTUDY was initiated as an on-going global non-interventional postmarketing safety surveillance study open to patients who are treated with or about to begin pegvisomant treatment with the main objective to monitor the long-term safety and outcome of this drug in medical practice. To our knowledge, it is the only active world-wide registry for acromegaly.
Recently, an interim analysis of ACROSTUDY data was reported confirming GPOS earlier safety data [11,13,14]. In these surveillance studies, efficacy of Pegvisomant seems to be reduced in comparison to clinical trials. Since ACROSTUDY was designed as a safety study and not as an efficacy study, these efficacy data likely reflect real clinical practice, with dosing and optimization of dosing based on the treating physician’s discretion. In terms of safety, no significant differences were observed [13,15].
Treatment practice differences in the management of acromegaly have to be considered according to both national and international guidelines in addition to standard of care and differences in availability of health system services such as neurosurgery and radiotherapy besides access to a range of medications. Furthermore, in clinical
practice, the endocrinologists may work independently with their own patients [16]. In terms of safety, the popu-lation genetic background has also to be considered. As an example, recent studies have reported on the possible dif-ference in efficacy or safety of pegvisomant in relation to the polymorphism of liver GH receptors or pegvisomant-induced liver injury according to the UGT1A1*28 poly-morphism of Gilbert’s syndrome [17]. Although the GPOS allowed exploration of pegvisomant treatment practice in German acromegaly patients, the global ACROSTUDY has not yet fully accounted for country differences. Therefore, national and regional data may increase our understanding in order to improve treatment practices.
We report, for the first time, a detailed analysis from 341 acromegaly patients who have been included in the Italian ACROSTUDY registry. The data presented include a new group of 156 acromegaly patients not included in previous reports and with a longer follow-up. Clinical practice with pegvisomant in the Italian population including safety and treatment outcomes has been investigated.
Patients and methods
ACROSTUDY is an open-label, non-interventional, post marketing surveillance study performed to monitor the long-term safety and outcomes of pegvisomant treatment in clinical practice. All information collected for each patient was based on the standard of care at the respective clinic. Treatment dose and schedule and timing of assessments were at the discretion of each treating investigator.
The study was conducted in compliance with the Dec-laration of Helsinki. Before the start of the study, every Italian centre obtained approval of the local Institutional Review Board or Independent Ethics Committee. Written informed consent from participating subjects was obtained prior to enrollment into the study.
ACROSTUDY is open to patients with acromegaly who are already being treated with pegvisomant or those who are planning to start treatment with pegvisomant. Exclusion criteria to enter into the study included patients who require surgery to decompress the tumor or who should have nonmedical therapy because of visual field loss related to a tumor in contact with the optic chiasm, patients with cra-nial nerve palsies or intracracra-nial hypertension and women who are pregnant or lactating.
The following information was collected using elec-tronic web-based Case Report Forms (eCRF): date of informed consent, data on the diagnosis of acromegaly, pituitary function and hormone replacement therapy, pitu-itary imaging studies, physical examination (including height, weight, blood pressure), symptoms of acromegaly during the study recorded using a patient-assessment
acromegaly symptoms questionnaire (PASQ), visual fields, previous and current therapy for acromegaly, concomitant medications and laboratory assessment including IGF-I levels, liver function tests (ALT, AST), fasting blood glu-cose and HbA1c (for patients with diabetes mellitus only), adverse events, and acromegaly related co-morbidities. Furthermore, the following minimum evaluations were recommended: (1) pituitary imaging studies at baseline (i.e., the start of pegvisomant therapy), 6 and 12 months post-pegvisomant treatment start, and then annually; (2) liver function tests; and (3) IGF-I: at baseline, 1 and 3 months after dose titration, after 6 months of pegviso-mant treatment and every 6 months thereafter. Biochemical evaluations were performed locally, and assay methods as well as normal range levels were reported. MRI was per-formed locally, and a blinded central reading was requested if a significant change in the tumor volume was reported locally.
Statistical analysis
Statistical analyses were performed using the Statistical Analysis System 9.2 (SAS Institute, Inc., Cary, NC). Comparisons of proportions were analyzed using the Fisher’s exact test or the v2test as appropriate. Data are expressed as mean ± SD (range) unless otherwise speci-fied. Student’s t test was used for normally distributed variables; otherwise Wilcoxon Rank Sum test was used. Correlations were determined using Spearman’s Correla-tion Coefficient. Significance was accepted at p B 0.05.
