The Role of Radiotherapy in Acromegaly.

Neuroendocrinology (DOI:10.1159/000435776)

(Accepted, unedited article not yet assigned to an issue)

© 2015 S. Karger AG, Basel www.karger.com/nen

Advanced Release: June 17, 2015

Received: January 12, 2015 Accepted after revision: June 4, 2015

The Role of Radiotherapy in Acromegaly

Hannon MJ 1, Barkan A 2, Drake WM 1

1

Department of Endocrinology, Barts and the London School of Medicine, Queen

Mary University of London, London, United Kingdom 2

Division of Endocrinology, Diabetes and Metabolism, University of Michigan, Ann

Arbor, MI, USA

Contact Address: Dr. Mark Hannon, Department of Endocrinology, St. Bartholomew’s Hospital, West Smithfield, London EC1A 7BE, United Kingdom Telephone: +44 795 705 8763 Email: [email protected]

Downloaded by: Univ. of California Santa Barbara 198.143.33.34 - 6/22/2015 1:57:34 PM

Key Words: acromegaly, radiotherapy, survival, hypopituitarism


© 2015 S. Karger AG, Basel

2

Abstract

Radiotherapy has, historically, played a central role in the management of acromegaly, and the last thirty years have seen substantial improvements in the technology used in the delivery of radiation therapy. More recently, the introduction of highly targeted radiotherapy, or "radiosurgery", has further increased the therapeutic options available in the management of secretory pituitary tumors. Despite these developments, improvements in primary surgical outcomes, an increase in the range and effectiveness of medical therapy options and long-term safety concerns have combined to dictate that, although still deployed in selected cases, the use of radiotherapy in the management of acromegaly has declined steadily over the past two decades. In this article we review some of the main studies that have documented the efficacy of pituitary radiotherapy on growth hormone hypersecretion and summarise the data around its potential deleterious effects including hypopituitarism, cranial nerve damage and the development of radiation related intracerebral tumors. We also give practical recommendations to guide its future use in patients with acromegaly, generally as a third line intervention after neurosurgical


intervention in combination with various medical therapy options.



3

Introduction

Successful management of acromegaly is complex and requires multidisciplinary involvement. The three currently available approaches to controlling growth hormone (GH) and/or insulin-like growth factor I (IGF-I) excess are neurosurgical removal or debulking of the pituitary tumor, medical therapies to reduce GH hypersecretion and/or GH effect, and pituitary radiotherapy. Neurosurgical intervention is generally regarded as the best first-line therapy for most patients (1, 2). Patients with evidence of postoperative GH excess, and those unfit for primary surgery, require additional/alternative therapy and it is to these patients that this article largely pertains.

Although, historically, radiotherapy has played a central role in the multimodality treatment of patients with acromegaly, its use has declined signficantly in recent years, mainly because of the development of effective and safe medical therapies, including somatostatin analogs and the growth hormone receptor antagonist pegvisomant (1-4). Furthermore, concern has arisen around the propensity of radiotherapy to cause long term hypopituitarism, as well as the less easily measurable possibility that it may increase the risk of developing a second intracerebral tumor, cerebrovascular disease, and cognitive dysfunction (1-4). In this review we will discuss the role of radiotherapy in the management of acromegaly with particular focus on the effectiveness of different forms of radiotherapy at controlling GH hypersecretion; which patients benefit most from radiotherapy and when; and we

treatment.


attempt to provide a balanced view of the merits and shortfalls of this modality of



4

Techniques of Radiotherapy Used in Acromegaly

Conventional external beam radiation therapy was historically delivered via twodimensional beams using linear accelerator machines, with a single beam of radiation being delivered to the patient from more than one direction. The main issue with this type of radiotherapy is that the safe dose which can be administered is limited by the radiation toxicity capacity of healthy tissues adjacent to the target tumor. For this reason, it has largely been replaced as a treatment modality by 3dimensional conformal radiation therapy (3DCRT) (5). This form of therapy uses specialised CT and / or MRI imaging, together with planning software, a multileaf collimator and a variable number of radiotherapy beams, thereby reducing the relative toxicity of radiation to the surrounding normal tissues. This allows a higher dose of radiation to be delivered to the tumor than former techniques would allow (5).

