Abstract
Introduction
Persistent growth hormone hypersecretion can be observed in roughly 50% of patients operated for somatotroph adenomas, requiring additional treatments. Despite its proven antisecretory efficacy, the use of Gamma Knife radiosurgery (GK) is limited probably due to the lack of data on long-term side effects, including potential cognitive consequences.
Methods
The LATe Effects of Radiosurgery in Acromegaly study was a cross-sectional exposed/unexposed non-randomized study. The primary objective was to determine the long-term neurocognitive effects of GK focusing on memory, executive functions, and calculation ability. Exposed patients had been treated by GK for acromegaly at least 5 years before inclusion. Unexposed patients (paired for age) had to be cured or controlled at last follow-up without any radiation technique. Patients of both groups were cured or controlled at the last follow-up.
Results
Sixty-four patients were evaluated (27 exposed and 37 unexposed). Mean follow-up after GK was 13 ± 6 years (including 24 patients followed for at least 10 years). While up to 23.8% of the patients of the whole cohort presented at least one abnormal cognitive test, we did not observe any significant difference in neurocognitive function between both groups. During the follow-up, 11 patients presented at least one new pituitary deficiency (P = 0.009 for thyroid-stimulating hormone deficiency with a higher rate in exposed patients), two presented a stroke (1 in each group), and one presented a meningioma (12 years after GK).
Conclusions
While GK exposes patients to a well-known risk of pituitary deficiency, it does not seem to induce long-term cognitive consequences in patients treated for acromegaly.
Introduction
In 2014, the Endocrine Society Clinical Practice guidelines on the management of acromegaly stated that ‘radiation therapy may be considered at any point following incomplete surgery’ (1). Four years later, the ‘consensus statement on acromegaly therapeutic outcomes’ reported that ‘radiotherapy remains an option in patients with persistently active acromegaly, but rates of control and safety have only marginally improved with the use of stereotactic radiosurgery instead of conventional fractionated radiotherapy’ (2). These concerns and the regular use of pegvisomant likely explain the progressive decline of radiotherapy in acromegaly over the last 10 years, as is shown by the data from the French registry of acromegaly: between 2000 and 2012, the rate of patients treated by radiotherapy in France fell drastically from roughly 30 to 10% (3).
However, several reports have emphasized the antisecretory efficacy of Gamma Knife radiosurgery (GK) in acromegaly (4, 5, 6). Indeed, the largest study thus far reported, which was based on 371 patients followed worldwide, showed that 59% of the patients treated using GK were disease-free 10 years after the procedure (7). This result was similar to that reported more than 10 years ago in the largest study on conventional radiotherapy in acromegaly (8). Both procedures thus showed a high level of antisecretory efficacy allowing cure in more than half of the patients. Short-term side effects are also well-known. The risk of hypopituitarism is estimated to be 20–50% and 50–80% for radiosurgery vs radiotherapy, respectively (9, 10), and GK can also lead to optic neuritis in 1% of the cases, when the target tissue is too close to the optic chiasm, and/or the dose delivered to the optic chiasm is too high (11). Long-term side effects of conventional radiotherapy are also well described, with an increased risk of secondary brain tumors (12) and stroke (13), while variable results have been reported for cognitive effects (for review see (14)). These points have not previously been raised for GK due to the lack of long-term (up to 10 years) evaluation of the procedure regardless of the indication. Indeed, long-term side effects of radiotherapy have been described more than 10 years after the procedure. Recently, Tooze and coworkers reported for the first time the lack of short- to mid-term neurocognitive differences in 51 patients treated for pituitary adenomas with GK, after a mean follow-up of 53 ± 35 months (15). However, the follow-up was rather short, and the group of patients was also heterogeneous in terms of secretion. These results suggested that the technique of GK, focusing on the target and theoretically sparing the surrounding structures, might be less toxic than conventional radiotherapy.
To determine the long-term cognitive side effects of GK in a specific type of pituitary adenoma, we conducted a prospective evaluation of patients in remission for acromegaly who were followed long-term in our department. Extra-pituitary outcomes in these patients were compared according to whether patients received treatment with GK or not.