Results
Patient population
The data of 341 acromegaly patients (171 males) were available for analysis using data freeze (12 September 2012). At that time, 283 patients were still active in ACROSTUDY, 7 patients were nonactive, 39 patients have dropped out, and 12 patients have deceased. The reasons for exit from ACRO-STUDY were lost to follow-up in 9 cases, discontinuation of pegvisomant therapy in 29 cases, and for unspecified reasons in 1 case. Patients were enrolled in 25 Italian endocrine centres (mean of 13.6 patient per site; range 3–45 patients per site). Sixty percent of patients were enrolled in 6 sites. The majority of the acromegaly patients were Caucasian (98.2 %), 2 patients were from Africa, and 1 patient was Asian. The fol-lowing syndromes associated to acromegaly were reported: MEN-1 (1 patient), McCuneAlbright syndrome (1 patient), Carney complex (1 patient), Familial acromegaly (1 patient), and one unspecified associated syndrome (1 patient). The
mean age of patients at diagnosis of acromegaly was 42.3 ± 13.7 years (range 6.6–78.1 years), and duration of acromegaly before pegvisomant start was\1 year in 6.7 % of cases, 1 to\3 years in 28.2 % of cases, 3–5 years in 15 % of cases, and [5 years in 49.6 % of cases. In the whole Italian cohort, mean duration of acromegaly before pegvisomant start was 8.1 ± 7.9 years (range 0–40.9 years). The majority of patients were diagnosed with acromegaly in the age range of 30–39 years (26.1 %) or 40–49 years (26.1 %). Before peg-visomant start, the majority of acromegaly patients had been treated with medical therapy and surgery (54.3 %), while a smaller proportion of subjects received medical therapy only (22.9 %) or medical plus radiation and surgical therapy (15.8 %). In particular, 96.4 % of the surgically treated acromegaly patients had undergone transsphenoidal surgery, while 7.6 % had a craniotomy. Considering previous radio-therapy, 40.7 % was treated with conventional radioradio-therapy, whereas 55.9 % was treated with stereotactic radiotherapy.
At pegvisomant start, the mean age of the acromegaly population was 50.4 ± 14.2 years (range 17.5–83.9 years), the mean weight was 81.2 ± 16.3 kg (range 51–126 kg), and the mean BMI (weight in kg/height in m2] ) was 28.3 ± 5.3 (19.2–48 kg). Most of the patients started pegvisomant between 40–49 years (22.3 %) and 50–59 years (25.2 %). Duration of pegvisomant therapy was 4.3 ± 2.52 years while in ACROSTUDY 3.0 ± 1.48 years. A follow-up[5 years is available for 79 patients on pegvisomant therapy (Table1).
Safety
The data from 341 acromegaly patients were available for adverse events analysis. Twelve patients deceased for the
Table 1 Total Pegvisomant therapy duration and during ACROSTUDY Male (n = 171) Female (n = 170) All (n = 341) Years (±SD) on Pegvisomant 4.3 ± 2.53 4.4 ± 2.52 4.3 ± 2.52 Year (±SD) in Acrostudy 2.9 ± 1.49 3.0 ± 1.48 3.0 ± 1.48 Patients \ 1 year in Acrostudy n (%) 25 (14.6 %) 18 (10.6 %) 43 (12.6 %) Patients 1–3 years in Acrostudy n (%) 55 (32.2 %) 59 (34.7 %) 114 (33.4 %) Patients 3–5 years in Acrostudy n (%) 82 (48 %) 83 (48.8 %) 165 (48.4 %) Patients [ 5 years in Acrostudy n (%) 9 (5.3 %) 10 (5.9 %) 19 (5.6 %) Patients [ 5 years on Pegvisomant n (%) 43 (25.1 %) 36 (21.1 %) 79 (23.1 %)
Years years of therapy, SD standard deviation, n number of subjects, % percentage of subjects
following reasons and not related to pegvisomant therapy: cancer (5), pulmonary edema or cardiac failure (2), disease progression (1), general deterioration of health status (1), acute myocardial infarction (1), respiratory failure (1), or unknown causes (1). During the observation period, 199 adverse events were reported in 98 patients (28.7 %). Serious adverse events (SAEs) were documented in 29 (8.5 %) acromegaly patients, and pegvisomant medication was eventually withdrawn (temporarily or permanently or delayed) in 19 patients (5.6 %). Two cases were considered drug related (acute hepatitis; diplopia); in both patients, pegvisomant was withdrawn, and they were recovered. Diplopia was due to cavernosus sinus syndrome because of adenoma increase in a patient never treated with surgery or radiotherapy. In 320 of 341 subjects (94 %), at least one liver enzyme test (AST or ALT or ALP or bilirubin or GGT) after pegvisomant start was available. Incidence of liver test abnormalities ([39 ULN of ALT or AST, [19 ULN of ALP, bilirubin or GGT) at pegvisomant start and during treatment at any time point was observed in 27 acromegaly patients (8.4 %). A significant increase of transaminases ([59 ULN of ALT or AST) was reported in 3 patients (0.9 %) after 3 months of pegvisomant therapy but nor-malized spontaneously or after pegvisomant withdrawn.