Since the late 1980s, more sophisticated and targeted forms of radiotherapy have become available; these are generally referred to as stereotactic radiotherapy. However, the precise method of its delivery varies between manufacturers and countries. The two main techniques utilised in the management of acromegaly are gamma knife radiosurgery and linear accelerator radiosurgery (LinAc).

Gamma

knife

radiosurgery

typically

utilises

201 cobalt-60 sources,

each

of

approximately 30 curies (1.1 TBq) emitting energy of approximately 1.25 MeV, placed in a circular array around the patient’s brain. The patient wears a specialised helmet

tumor) immobile, ensuring that the 201 radiation beams converge precisely on the treatment target with relative sparing of the surrounding tissues. LinAc uses a linear


that is surgically fixed to the skull; this keeps the patient’s head (and therefore the



5

accelerator to produce a photon beam which targets the tumor. Unlike gamma knife radiosurgery, there is only one energy source, which is held on a moveable gantry which can change the radiation delivery angle. In some centres, a small linear accelerator mounted on a moving arm is used to deliver treatment; this is known as Cyberknife therapy and allows a minor degree of patient movement which can be allowed and corrected for during treatment.

Although gamma knife and LinAc are both referred to as stereotactc radiotherapy (sometimes also called ‘radiosurgery’), LinAc does not use radioisotopes and thus by definition does not use gamma rays. Both are being used in parallel with, and as an alternative to, 3DCRT.

The Effectiveness of Radiotherapy in Acromegaly.

Prior to the introduction of the somatostatin analogs, medical therapies for acromegaly (mainly dopamine agonists such as bromocriptine and cabergoline) achieved biochemical control in only a small minority of patients. Hence, radiotherapy was used as second line therapy in almost all of those with residual postoperative disease.

Historical series reporting the effectiveness of pituitary radiotherapy must be viewed against a background of the prevailing opinion at the time as to what represented ‘biochemical control’ or a ‘safe’ GH level. Hence, the report by Eastman et al showing

less than 5 ng/mL, ten years after conventional pituitary irradiation, from a pretreatment mean GH of 60 ng/mL and a pre-treatment median of 35 ng/mL


that 81% of patients had a serum GH less than 10 ng/mL, and 69% had a serum GH



6

represented, at the time, relative therapeutic success against a backdrop of unsatisfactory medical options (6). However, with modern, more stringent biochemical targets for GH control, the number of patients in that series that would be considered to have satisfactory control of GH would be substantially lower. In the report of Feek et al conventional pituitary irradiation as primary treatment (an approach rarely adopted in more recent times) led to a 28% yearly fall in serum GH levels over the first five years, with a lower rate of fall thereafter. Those patients who had surgery before radiotherapy experienced a similar rate of long term fall in serum GH levels (7). These, and other, studies led to a prevailing consensus view in the literature in the early 1990s that pituitary irradiation had “stable effects on tumor mass, GH, and pituitary function” with “approaching 90%” of treated patients achieving a serum GH of less than 5 ng/mL fifteen years after radiotherapy (8).

Since these early publications various developments in the monitoring and treatment of acromegaly have led to a re-examination of the role and benefits of pitutiary radiotherapy. First, it is now well established that a definition of “remission” of acromegaly using a serum GH cut off of 5 ng/mL is very liberal, given that the majority of GH concentrations in normal individuals are below 0.2 mg/L (9). Measurement of GH using modern immunoradiometric assay (IRMA) would suggest that the upper limit of normal for GH following glucose tolerance test suppression in non-acromegalic subjects is as low as 0.14 ng/mL (10), and surrogate markers of acromegaly-related morbidity such as decreased insulin sensitivity can be observed in patients with a GH nadir even slightly above this level during glucose tolerance

2 ng/mL is required to normalise mortality in acromegaly, especially in young patients who have a long duration of exposure to elevated GH levels (12). The Acromegaly


testing (11). More recent data would suggest that a prevailing GH of a least less than



7

Consensus Group supports the statement that a patient's acromegaly can only be considered "controlled" if he/she has a random GH of less than 1 µg/L (or a nadir GH after glucose tolerance testing of less than 0.4 µg/L) and an IGF-I within the age and gender adjusted normal reference range (13).