Methods
Patients
The Later-Ac (LATe Effects of Radiosurgery in Acromegaly) study was a cross-sectional, exposed/unexposed, non-randomized study based on cured or controlled patients with acromegaly. The Later-Ac prospective subject inclusion was in the period from mid-2014 to mid-2017. The main objective of the study was to determine the long-term neurocognitive effects of GK in patients in remission of acromegaly, focusing on memory (Grober and Buschke test), executive functions (Stroop and Trail Making test), and speed and flexibility of auditory information processing, as well as calculation ability (Paced Auditory Serial Attention Test). For this, we compared two groups of patients, the first who were treated by GK (exposed subjects) and the second who were treated with therapeutic modalities other than radiation techniques (unexposed subjects):
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Exposure was defined by a single treatment with GK during the course of acromegaly treatment: exposed patients were eligible for inclusion if they were ≥18 and <75 years old, if they had been treated with GK at least 5 years before study inclusion, and had been followed long-term in the Department of Endocrinology, La Conception Hospital, Marseille, France (at least one evaluation every year by a physician from the Department during the follow-up period). Patients who had been followed for less than 5 years in our Department or who had been treated twice by radiosurgery or who had undergone treatment with other radiation techniques were not included.
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Unexposed patients were recruited from the departments of endocrinology of Marseille, Montpellier, and Toulouse hospitals, France: they had to be ≥18 and <75 years old, followed up for acromegaly for at least 5 years, and considered cured or controlled without the use of GK or any other radiation technique.
Cure was defined by normal age and sex-insulin-like growth factor 1 (IGF1) levels and an oral glucose tolerance test growth hormone (GH) level <0.4 ng/mL at least 6 months after withdrawal of antisecretory drugs for those patients without a glucose anomaly. Control was defined by normal age and sex-IGF1 levels and a mean of six samples of GH measured every 15 min that was below 1 ng/mL on antisecretory drugs.
We hypothesized that the focused delivery of radiation by GK would not lead to altered cognitive function. Our secondary objectives were to compare the levels of fatigue, quality of life, and anxiety between the two groups and to determine the rates of stroke, secondary brain tumors, and induced pituitary deficiencies between exposed and unexposed patients.
All patients gave their signed written informed consent, as approved by the ‘Comite de Protection des Personnes Sud-Mediterranee’ A00504-43. The study was registered in clinical trials as NCT02296216.
Study course
During the course of their classical follow-up, patients were asked to participate in this study. A pituitary evaluation (08:00 adrenocorticotrophic hormone and cortisol; thyroid-stimulating hormone, free T4, free T3; luteinizing hormone, follicle-stimulating hormone, and estradiol/testosterone) was performed at the time of study inclusion to ensure that pituitary deficiencies, if any, had been correctly treated for at least 6 months. A brain MRI was performed in all patients to look for evidence of a history of stroke or secondary brain tumors.
Several evaluations were then performed by a dedicated neuropsychologist (C J), and for each specific test (Grober and Buschke test, Stroop and Trail Making Test, and the Paced auditory serial attention test (PASAT)), each patient was classified as presenting with normal or altered cognitive function, based on the respective specific normal values of the French reference population (16, 17, 18). Questionnaires were also filled out by the patients to evaluate the following parameters: quality of life was evaluated based on a generic questionnaire, SF36 (19), and a specific-disease questionnaire dedicated to acromegaly quality of life (AcroQoL) (20). For both questionnaires, a higher score value indicates better quality of life. Fatigue was evaluated using the Modified Fatigue Impact Scale (MFIS), which explores three different domains: physical, psychological, and psychosocial. A higher score on these tests indicates a higher level of fatigue (21). Anxiety was evaluated based on the State Trait Anxiety Inventory (STAI) questionnaire. A higher score here indicates a higher level of anxiety (22). Depression was evaluated based on the Beck Depression Inventory (23). A total score >16 suggests severe depression while a score between 8 and 15 suggests mild depression.
Statistical analysis
Two groups were compared, that is, patients exposed or unexposed to GK. Demographics and clinical data were compared between the groups in accordance with the nature of the variable (χ2 tests or Fisher’s exact test; Student’s t-test or Mann–Whitney tests). The proportions of abnormal tests, based on the definitions described above, were compared between groups (χ2 tests or Fisher’s exact test). Scores for mood status, quality of life, anxiety, and fatigue were compared between groups (Student’s t-test or Mann–Whitney tests). Statistical analyses were performed using SPSS software (IBM SPSS PASW Statistics Inc.). All tests were two-sided. P < 0.05 was considered statistically significant.