After pegvisomant start, 24 (7 %) acromegaly patients underwent a surgical procedure for pituitary adenoma (transsphenoidal surgery in 95.8 % and craniotomy in 8.3 %; 1 patient had both procedures) and 23 (6.7 %) received radiotherapy (conventional in 8.7 % and stereo-tactic in 91.3 %).
MRI evaluation was available in 249/341 patients (73 %); in these, the majority (177/249 patients, 71.1 %) had no signifi-cant change in pituitary tumor volume according to the local MRI reading during pegvisomant therapy compared to baseline MRI at start of therapy (Fig.1a, b). In a small proportion of patients, a change in tumor volume was reported as decreased at least once (34/249 patients, 13.7 %), increased at least once (22/249 patients, 8.8 %), or both increased and decreased (16/ 249 patients, 6.4 %) but in different phase of treatment. Central MRI reading was performed in 34 patients, in 10 with reported significant changes in tumor volume. In 7 patients, an increase in tumor volume was confirmed; a decrease in tumor volume in 2 patients, an increase and decrease tumor volume in 1 patient, and no change in tumor volume in 5 patients were found. Given the lack of homogeneity and the small number of patients, we did not perform further specific analysis. In one case, lipohy-pertrophy in site of administration was reported.
Efficacy
Before pegvisomant start, 66.4 % of acromegaly patients were on treatment with somatostatin analogs, while 33.3 %
was receiving SSAs in combination with cabergoline. When pegvisomant started, 41.9 % (n.143) is in pegvisomant monotherapy, 50.4 % (n.172) in combination of SSA ? Pegvisomant, 5 % (n. 17) SSA ? Pegvisomant ? cabergo-line, and 2.6 % (n. 9) in Pegvisomant ? cabergoline; the proportion of patients who were treated during Acrostudy with pegvisomant monotherapy or combined with other treatments is summarized in Fig.2. Titration of pegvisomant therapy is summarized in Fig.3.
Efficacy, in terms of IGF-I control, progressively increased since the start of pegvisomant therapy from year 1 to year 6 (Fig. 4a, b). After 6 years, normal IGF-I levels were found in 70.9 % of patients at a mean daily pegvi-somant dose of 18.1 mg, while 25.3 % had elevated IGF-I with a mean daily dose of 22.3 mg (Fig.4a, b). In a small proportion of patients during pegvisomant therapy, IGF-I
0 20 40 60 80 100 0.5 1 2 3 4 5 6 Time of therapy (years)
NK Patients (%) 0 20 40 60 80 100 1 2 3 4 5 6 Patients (%) NA NK
Time of therapy (years)
(a)
(b)
Fig. 1 a Change of pituitary tumor size by MRI in comparison to baseline (a) or last pituitary examination (b). NK not known, NA Not available,$ no variation of pituitary tumor size, ; decreased size of pituitary tumor, : increased size of pituitary tumor
0 20 40 60 80 100 PEG PEG + SSA Patients (%) Start 1 2 3 4 5 6 Time of therapy (years)
Fig. 2 Proportion of patients on treatment with Pegvisomant only (PEG) or Pegvisomant plus somatostatin analogs (PEG ? SSA)
levels were pathologically low (years 1–6: 0.7–3.8 %). In this subgroup of acromegaly patients, the mean daily pegvisomant dose ranged from 5.7 to 20 mg.
Male acromegaly subjects were treated with higher mean pegvisomant dosages in comparison to females (p \ 0.05; Fig.5). Furthermore, in female acromegaly patients, we observed a higher percentage of normalized IGF-I in comparison to male patients in the majority of yearly evaluations and especially in the first years of therapy (year 1: 68 vs 52 %, year 2: 66 vs 58 %, year 3: 69 vs 62 %, year 4: 64 vs 64 %, year 5: 73 vs 65 %, year 6: 67 vs 72 %, respectively). A positive correlation between dose and age at start was documented (p \ 0.001). In elderly subjects, a lower pegvisomant doses are reported (p \ 0.05; Fig.6). Higher pegvisomant dose titration was associated with higher baseline weight (r = 0.45;
p = 0.0001) and higher baseline IGF-I (r = 0.26; p = 0.0051) but not with age at pegvisomant start.