Second, although the potential use of serum IGF-I (then called Somatomedin-C) as a diagnostic and monitoring tool for patients with acromegaly was first described in the late 1970s (14), high-throughput assays were not available for several years afterwards, with an inevitable subsequent delay in the availability of appropriate outcomes-based studies. With the demonstration that IGF-I is responsible for the majority of the clinical manifestations of acromegaly (15), that it is less fluctuant than serum GH and not secreted in a pulsatile manner (16), interest grew that it may be a more sensitive indicator of disease activity, particularly in patients with minimally active or “cured” disease as judged by consensus GH criteria (17). This is presumably due to the fact that, in the absence of normal pulsatility, relentless tonic secretion of even low levels of GH may lead to serum IGF-I concentrations above the age-adjusted reference range (18). Judged against modern consensus critieria for the use of both serum GH and IGF-I for the monitoring of acromegaly, pituitary irradiation appears to perform substantially less well in achieving ‘remission’ compared to case series that have used serum GH as the sole marker of disease activity (19).

Third, the introduction of 3DCRT and stereotactic radiosurgery has enabled pituitary

tissues (5). Stereotactic radiotherapy, particularly, allows a high radiation dose to be delivered with sub-millimetre precision to a tightly-defined target. Although


tumors to be treated in a more focussed manner with less damage to surrounding



8

comparable outcome data fall short of demonstrating superior efficacy over conventional, fractionated radiotherapy, it is self-evident that it is less timeconsuming for patients (a single day of treament as opposed to five to six weeks of daily treatment) and is associated with lower doses of irradiation doses to normal brain tissue (20).

Fourth, and probably most important, the introduction of successful medical therapies for acromegaly, including long-acting somatostatin analogs and the growth hormone receptor antagonist, pegvisomant, have, for clinicians in many countries, supplanted radiotherapy as second line therapy after pituitary surgery (1, 2). Although the percentage of patients that achieve biochemical control through the initial or postoperative use of somatostatin analogs may not be as high as initially reported (21), it is generally accepted that up to 35% will achieve normalisation of IGF-I (2, 22), with over half achieving a 50% reduction in tumor volume (23). Pegvisomant has been shown to achieve control of IGF-I in 63% of patients in a recently published surveillance study (24), and rates of control rise to as high as 95% when somatostatin analogs are combined with pegvisomant therapy (25). Crucially, these rates of disease control are achieved without any deleterious effect on residual pituitary function (2) which increases their attractiveness to patients, although lifelong administration is required.

The study of Barkan et al examined the effectiveness of radiation in acromegaly in light of the above developments, measuring both GH and IGF-I as markers of

radiotherapy (19). Although radiotherapy again demonstrated an excellent effect on GH levels, the effect on IGF-I was substantially less impressive, with only 2/38


remission, and including patients who had received both standard and stereotactic



9

achieving a normal IGF-I level (19) after a mean follow up of 6.8 years (range 1 - 19). These data, together with the emergence of powerful medical therapies for acromegaly, led the authors to recommend that the role of radiotherapy in the treatment of acromegaly required re-evaluation.

Subsequent studies with a similar design have had varying results. Powell et al found that the use of radiotherapy led to a normalisation of IGF-I levels in 69.2% of patients at six or more years following radiotherapy (26). The number considered in remission using GH criteria dropped to 44% when the lower GH cut off of 2.5 ng/mL was implemented. Also, 2 patients would have been considered cured by GH criteria but not by IGF-I criteria. Biermasz et al reported more positive results, with 84% of patients achieving a normal IGF-I concentration at 15 or more years after radiotherapy, and 65% considered “cured” by both GH and IGF-I criteria at 15 or more years after treatment (27). Jenkins et al and Minniti et al showed a similar number achieving long term control based on both GH and IGF-I criteria at 10 or more years after diagnosis (28, 29). Comparison between studies is hindered by the fact that patients were generally recruited from multiple sites and had a variety of different radiotherapy doses and schedules. However, it is clear that pituitary radiotherapy is slow acting and takes several years to have its full effect.