Results
From a total of 45 patients treated using GK who were exclusively followed in our Department, who were considered controlled or cured at last follow-up, 18 were not included (4 were treated using another radiation technique in addition to GK during the course of their management, 2 were treated twice with GK, 8 were lost to follow-up, and 4 declined to participate in the study). A total of 27 patients were thus included in the exposed group, and a total of 37 patients were included in the unexposed group. Exact sociodemographic, diagnostic, therapeutic, and follow-up comparative characteristics between the groups of exposed and unexposed patients are outlined in Tables 1 and 2. In the whole cohort of 64 patients, cognitive dysfunction was observed in 18, 24, 8, and 8% of patients for the Grober and Bushke test (for short free, short total, long free and long total memory, respectively), 15, 13, and 10% of patients for the Stroop test (for A, B, and C evaluations, respectively), and 2, 2, and 3% of patients for the Trail making test (for A, B, and B-A evaluations, respectively). During the follow-up period, 11 patients (17%) presented at least one new pituitary deficiency, 2 patients (3%) presented with a stroke, and one presented with a meningioma.
Main sociodemographic characteristics of patients exposed or unexposed to Gamma Knife radiosurgery.
| Exposed (n = 27) | Unexposed (n = 37) | P | |
|---|---|---|---|
| Sex ratio | 0.01 | ||
| Females | 21 (78%) | 17 (46%) | |
| Males | 6 (22%) | 20 (54%) | |
| BMI (kg/m2) | 28 ± 5.4 | 28 ± 4.5 | |
| Familial status | 0.30 | ||
| Single | 10 (37%) | 9 (25%) | |
| Couple | 17 (63%) | 27 (75%) | |
| Scholar status | 0.75 | ||
| Up to high school | 12 (44%) | 17 (49%) | |
| University | 15 (56%) | 18 (51%) | |
| Professional status | 0.82 | ||
| Active | 12 (44%) | 15 (42%) | |
| Non active | 15 (56%) | 21 (58%) | |
| Tobacco | 5 (18%) | 9 (25%) | 0.54 |
| Hypertension | 11 (59%) | 19 (51%) | 0.40 |
| Statins | 6 (22%) | 12 (32%) | 0.37 |
| Diabetes | 5 (18%) | 9 (24%) | 0.58 |
| Cardiovascular history | 3 (11%) | 4 (11%) | 1 |
| Familial cardiovascular history | 9 (35%) | 15 (42%) | 0.57 |
Main diagnostic, therapeutic, and follow-up characteristics between patients exposed or unexposed to Gamma Knife radiosurgery. Data are presented as n (%) or as mean ± s.d.
| Exposed (n = 27) | Unexposed (n = 37) | P | |
|---|---|---|---|
| Age at inclusion (years) | 56.7 ± 12.3 | 60.3 ± 11.2 | 0.23 |
| Age at diagnosis (years) | 39.9 ± 13.0 | 44.2 ± 11.8 | 0.17 |
| Pituitary adenoma | 0.73 | ||
| Microadenoma | 5 (18%) | 5 (13%) | |
| Macroadenoma | 22 (82%) | 32 (87%) | |
| Transsphenoidal surgery | 17 (63%) | 23 (62%) | 0.95 |
| Age at surgery* | 35.6 ± 11.8 | 40.3 ± 9.7 | 0.19 |
| Age at GK | 43.8 ± 14.3 | – | – |
| Follow-up since diagnosis | 16.7 ± 7.6 | 16.4 ± 9.8 | 0.90 |
| Follow-up since GK | 13.3 ± 6.1 | – | |
| Final secretory status | <0.0001 | ||
| Cured | 16 (59%) | 1 (3%) | |
| Controlled on drugs | 11 (41%) | 36 (97%) | |
| Adenoma remnant on MRI | 0.002 | ||
| Visualized | 8 (22%) | 23 (92%) | |
| Not visualized | 29 (78%) | 2 (8%) | |
| Pituitary deficiencies | |||
| TSH deficiency | 9 (33%) | 2 (6%) | 0.009 |
| ACTH deficiency | 4 (15%) | 1 (3%) | 0.17 |
| LH/FSH deficiency | 2 (7%) | 3 (10%) | 1 |
*Age at surgery: 40 patients were operated.