The majority of patients were treated with daily injec-tion of pegvisomant (87.1 %) although in a small propor-tion of cases, the medicapropor-tion was administered 2–6 times per week (8.8 %) or with weekly injections (3.8 %). The daily dose of pegvisomant was \10 mg in 10.3 % of cases, 10–15 mg in 74.8 %, 15–20 mg in 7.6 %, 20–25 mg in 4.1 %, 25–30 mg in 1.5 %, and [30 mg in 1.8 %. weekly or 2–6 times week injections were administered with lower dosages only (\15 mg).
Discussion
This study reports the clinical results in a large cohort of Italian patients with active acromegaly under treatment with the GH antagonist pegvisomant followed up in an observational protocol. The results of the present study are in agreement with previous studies demonstrating that treatment with the GH antagonist displays high efficacy and safety. It reflects a country-specific real clinical prac-tice of the use of pegvisomant in acromegaly patients. We do believe that these data confirmed that pegvisomant has an excellent efficacy, even in patients with resistant acro-megaly, coupled with excellent safety profile. ACRO-STUDY is an observational global study, and the first results were published in recent years related to the worldwide acromegaly population [13,16,18,19]. One of the advantages of the global ACROSTUDY study is the
0 20 40 60 80 100 Start 1 2 3 4 5 6 Time of therapy (years)
> 30 mg 25-30 mg 20-25 mg 15-20 mg 10-15 mg < 10 mg Patients (%) Pegvisomant daily dose
Fig. 3 Titration of Pegvisomant therapy
0 20 40 60 80 100 Normal IGF-I High IGF-I Start 0.5 1 2 3 4 5 6 Time of therapy (years)
Patients (%) 0 5 10 15 20 25 Normal IGF-I High IGF-I 0.5 1 2 3 4 5 6 PEG (mg/day)
Time of therapy (years)
(a)
(b)
Fig. 4 Efficacy (a) and Pegvisomant mean dose (b)
0 5 10 15 20 25 30 35 0 1 2 3 4 5 6 PEG (mg/day ) Males Females
Time of therapy (years)
* * *
Fig. 5 Pegvisomant mean dose by gender *p \ 0.05
0 5 10 15 20
25 age < 20 years age 20-40 years age 40-60 years age > 60 years
0 1 2 3 4 5 6
PEG (
m
g/day)
Time of therapy (years)
* * * * * *
number of patients enrolled, which is about four times greater than the Italian ACROSTUDY. However, it is also acknowledged that in the global ACROSTUDY, there is a certain lack of homogeneity in the number of patients enrolled in the various countries which could affect the results in term of selection bias. With regard to the origi-nality of the Italian ACROSTUDY, we evaluated a larger population because the number of Italian patients had almost doubled since the last global ACROSTUDY pub-lication and the observation period were longer. Even in the recent retrospective multicentre epidemiologic Italian study on acromegaly, only a small proportion of the patients investigated was on treatment with pegvisomant [20]. In the present study, we observed that 60 % patients on pegvisomant therapy normalized IGF-I levels from the first year of therapy with a mean daily dose of 15 mg. In the following years, a constant trend towards an improve-ment in disease control was observed (approximately 69 and 70 % of cases in the fifth and sixth year of observa-tion). The IGF-I reduction was obtained by titrating grad-ually the medication and reaching a mean pegvisomant dose always less than 20 mg daily in patients controlled. It was interesting to note that in a small percentage of patients (approximately 2–4 %), the drug was so effective to result in low levels of IGF-I. Only in subjects treated for more than 5 years, a significant proportion (approximately 20 %) required doses above 30 mg daily, as observed also in a recent study [21]. Even in patients who have not achieved biochemical control, the mean pegvisomant dose in the sixth year was only slightly higher than 20 mg daily. These data lead us to speculate that a correct titration to the maximum allowed dose of 30 mg daily could theoretically lead to further disease control for the remaining 10–20 % of patients and therefore very close to that observed in first RCT [9]. There are no known reasons for non-titration of pegvisomant. The problem could be due to (1) the lack of a single vial containing dose of more than 20 mg and tech-nical difficulties of administration, (2) poor patient com-pliance, (3) economic reasons (costs are calculated in mg), or (4) perception of side effects with higher doses.