Interpreting data on stereotactic radiotherapy requires an understanding that different centers use different techniques and that the duration of follow-up is shorter compared to historical series using conventional pituitary irradiation. Further, the

which is well defined on MR imaging, dictate that a degree of selection bias is inevitable (30). Overall remission rates following radiosurgery vary between 29 and


anatomical constraints of radiosurgery, demanding a discrete, relatively small lesion



10

60%, but all studies have had a length of follow up less than ten years, and mostly less than six years (31-35). However, structural control of the tumor is achieved in over 90% of cases, using stereotactic radiotherapy as either an adjunctive (so-called “salvage”) or primary treatment strategy (29, 31, 33, 35-40). Pollock et al found, unsurprisingly, that smaller tumor size correlated with improved outcome, confirming the inherent selection bias present (34). This study and others also suggested that the absence of pituitary suppressive medications such as somatostatin analogs made successful treatment more likely; however these results are not consistent and the putative pathophysiological mechanism for this is unclear (34, 41, 42). Data from our own center suggest that gamma knife is safe and effective when used as “salvage” therapy, with 80% of patients achieving IGF-I control and 30% achieving GH control (40). It has been speculated that radiosurgery may lead to a more rapid normalisation of GH and IGF-I than 3DCRT, but the small size, short duration and selection bias of many of the trials mentioned above dictate that this cannot be regarded as proven. In line with data on conventional external beam irradiation, patients with the highest GH and IGF-I levels before treatment take the longest to achieve biochemical control (30). The potential for more rapid normalisation of GH and IGF-I using stereotactic radiosurgery rather than 3DCRT, and also its ease of administration and potentially lower rate of adverse events (see below) due to its highly targeted nature, have resulted in the most recent consensus guidelines on the management of acromegaly recommending stereotactic radiosurgery over 3DCRT in patients whose disease required the use of radiotherapy (2, 30). Although it is currently not recommended for patients that do not have lesions which can be easily

been previously overstated and more recent data suggest that the overall risk to the optic pathways is low (see below) (30, 43). We would support the use of stereotactic


targeted or whose tumours are close to the optic pathways, this risk appears to have



11

radiosurgery as a second or third line therapy in patients with small, well defined tumours, unless there is clear impingement on the optic pathways. There are not enough data currently to support the preferential use of either gamma knife radiosurgery or proton beam therapy (2, 30).

To summarise, although both 3DCRT and stereotactic radiosurgery can be regarded as "effective" treatments for the patient with acromegaly, the proportion of patients whose disease is fully controlled through the use of radiotherapy is lower than previously thought due to the increasingly strict criteria used to define disease control, and the fact that radiotherapy appears to generate a disparity between those considered controlled by GH criteria and those considered controlled by IGF-I criteria. Furthermore, the presence of safe and effective alternative medical treatments had led to an overall reduction in the overall use of radiotherapy in acromegaly.

The Safety of Radiotherapy in Acromegaly.

Ionising radiation leads directly to double strand breaks in the DNA of cells. Cells which are rapidly dividing are most prone to radiation-induced damage. However, as pituitary tumors are generally benign and slow growing, radiotherapy has a slow pace of clinical effectiveness when used to treat these tumors, with full structural and hormonal control of the tumor often not being achieved until many years after the

Given the deleterious effects of radiation on the DNA structure of cells, the main ‘debating point’ around its use in the treatment of pituitary tumors, including GH-


initial use of radiotherapy.



12

secreting lesions, has been its safety, especially with the advent of effective medical therapies. The most common complication to occur after the administration of radiotherapy is the development of hypopituitarism, which is less of a clinical issue if this is already present consequent upon the compressive effects of the tumor itself and/or its prior surgical treatment. Hypopituitarism tends to occur slowly over time following radiotherapy and its development parallels the achievement of control over GH and IGF-I levels (27-29), with well over 50% of patients developing hypopituitarism at 15 or more years after 3DCRT (27, 29). Long term data on hypopituitarism following stereotactic radiosurgery are lacking; however, up to 50% may have new hypopituitarism of at least one axis at 10 years following radiosurgery (35). Hypopituitarism following radiosurgery appears to be more common in those patients whose treatment was directed at a larger target without clear demarcation from adjacent normal pituitary (30); recent studies have shown that the development of hypopituitarism following radiosurgery may be avoided by controlling the maximum radiation dose administered to the pituitary and stalk tissue. Leenstra et al did not find any cases of hypopituitarism in those patients receiving less than 7.5 Gy (44); this and other similar studies (45, 46) support the presence of a radiation dosedependent incidence of hypopituitarism following radiosurgery. However, these studies have a short duration of follow up and contain patients with pituitary tumors of heterogeneous etiologies.