Exposed and unexposed patient groups
A total of 27 patients were included in the exposed group, that is they were treated by GK (for a macroadenoma in 22 cases). Seventeen (63%) had been first treated with (failed) transsphenoidal surgery, followed by GK after a mean time of 3.4 ± 1.5 years. At the time of inclusion, 16 (59%) were cured by GK, that is without administration of any antisecretory drug for at least 6 months, while 11 (41%) were controlled on drugs (including 5 on somatostatin analogs alone, 1 on somatostatin analogs and cabergoline, and 5 on pegvisomant alone). Mean margin dose was 25.6 ± 6.8 Gy, mean dose to the stalk was 15.8 ± 6.9, and mean dose to the chiasm was 5.5 ± 2.3 Gy. Mean target volume was 2 ± 1.2 mm3. The mean follow-up post GK was 13.3 ± 6.1 years. All but three of them were followed for at least 10 years after GK treatment.
A total of 37 patients were included in the unexposed group, including 32 (87%) who presented with a macroadenoma. Twenty-three (62%) had been treated by (failed) transsphenoidal surgery. All but one of the patients were treated with antisecretory drugs at the time of the study, including 31 treated with somatostatin analogs alone, 2 with cabergoline alone, and 2 with pegvisomant alone. The mean follow-up after diagnosis was 15.8 ± 9.8 years.
Neurocognitive function and outcome after GK
As shown in Tables 1 and 2, there was no significant difference in terms of age at inclusion (56.7 vs 60.3 years, P = 0.23) and duration of disease since diagnosis (16.7 vs 16.4 years, P = 0.90) between the exposed and unexposed patient groups. No significant differences were observed in family, educational, and professional status nor in cardiovascular risk profiles between the groups. Both groups could thus be compared for the potential toxicity of GK. Our primary objective was to compare the cognitive status of exposed and unexposed patients. As shown in Table 3, the results of Grober and Buschke test, Stroop Tail Making test, and PASAT did not show any significant difference between exposed and unexposed patients. Our secondary objectives were to compare the levels of quality of life, anxiety, and depression between groups. No significant differences were observed between the groups for any of these parameters (Table 3). Of note, the Beck status was significantly different between both groups, with more patients presenting with mild depression in the exposed patients and more patients presenting with severe depression in the unexposed patients.
Comparison of cognitive and quality of life markers between patients exposed or unexposed to Gamma Knife radiosurgery. Data are presented as n (%) or as mean ± s.d.
| Exposed (n = 27) | Unexposed (n = 37) | P | |
|---|---|---|---|
| Headaches | 3 (11%) | 7 (21%) | 0.49 |
| Cognitive complaints | 4 (15%) | 5 (14%) | 1 |
| Stroke | 1 (4%) | 1 (3%) | 1 |
| Secondary brain tumor | 1 (4%) | 0 (0.0%) | 0.4 |
| Mean age at last MRI (years) | 55.5 ± 12.5 | 60.2 ± 11.4 | 0.13 |
| Mean time between GK or surgery and last MRI (years) | 12 ± 6.5 | 18.2 ± 11.3 | 0.03 |
| Grober and Buschke test | |||
| Abnormal short free memory Abnormal short total memory Abnormal long free memory Abnormal long total memory |
4 (15%) 6 (23%) 2 (8%) 2 (8%) |
7 (20%) 9 (24%) 3 (9%) 3 (9%) |
0.74 0.91 1 1 |
| Stroop test | |||
| Abnormal stroop A Abnormal stroop B Abnormal stroop C Abnormal stroop inter C-A |
4 (15%) 3 (11%) 4 (15%) 2 (7%) |
5 (14%) 5 (14%) 2 (6%) 0 (0%) |
1 1 0.39 0.19 |
| Trail Making test | |||
| Abnormal TMT A Mean TMT A (seconds) Abnormal TMT B Mean TMT B (seconds) Abnormal TMT (B-A) |
1 (4%) 39 ± 14.1 0 (0.0%) 94 ± 53.6 0 (0.0%) |
0 (0.0%) 44.8 ±18.7 1 (3%) 101.7 ± 51.9 2 (6%) |
0.44 0.29 1 0.18 0.50 |
| Paced Auditory Serial Attention test | 0.07 | ||
| Normal focus Abnormal focus |
95.2% 4.8% |
73.5% 26.5% |
|
| Beck score | 6.8 ± 8 | 5.1 ± 4.2 | 0.30 |
| Beck status | 0.005 | ||
| Normal Mild Moderate Severe |
15 (56%) 2 (7%) 6 (22%) 4 (15%) |
13 (36%) 17 (47%) 5 (14%) 1 (3%) |
|
| AcroQoL | 75.5 ± 18.7 | 71.2 ±16.3 | 0.37 |
| SF-36 | |||
| Physical Social life Physical limitations Emotional limitations Mental health Vitality Physical pain Perceived health Physical score Psychical score |
72.2 ± 25.2 68.5 ± 29.3 71.6 ± 28.7 59.2 ± 13.1 55.8 ± 26.9 44 ± 23.1 57.7 ± 32.7 49.5 ± 27.6 45.2 ± 11.4 40.6 ± 10.9 |
71.8± 21.8 75 ± 24.4 62.7 ± 24.8 59.1 ± 12.6 60.2 ± 20.9 45. ±20.6 51.3 ± 23.8 51.3 ± 16.2 43 ± 8.5 43.5 ± 8.4 |
0.95 0.34 0.19 0.94 0.46 0.74 0.39 0.76 0.38 0.25 |
| ASTA | |||
| State | 39.7 ± 15 | 36.4 ± 10.9 | 0.3 |
| Trait | 45.6 ± 12.1 | 44.5±12.5 | 0.75 |
| MFIS | |||