Compared to the global ACROSTUDY population, we have observed that some factors such as gender, age of patients, and their weight may affect the response to treatment with pegvisomant. These factors should be con-sidered for titration of pegvisomant. In fact, we confirmed the reports of other studies that patients with higher weight and IGF-I at the time of recruitment required higher doses of pegvisomant during titration. In particular as regards to the effect of gender, it has been already observed that women require a higher dose of pegvisomant to obtain a normalization of IGF-I and that standardization was more easily obtained in male subjects [22]. In our study, disease control was on average higher in females and with lower
doses of pegvisomant. We cannot exclude that females acromegaly patients had a less aggressive disease or were less resistant to the medication in comparison to males. Unfortunately, the nature of this study did not allow us to explore this further. A good point of discussion is whether more than 5 years is a reasonable period of time to achieve, in some cases, the biochemical control. It should be emphasized that in our study most of the patients after 1 year of treatment had achieved the hormonal goal although most of them were resistant to all other treat-ments. On the other hand, in previous studies, the achievement of the hormonal target after many more years was considered a success not negligible [23].
For specific regulatory rules in force in Italy, most of the prescriptions of pegvisomant are limited to a small number of Neuroendocrine Centres. In the GPOS, the number of centers was 3 times higher compared to ACROSTUDY Italian centres, and fewer patients per centre on average were enrolled. In Italy, approximately, 60 % of patients were recruited from one quarter of the total number of centres. Another peculiar aspect in Italian cohort is that a great number of patients (12.6 %) were treated in off-label regimen in terms of way of administration. These patients in fact received pegvisomant less frequently than that in daily administration (1–6 days/week). Only practice on the field can justify and explain this clinical behavior which is a new drug application.
Considering safety, 28.7 % of our patients experienced adverse events, and 8.5 % of these were reported as serious. The most recent paper focused on safety which reports data of Global ACROSTUDY [13] with 1288 patients showed AEs in 37 % of patients and SAEs in 12.3 % of patients. It is reassuring to note that in the Italian population of 341 patients only in 2 cases (0.1 %), SAEs were considered drug related and moreover, these SAEs were transient, and com-plete recovery was observed after discontinuation of therapy. A very low percentage of Italian patients showed a significantly increase in tumor volume, and this is in line with previous published data [12,18]. On the other hand, in a proportion of patients, a reduction of the tumor volume was also observed during pegvisomant, although in these cases, we cannot exclude that this effect was due to the concomitant use of SSAs [10]. These results also confirm in our patient population that tumor growth under pegvi-somant is a rather infrequent event and likely related, when it happens, to the specific tumor aggressiveness. As already emphasized, in a broader population, centralized MRI reading allows a greater diagnostic accuracy, but it implies greater time expenditure. A limitation of the present study is the low number of MRIs sent for re-evaluation by central reading with respect to the number of subjects in which a volumetric change of the tumor has been documented. Another limitation is that the available data neither allow
us to quantify the size of the increase of tumor volume nor which treatment options was subsequently received, whe-ther surgery, radiowhe-therapy, or addition of SSAs.
During the treatment, a small number of patients underwent pituitary surgery or treatment with radiotherapy. It is unknown if the treatment choice was due to evolution of the lesion, failure in disease control, or patient’s choice. Liver toxicity is an important point to be discussed as it has been previously reported as one of the most common side effects. Our data showed [39 ULN elevation of liver enzymes in 8.4 % and [59 ULN elevation in three patient only (0.9 %). In the German pegvisomant surveillance experience group, the rates were 8.4 and 2.8 %, respec-tively, while in the global ACROSTUDY, these rates were 2.5 and 0.93 % [13,24]. To explain the lower rate of higher elevation ([59 ULN) of liver enzyme abnormalities in the Italian ACROSTUDY in comparison to other series, we may consider the gradual titration of pegvisomant doses, starting with the lowest possible dose. In routine clinical practice in Italy, the loading dose (80 mg) is not commonly used. Furthermore, in view of the retrospective nature and timing of the study, it is possible that transient variations in liver enzymes detectable in the early months of therapy may have been missed. Nevertheless, absence of persis-tence liver enzymatic changes supports the limited toxicity of the drug. Finally, we cannot exclude some degree of AE underreporting or a protective genetic background.
In conclusion, if we consider that pegvisomant is cur-rently available in Italy as third-line therapy (i.e., after surgery or RT and after SSA failure) and therefore in patients never normalized by any other type of treatment, we can confirm that it is a drug with a favorable safety profile and highly efficacious.