Hypopituitarism itself is associated with increased mortality regardless of its underlying etiology (47-49), and logic would suggest that any treatment which causes

published from the West Midlands cohort (12, 49, 50). Set against this argument must be placed the observation that historical mortality studies in acromegaly, prior to


hypopituitarism could contribute to this excess mortality – a suggestion made in data



13

the development of modern medical therapies, included large numbers of patients treated with external pituitary irradiation as a means of controlling GH concentrations to ‘safe’ levels. Those patients with ‘controlled’ GH levels demonstrated a standardized mortality ratio that was no different from background, suggesting that if there is an adverse effect on mortality due to radiotherapy itself, it is modest compared to the beneficial effects conferred by control of the underlying GH excess.

Radiotherapy also carries a small but important risk of visual damage and other cranial nerve defects. In those patients who have received conventional radiotherapy the rates of visual or other nerve damage appear very low, particularly in the more recent studies which use 3DCRT (8, 27-29). However, stereotactic radiosurgery appears to carry a higher risk of cranial nerve damage, with 5/90 suffering cranial nerve damage following radiosurgery in one series – however, most of these had received previous radiotherapy (3/5) or radiosurgery (4/5) and the series contained patients with Cushing’s disease rather than acromegaly (51). A more recent study which examined 217 patients with recurrent secretory (131/217) and non secretory (86/217) adenomas found that 9/217 (4%) developed new visual dysfunctions which developed from 6 hours to 34 months following radiosurgery, of which 3 were left with permanent dysfunction (52). Again, 5/9 had received conventional radiotherapy previously, although other factors such as maximal radiation dose, tumor margin and optic nerve doses, tumor volume, cavernous sinus involvement, and suprasellar extension were not significantly related to the development of visual dysfunction. It appears that the risk of visual dysfunction following stereotactic radiosurgery is far

low if one avoids lesions that abut the visual pathways, as discussed earlier in this article (30, 43).


higher in those patients who have previously received 3DCRT, and the overall risk is



14

Concern has also been expressed about the possibility that pituitary irradiation may predispose to the subsequent development of a separate intracerebral tumor, chiefly meningioma. A large UK study found 11 patients with a second brain tumor from a total of 426 patients (and 5749 patient-years) who had received conventional radiotherapy for pituitary adenomas. The cumulative risk was low – 2.4% at twenty years following radiotherapy (53). An older UK study found a similarly low rate of second intracerebral tumor development (54), and neither showed any link to later development of systemic malignancy. A more recent Dutch study did not show any relationship between the use of conventional pituitary irradiation and the later development of any sort of malignancy (55). Radiosurgery has not been shown to confer an increased risk of a separate intracerebral tumor, but long term data are currently lacking.

It has also been suggested that patients who have received pituitary radiotherapy are at higher risk of cerebrovascular disease due to radiation vasculopathy (1). Brada et al showed that the dose of radiotherapy, but not the use of radiotherapy per se, increased the likelihood of cerebrovascular accident (56). Ayuk et al showed that treatment with radiotherapy independently and significantly increased mortality (RR = 1.67, p = 0.018), with cerebrovascular disease being the most common cause of death (12), as shown in Table 1 - findings repeated in a more recent analysis by the same group (50). Further analysis of a heterogeneous cohort of UK patients with secretory pituitary tumors further supported the hypothesis that pituitary radiotherapy


may be independently associated with cerebrovascular disease (49).



15

There has been concern that brain irradiation may lead to neurocognitive deterioration. This has particularly been the case in patients who receive high dose whole brain irradiation for cerebral metastases or haematological malignancy (5759). However, in pituitary disease, the radiation dose is smaller and confined to a more limited area of brain tissue. Some data suggest that pituitary irradiation itself may independently lead to subtle cognitive deficits (60), but more recent studies have not found this association (61-63); there are few data on this topic focusing on acromegaly alone rather than pituitary disease in general, which probably relates to the rarity of acromegaly and the difficulty of performing detailed neurocognitive evaluation.

It is likely that at least part of the incidence of long term side effects following radiotherapy is due to the historical use of conventional external beam radiotherapy; a modality which led to a much higher incidence of radiation damage to surrounding brain tissue when compared with more modern methods of radiotherapy. There are no long term data to determine the risk of a second intracerebral tumor in patients who have had exclusively 3DCRT or stereotactic radiosurgery. Furthermore, if the historic use of radiotherapy truly led to serious consequences such as cerebrovascular disease and a second intracerebral tumor, one would expect radiotherapy to be associated with increased mortality in the older studies of the use of radiotherapy in acromegaly. However, this is not that case, and indeed the older studies showed that radiotherapy (even the less targeted, conventional radiotherapy used at the time due to a lack of effective medical therapies) actually normalised


mortality in patients who achieved a serum GH of less than 5 ng/mL (8).