| Physical | 15.3 ±10.5 | 17.6 ± 8.1 | 0.34 |
| Cognitive | 15.1 ± 10.4 | 16.5 ± 7.5 | 0.53 |
| Psychosocial | 3 ± 2.6 | 3.5 ± 2.2 | 0.36 |
| Total | 33.9 ± 22.5 | 37.7 ± 15.9 | 0.43 |
Stroke: clinical signs or MRI suggestive of history of stroke.
TMT, Trail making test; Beck score (higher score = higher depression); ASTA (higher score = anxiety); MFIS (higher score = more severe fatigue).
As anticipated, a higher rate of pituitary deficiencies was found in the exposed patients (Table 2). As mentioned in the methods, all patients were on a stable dose of replacement treatments at the time of inclusion. We also determined the rate of patients who presented with secondary brain tumors (one patient had a meningioma 12 years after GK, while none had tumors in the unexposed group), and the rate of stroke (one patient in both groups had a history of asymptomatic stroke incidentally identified on MRI). Again, no significant difference was observed between the two groups (Table 3).
Discussion
Patients with long-term remission of acromegaly (greater than 10 years) may present with neurocognitive sequelae. Indeed, despite having long-term cure or control of GH secretion, almost a quarter of our patients showed at least a mild cognitive deficiency when compared to a reference population. In a review looking at cognitive dysfunction and pituitary adenomas, Pertichetti et al. reported that 2–33% of patients with active acromegaly presented with neurocognitive dysfunction (24), as has been detailed in several studies (25, 26). Surprisingly, Tiemensma et al. did not report any cognitive dysfunction after long-term cure (13 years) of patients with acromegaly, when compared with 68 matched controls and 60 patients treated for non-functioning pituitary adenomas. Interestingly, the authors also reported specific maladaptive personality traits, an observation that has not subsequently been reported in patients in remission of acromegaly (27). In contrast, Brummelman et al. reported no significant difference between patients with active (n = 22) or controlled (n = 28) acromegaly after a mean of 8 years follow-up, while patients with active acromegaly scored worse than controls in terms of cognitive function (28). These discordant results could be explained by the use of different tests or by a different profile of the patients studied (including patients immediately cured by surgery vs patients controlled by somatostatin analogs). Despite that, we consider that our results show the need for optimal management of the cognitive consequences of acromegaly, as soon as the treatment is begun, to avoid sequelae due to GH hypersecretion.
In our relatively small cohort of patients, GK treatment per se did not increase the risk of cognitive deficiency in comparison to unexposed controls after a median follow-up of 13.3 years. The cognitive effects of conventional radiotherapy in pituitary adenoma remain however controversial. In a cohort of 43 patients with non-functioning pituitary adenomas, Brummelman et al. reported that radiotherapy had been received more frequently by those patients in whom they identified one or more impairments on verbal memory function (29). In a large study on 124 patients with secreting and non-secreting pituitary adenomas, Lecumberri et al. reported that radiotherapy (n = 56 patients) was independently and statistically associated with an impairment of verbal memory and executive function (30). In contrast, Crouzeix et al., in a study based on 46 patients followed for almost 10 years, reported that patients treated with radiotherapy for non functioning pituitary adenoma (NFPA) did not present with cognitive deficits but did show altered quality of life. However, they also suggested that this might be due to a higher rate of pituitary deficiencies rather than to the radiotherapy itself (31). To our knowledge, only one retrospective cross-sectional study has evaluated the cognitive effects of GK in patients treated for a pituitary adenoma. In a study of a total of 51 patients, including 21 who were treated by GK, memory scores were reported to be not significantly different among exposed and unexposed patients. However, this study was very heterogeneous in terms of secretion profiles (for instance, 10 vs 4 patients with Cushing’s disease were included in the unexposed and exposed groups, respectively, and this could then overestimate the rate of cognitive deficits in unexposed patients). Moreover, the mean follow-up after GK in the study was only 53.3 ± 35 months (15). Our study thus represents the first to suggest the lack of cognitive long-term side effects of GK in patients with acromegaly.