Acknowledgments The authors thank the patients, clinicians, nur-ses, and study coordinators for providing the primary data on their patients. ACROSTUDY is sponsored by Pfizer Inc.
Conflict of interest S. G., P. M., F. B., S. C., A. C., E. G., L. D. M. received honoraria from Pfizer as members of the ACROSTUDY Italian National Board. E. G. receives honoraria from Pfizer as member of the ACROSTUDY Strategic Advisory Board. R. G., M. M, E. G., and P. J. are permanent employees of Pfizer. None of the authors were paid for for their contribution to this manuscript.
Appendix
Italian ACROSTUDY Group:
Angeletti G, Sbroma Tamaro E. Dipartimento. di Med-icina Interna sezione MedMed-icina Interna e, Scienze Endo-crine e Metaboliche Universita` di Perugia
Appetecchia M, Baldelli R. Unita` Operativa di Endo-crinologia Istituto Nazionale Tumori Regina, Elena IRCCS Roma
Beck Peccoz P, Machiodi E. Fondazione IRCCS Ca` Granda Policlinico,Universita` degli Studi di, Milano
Carani C, Rochira V. Clinica Endocrinologia e Malattie del Metabolismo, Azienda Policlinico di, Modena, Nuovo Ospedale S Agostino Estense Baggiovara (Modena)
Persani L, Sciortino G. Istituto Auxologico Italiano Reparto di Medicina Generale ad Indirizzo, Endocrino-Metabolico, Milano
Grasso L. Dipartimento di Medicina Clinica e Chirurgia Sezione di Endocrinologia Universita` Federico II di Napoli Ambrosio MR, Zatelli MC. Sezione di Endocrinologia, Dipartimento di Scienze Biomediche e Terapie Avanzate, Universita` degli studi di Ferrara
Bianchi A. UOS patologia ipofisaria istituto di Patologia medica policlinico universitario A. Gemelli, Roma
De Menis E, Sartorato P. Endocrinologia, Medicina 2, Ospedale S. Maria di Ca’ Foncello, Treviso
Prencipe N, Dipartimento di Scienze Mediche Divisione di Endocrinologia, Diabetologia e Metabolismo, AO Citta` della Salute e della Scienza di Torino, Universita` di Torino
Giordano C, Ciresi A. AOUP Palermo ,Endocrinologia e Malattie Metaboliche, Dipartimento Assistenziale Bio-medico Medicina Interna e Specialistica, Universita` di Palermo
Giorgino F, Patruno P. Azienda Ospedaliera Consorziale Policlinico,Dipartimento di Medicina Interna Endocrino-logia e Malattie Metaboliche, Bari
Lanzi R, Rossini A. Clinica Endocrinologica, Fondazi-one Centro S. Raffaele del Monte Tabor, Milano
Loli P, Cozzi R. S.C. di Endocrinologia Ospedale Ni-guarda Ca’ Grande, Milano
Scaroni C, Ceccato F. Azienda Ospedaliera Universi-taria di Padova, UO di Endocrinologia, Padova
Martino E, Lombardi M. Dipartimento di Medicina Clinica e Sperimentale, Sezione di Endocrinologia, Uni-versita` di Pisa
Minuto FM, Ferone D. Clinica Endocrinologica, Azi-enda Ospedaliera San Martino, Genova
Trimarchi F, Ragonese M. Dipartimento di Medicina Clinica e Sperimentale, Universita` di Messina
Pagani G, Cortesi L. Ospedali Riuniti di Bergamo, Bergamo
R.Pasquali R, Ribichini D. UO di Endocrinologia, Ospedale S. Orsola-Malpighi Bologna
Sicolo N, Martini C. Clinica Medica 3^, Dipartimento di Medicina, Azienda Ospedaliera di Padova
Gargiulo P, Mercuri V. I Cattedra di Endocrinologia-Dipartimento di Medicina Sperimentale- ‘‘Sapienza’’ Uni-versita` di Roma
Terzolo M, Reimondo G. Clinica Endocrinologica, Di-partimento di Scienze Cliniche Biologiche ASO San Luigi, Orbassano (TO)
Vigneri R, Tita P. Azienda Ospedaliera Garibaldi-Nes-ima, Dipartimento di Medicina Interna e Medicina Spe-cialistica Cattedra di Endocrinologia, Catania
Tota N, Matera L. Divisione di Endocrinologia,Ospe-dale Generale Regionale F. Miulli, Acquaviva delle Fonti, Bari
References
1. A. Giustina, P. Chanson, M.D. Bronstein, A. Klibanski, S. Lamberts, F.F. Casanueva, P. Trainer, E. Ghigo, K. Ho, S. Mel-med, A consensus on criteria of cure of acromegaly. J. Clin. Endocrinol. Metab. 95, 3141–3148 (2010)
2. A. Giustina, P. Chanson, D. Kleinberg, M. Bronstein, D.R. Clemmons, A. Klibanski, A.J. van der Lely, C.J. Strasburger, S.W. Lamberts, K.K. Ho, F.F. Casanueva, S. Melmed, Expert consensus document: A consensus on the medical treatment of acromegaly. Nat Rev Endocrinology 10, 243–248 (2014) 3. S. Melmed, A. Colao, A. Barkan, M. Molitch, A.B. Grossman, D.