16

In summary, the use of 3DCRT significantly increases the risk of long term hypopituitarism. However, evidence for the development of visual compromise, a second intracerebral tumor, cerebrovascular disease or dementia suggests that any potential risk is small, and may be due to the historic use of conventional nontargeted radiotherapy rather than 3DCRT. Long term data concerning the safety of radiosurgery are lacking. However, the fact that modern medical therapies such as somatostatin analogs and pegvisomant can achieve control of both GH and IGF-I in almost all patients means that radiotherapy has been relegated to third line treatment in the vast majority of patients with acromegaly.

Conclusions

The effectiveness of 3DCRT in reducing serum GH in patients with acromegaly is clear, although its effect on achieving a normal serum IGF-I may be a little less powerful. Data for stereotactic radiosurgery are somewhat more limited but it seems to have a beneficial effect on both GH and IGF-I levels. Studies with more homogeneous patient populations would be required to accurately assess the relative efficacy of 3DCRT vs. radiosurgery. However, the likelihood of long term hypopituitarism developing following any type of pituitary radiotherapy must be considered by both clinician and patient. The potential for other long-term complications of radiotherapy such as the development of a second intracerebral tumor, cerebrovascular disease, and neurocognitive defects requires further evaluation, particularly in relation to

acromegaly, it is generally currently regarded as third line behind surgery and medical therapy, given the high efficacy and safety of medical therapy, the propensity


radiosurgery. Although radiotherapy still has a role to play in selected cases of



17

of radiotherapy to cause hypopituitarism and the uncertain long term complication rate of radiotherapy. However, as with most complex medical management decisions, treatment needs to be individualised with an experienced multidisciplinary


team weighing up the benefits and risks for each patient.



18

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2012;166(2):171-9.



26

Table 1. All-cause and cause-specific mortality in patients with acromegaly treated with radiotherapy. Cause

All-cause

Observed

Expected

Deaths

Deaths

59

37.4

SMR (95% CI)

P

1.58 (1.22 -

0.005

2.04) Cerebrovascular

16

3.6

4.42 (2.71 -

0.005

7.22) Cardiovascular

20

12.5

1.60 (1.03 -

0.096

2.48) Respiratory

7

4.0

1.75 (0.84 -

0.261

3.68) Malignancy

12

12.0

1.00 (0.57 -

1.000

1.76)

From (12), with permission. Neuroendocrinology (International Journal for Basic and Clinical Studies on Neuroendocrine Relationships) Journal Editor: Millar R.P. (Edinburgh) ISSN: 0028-3835 (Print), eISSN: 1423-0194 (Online)

www.karger.com/NEN Disclaimer: Accepted, unedited article not yet assigned to an issue. The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content. Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center. © 2015 S. Karger AG, Basel


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The role of Sandostatin in acromegaly.

Ultrastructural-morphometric effects of radiotherapy on pituitary adenomas in acromegaly.

The role of pasireotide in the treatment of acromegaly.

The role of diabetes in acromegaly associated neoplasia.

Acromegaly first diagnosed in pregnancy: the role of bromocriptine therapy.

Results of radiotherapy in the treatment of acromegaly: lack of ophthalmologic complications.

The role of radiotherapy in palliative care.

The role of radiotherapy in bladder cancer.

Long-term results of fractionated stereotactic radiotherapy as third-line treatment in acromegaly.

[Fahr syndrome: a rare complication of brain radiotherapy occurring in patient with acromegaly].

Paediatric haemangiomas: the role of radiotherapy.

Epithelial ovarian cancer: the role of radiotherapy.

The Emerging Role of Carbon-Ion Radiotherapy.

The role of radiotherapy in the management of POEMS syndrome.

The role of radiotherapy in the management of penile cancer.

The role of radiotherapy in the management of multiple myeloma.

The role of stereotactic radiotherapy in the treatment of oligometastases.

[The therapy of acromegaly].

The History of Acromegaly.

Cardiovascular events in acromegaly: distinct role of Agatston and Framingham score in the 5-year prediction.

Role of IGF1-(CA)19 promoter microsatellite in the clinical presentation of acromegaly.

Acromegaly.

Acromegaly.