Quality of life, fatigue, and anxiety were found to be not significantly different between exposed and unexposed patients with acromegaly. Quality of life is known to be altered in patients with acromegaly, even after long-term remission, as suggested by the specific acroQoL questionnaire (20). Notably, Kunzler et al. recently showed, in a pilot study including 10 patients, that cognitive-behavioral therapy could improve the quality of life of patients with acromegaly (32). Interestingly, the fact that those patients treated by GK had more pituitary deficiencies than unexposed patients did not worsen their quality of life, probably because the patients were required to have effective hormone replacement for at least 3 months at the time of inclusion. The rate of pituitary deficiencies induced by GK in our study was comparable to that reported previously in the literature, with a third of patients presenting with at least one new pituitary deficiency (10). In contrast to GK, conventional radiotherapy has been shown, in several studies, to alter the quality of life in patients treated for pituitary adenomas (31, 33). However, this was generally considered to be due to the induced pituitary deficiencies, a side effect that is usually more frequent in patients treated by radiotherapy than with GK. Though this was not our primary criterion, we did not observe any increased risk of brain tumor or stroke in exposed patients. In the largest retrospective study published to date on radiation-induced brain tumors (3236 patients with pituitary adenoma treated by radiotherapy vs 4927 without), Burman et al. reported a 3.3 relative risk in patients treated by radiotherapy, with the risk being increased in those patients treated at a younger age. However, the authors did not report any radiation-induced brain tumors in the smallest group of patients who were treated by GK (12). To our knowledge, only rare cases of secondary brain tumors have been reported after GK for indications such as meningioma or arteriovenous malformation (34). Finally, while the increased risk of stroke has been described after conventional radiotherapy (for review see (13)), it has not been shown for GK in pituitary adenomas, while the prevalence of stroke was 9% after 21 months follow-up in patients treated for arteriovenous malformations (11).
There are several limitations in our study. First, only 27 patients could be evaluated in the exposed group. This was due to the fact that we included only patients with at least 5 years of follow-up and who were still followed regularly in our Department. Our conclusions will thus need to be confirmed by studies with a larger number of patients. This low number makes our results concerning secondary criteria of evaluation less stringent. This is especially the case for strokes and brain tumors, for which a larger population would be necessary, given the low incidence of such events even in patients treated by conventional radiotherapy. Secondly, while our median follow-up was 13 years, we did include three patients who had been treated with GK less than 10 years before. However, the large majority of the patients in our study had been treated more than 10 years before, and thus we do not believe that these three patients would have biased our results. Thirdly, an ideal study design would have been to include controls treated with antisecretory drugs during the same time as the patients who were treated with GK since they would be treated using somatostatin analogs while waiting for maximal efficacy of GK. While 40% of patients were on somatostatin analogs in the exposed group, more than 90% were receiving medical treatment in the unexposed group. We decided to exclude patients who would have been treated by a curative surgery to avoid the fact that these patients would be immediately cured. Of note, the rate of surgical treatment of patients was the same in the exposed and unexposed groups. Finally, when we discuss GK toxicity, comparison with conventional radiotherapy is usually made: we decided not to include a group of patients treated with these techniques as recent improvements of radiotherapy would have made this comparison outdated.
To conclude, our study shows, for the first time, the long-term cognitive safety of GK in patients treated for acromegaly, a population which may have cognitive sequelae of GH hypersecretion, regardless of the treatment. Despite the fact that our results should be interpreted with caution given the relatively small number of patients included, they may provide reassurance to physicians when they are considering a modern modality of radiation technique for patients with acromegaly.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this study.
Funding
This study was supported by a grant from the French Ministry of Health (PHRC-IR, 2013, PHRC I 2013 – 13-011).
Data sharing statement
Data collected for the study, including individual participant data and a data dictionary defining each field in the set, will be made available upon reasonable request to the corresponding author.
Acknowledgements
The authors would like to thank Dr Cuny for fruitful discussions, and Ian Darby for English editing.
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