Kleinberg, D. Clemmons, P. Chanson, E. Laws, J. Schlechte, M.L. Vance, K. Ho, A. Giustina, Guidelines for acromegaly manage-ment: an update. J. Clin. Endocrinol. Metab. 94, 1509–1517 (2009) 4. M.O. Thorner, C.J. Strasburger, Z. Wu, M. Straume, M. Bid-lingmaier, S.S. Pezzoli, K. Zib, J.C. Scarlett, W.F. Bennett, Growth hormone (GH) receptor blockade with a PEG-modified GH (B2036-PEG) lowers serum insulin-like growth factor-I but does not acutely stimulate serum GH. J. Clin. Endocrinol. Metab. 84, 2098–2103 (1999)
5. J.J. Kopchick, C. Parkinson, E.C. Stevens, P.J. Trainer, Growth hormone receptor antagonists: discovery, development, and use in patients with acromegaly. Endocr. Rev. 23, 623–646 (2002) 6. A. Colao, G. Arnaldi, P. Beck-Peccoz, R. Cozzi, E. degli Uberti,
L. De Marinis, E. De Manis, D. Ferone, V. Gasco, A. Giustina, S. Grottoli, G. Lombardi, P. Maffei, E. Martino, F. Minuto, R. Pivonello, E. Ghigo, Pegvisomant in acromegaly: why, when, how. J. Endocrinol. Invest. 30, 693–699 (2007)
7. M. Gola, S. Bonadonna, G. Mazziotti, G. Amato, A. Giustina, Resistance to somatostatin analogs in acromegaly: an evolving concept ? J. Endocrinol. Invest. 29, 86–93 (2006)
8. A. Giustina, M.D. Bronstein, F.F. Casanueva, P. Chanson, E. Ghigo, K.K. Ho, A. Klibanski, S. Lamberts, P. Trainer, S. Mel-med, Current management practices for acromegaly: an interna-tional survey. Pituitary 14, 125–133 (2011)
9. P.J. Trainer, W.M. Drake, L. Katznelson, Treatment of acro-megaly with the growth hormone-receptor antagonist pegviso-mant. N. Engl. J. Med. 342, 1171–1177 (2000)
10. A.J. van der Lely, R.K. Hutson, P.J. Trainer, Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist. Lancet 358, 1754–1759 (2001)
11. C.J. Strasburger, M. Buchfelder, M. Droste, K. Mann, G.K. Stalla, B. Saller, German Pegvisomant Investigators: experience from the German Pegvisomant Observational Study. Horm. Res. 68, 70–73 (2007)
12. M. Buchfelder, D. Weigel, M. Droste, K. Mann, B. Saller, K. Bru¨bach, G.K. Stalla, M. Bidlingmaier, C.J. Strasburger, On behalf of the investigators of the German Pegvisomant Obser-vational Study, Pituitary tumour size in acromegaly during peg-visomant treatment: experience from MR re-evaluations of the German Pegvisomant Observational Study. Eur. J. Endocrinol. 161, 27–35 (2009)
13. A.J. van der Lely, B.M. Biller, T. Brue, M. Buchfelder, E. Ghigo, R. Gomez, J. Hey-Hadavi, F. Lundgren, N. Rajicic, C.J.
Strasburger, S.M. Webb, M. Koltowska-Ha¨ggstro¨m, Long-term safety of pegvisomant in patients with acromegaly: comprehen-sive review of 1288 subjects in ACROSTUDY. J. Clin. Endo-crinol. Metab. 97, 1589–1597 (2012)
14. I. Schreiber, M. Buchfelder, M. Droste, K. Forssmann, K. Mann, B. Saller, C.J. Strasburger, German Pegvisomant Investigators. Treatment of acromegaly with the GH receptor antagonist peg-visomant in clinical practice: safety and efficacy evaluation from the German Pegvisomant Observational Study. Eur J Endocrinol 156, 75–82 (2007)
15. M. Buchfelder, S. Schlaffer, M. Droste, K. Mann, B. Saller, K. Bru¨bach, G.K. Stalla, C.J. Strasburger, German Pegvisomant Observational Study. The German ACROSTUDY: past and present. Eur. J. Endocrinol. 161, S3–S10 (2009)
16. P.J. Trainer, ACROSTUDY: the first 5 years. Eur. J. Endocrinol. 161, S19–S24 (2009)
17. I. Bernabeu, M. Marazuela, T. Lucas, L. Loidi, C. Alvarez-Es-cola´, M. Luque-Ramı´rez, E. Fernandez-Rodriguez, A.E. Pania-gua, C. Quinteiro, F.F. Casanueva, Pegvisomantinduced liver injury is related to the UGT1A1*28 polymorphism of Gilbert’s syndrome. J. Clin. Endocrinol. Metab. 95, 2147–2154 (2010) 18. J.H. Buhk, S. Jung, M.N. Psychogios et al., Tumour volume of
growth hormone-secreting pituitary adenomas during treatment with pegvisomant: a prospective multicenter study. J. Clin. Endocrinol. Metab. 95, 552–558 (2010)
19. T. Brue, F. Castinetti, F. Lundgren, S. Go¨ricke, S. Hartz, S. Schulz-Heise, R. Klingebiel, M. Forsting, H. Bru¨ckmann, A. Do¨rfler, M. Jordan, M. Buchfelder, M. Knauth, Which patients with acromegaly are treated with pegvisomant? An overview of methodology and baseline data in ACROSTUDY. Eur. J. Endo-crinol. 161, S11–S17 (2009)
20. M. Arosio, G. Reimondo, E. Malchiodi, P. Berchialla, A. Bor-raccino, L. De Marinis, R. Pivonello, S. Grottoli, M. Losa, S. Cannavo`, F. Minuto, M. Montini, M. Bondanelli, E. De Menis, C. Martini, G. Angeletti, A. Velardo, A. Peri, M. Faustini-Fustini, P. Tita, F. Pigliaru, G. Borretta, C. Scaroni, N. Bazzoni, A. Bianchi, M. Appetecchia, F. Cavagnini, G. Lombardi, E. Ghigo, P. Beck-Peccoz, A. Colao, M. Terzolo, Italian Study Group of Acro-megaly, Predictors of morbidity and mortality in acromegaly: an Italian survey. Eur. J. Endocrinol. 167, 189–198 (2012) 21. A. Bianchi, F. Valentini, R. Iuorio, M. Poggi, R. Baldelli, M.
Passeri, A. Giampietro, L. Tartaglione, S. Chiloiro, M. Appe-tecchia, P. Gargiulo, A. Fabbri, V. Toscano, A. Pontecorvi, L. De Marinis, Long-term treatment of somatostatin analog-refractory growth hormone-secreting pituitary tumors with pegvisomant alone or combined with long-acting somatostatin analogs: a ret-rospective analysis of clinical practice and outcomes. J Exp Clin Cancer Res 21(32), 40 (2013)
22. C. Parkinson, P. Burman, M. Messig, P.J. Trainer, Gender, body weight, disease activity, and previous radiotherapy influence the response to pegvisomant. J. Clin. Endocrinol. Metab. 92, 190–195 (2007)
23. R. Cozzi, M. Montini, R. Attanasio, M. Albizzi, G. Lasio, S. Lodrini, P. Doneda, L. Cortesi, G. Pagani, Primary treatment of acromegaly with octreotide LAR: a long-term (up to nine years) prospective study of its efficacy in the control of disease activity and tumor shrinkage. J. Clin. Endocrinol. Metab. 91, 1397–1403 (2006)
24. H. Biering, B. Saller, J. Bauditz, M. Pirlich, B. Rudolph, A. Johne, M. Buchfelder, K. Mann, M. Droste, I. Schreiber, H. Lochs, C.J. Strasburger, Elevated transaminases during medical treatment of acromegaly: a review of the German pegvisomant surveillance experience and a report of a patient with histologi-cally proven chronic mild active hepatitis. Eur. J. Endocrinol. 154, 213–220 (2006)
