Radiotherapy and Oncology 114 (2015) 239–244
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Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
MRI in pituitary adenoma
Brain abnormalities on MRI in non-functioning pituitary adenoma patients treated with or without postoperative radiotherapy Margriet G.A. Sattler a,b,⇑, Linda C. Meiners c, Wim J. Sluiter d, Gerrit van den Berg d, Johannes A. Langendijk a, Bruce H.R. Wolffenbuttel d, Alphons C.M. van den Bergh a, André P. van Beek d a Departments of Radiation Oncology, University of Groningen, University Medical Center Groningen; b Department of Radiation Oncology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam; c Department of Radiology, University of Groningen, University Medical Center Groningen; and d Department of Endocrinology and Metabolic Diseases, University of Groningen, University Medical Center Groningen, The Netherlands
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i n f o
Article history: Received 31 August 2014 Received in revised form 27 December 2014 Accepted 3 January 2015 Available online 14 January 2015 Keywords: Non-functioning pituitary adenomas Postoperative radiotherapy Surgery Brain side effects MR imaging
a b s t r a c t Background and purpose: To assess and compare brain abnormalities on Magnetic Resonance Imaging (MRI) in non-functioning pituitary macro-adenoma (NFA) patients treated with or without postoperative radiotherapy (RT). Material and methods: In 86 NFA patients, treated between 1987 and 2008 at the University Medical Center Groningen, white-matter lesions (WMLs), cerebral atrophy, brain infarctions and abnormalities of the temporal lobes and hippocampi were assessed on pre- and post-treatment MRI scans in patients treated with (n = 47) or without RT. Results: The median MRI follow-up time for RT patients was 10 (range 1–22) years and 5 (range 1–21) years in patients treated without RT. In RT patients the cumulative incidence of WMLs was significantly lower compared to patients treated without RT (log-rank test RR 0.49, 95% CI 0.25–0.97, p = .042). The cumulative incidences of cerebral atrophy, brain infarctions, abnormalities of the temporal lobes and hippocampi, and the severity of WMLs and cerebral atrophy ratings were not significantly different between the two treatment groups. Conclusions: Brain abnormalities on MRI are not observed more frequently in NFA patients treated with RT compared to patients treated with surgery-alone. Furthermore, RT was not associated with an increased severity of WMLs and cerebral atrophy ratings in this cohort of NFA patients. Ó 2015 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 114 (2015) 239–244
In patients with non-functioning pituitary macro-adenoma (NFA), radiotherapy (RT) is usually applied as adjuvant treatment to prevent tumour progression after incomplete resection, or as salvage treatment in case of local recurrence after surgery, or as primary treatment in patients who are medically inoperable or refuse surgery. In NFA patients, RT results in excellent long-term local tumour control with reported rates of 90–97% at 10 years [1–4]. However, NFA are benign tumours, and therefore, concerns related to possible long-term side effects of RT to the brain are often used to delay or reject RT. Several studies have reported on long-term radiological brain effects in primary brain tumour patients treated with RT. Whitematter lesions (WMLs) and cerebral atrophy are well known radiological detectable abnormalities of the brain [5–7] and there appears to be a correlation with cognitive function [7]. ⇑ Corresponding author at: Department of Radiation Oncology, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. E-mail address: [email protected] (M.G.A. Sattler). http://dx.doi.org/10.1016/j.radonc.2015.01.003 0167-8140/Ó 2015 Elsevier Ireland Ltd. All rights reserved.
In NFA patients the long-term radiological brain effects of RT (i.e. WMLs and cerebral atrophy) are unknown and have not yet been investigated. Nevertheless, several studies reported on cognitive function [8–10]. Previously, we found no major influence of RT on cognition in NFA patients treated with RT compared to those treated with surgery-alone [8,9]. Furthermore, a dose–response relationship, by relating detailed radiation dosimetry to the temporal lobes, hippocampi and the prefrontal cortex, with cognition could not be established [10]. In addition, we showed that postoperative RT was not associated with an increased incidence of second tumours, stroke or mortality compared to pituitary adenoma patients treated with surgery-alone [11,12]. Lastly, we demonstrated that immediate postoperative RT in residual NFA has no additional negative impact on pituitary function compared to patients with residual disease and followed by an active surveillance policy [3]. In the light of our earlier results on the effects of postoperative RT, we postulated that RT has no additional adverse radiological brain effects. Therefore, our main objective is to assess and compare brain abnormalities on magnetic resonance imaging (MRI)
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(i.e. WMLs, cerebral atrophy, brain infarctions, abnormalities of the temporal lobes and hippocampi) in NFA patients treated with and without RT. Materials and methods Patients A total of 86 NFA patients underwent treatment between August 1987 and May 2008 at University Medical Center Groningen. The NFA diagnosis was based on the patient’s clinical history and presentation, endocrine evaluation, MRI outcome, and confirmed by postoperative histopathologic findings. To assure that acute and early-delayed post-treatment effects had resolved, RT patients and surgery-alone patients had an MRI follow-up of at least 6 months and 3 months, respectively. All patients were followed with MRI scans from the onset of diagnosis until November 2010 or date of death. Postoperative RT RT was indicated in case of residual disease after incomplete resection or as salvage treatment in patients with recurrent disease after surgery. All individual RT data were retrieved from the patient charts. The median total RT dose was 45 Gy (Gray) (range, 45–50.4 Gy) and most patients received 25 daily fractions of 1.8 Gy in 5 weeks. From 1987 to 2008 the RT patients (n = 47) were treated with linear accelerators with 4- to 18-MeV photons. The RT dose to the tumour was prescribed at the tumour encompassing isodose (n = 9) in the time period 1987–1990. From 1991 to 2008, the dose was prescribed at a central point in the tumour (n = 38) according to the recommendations of the International Commission on Radiation Units and Measurements (www.icru.org). In this time period, different conventional RT techniques were used: rotational (n = 1), 2 fields (n = 1), 2 fields and 3 fields (n = 6), 2 fields and 5 fields (n = 2), 3 fields (n = 22), 4 fields (n = 7) and 5 fields (n = 8). In the 1990s 3-dimensional (3D) RT treatment planning techniques were used. The gross tumour volume (GTV) is the grossly visible pituitary adenoma defined by Computed tomography (CT) or MRI. The planning target volume (PTV) was defined as the GTV plus a 1cm margin. MRI scans All MRI scans were all obtained from the Department of Radiology at the University Medical Center Groningen between July 1987 and November 2010. The MRI scans were primarily done for diagnosis and post-treatment NFA follow-up. MRI scanning was performed according to a standard NFA protocol. This protocol consisted of coronal T2 weighted images, and coronal and sagittal T1 weighted images without contrast, of the pituitary gland region, including the frontal and temporal lobes. The MRI scans were made on a 1 Tesla system using a regular head coil. All MRI scans (i.e. diagnosis and follow-up) were made on this same system during the study time period 1987–2010 in view of enabling comparison. The frontal and temporal lobes were assessed, as well as the frontal and temporal horns, central and peripheral cerebrospinal fluid (CSF) spaces and the hippocampi. Rating of MRI abnormalities MRI scans were presented randomly and rated by an experienced neuroradiologist (LM) blinded to clinical data and treatment. WMLs were defined as subcortical or periventricular focal or confluent areas of abnormal high signal intensity on T2 weighted
images in the white matter of the brain. The severity of WMLs was rated on a four point visual rating scale (Fazekas classification: grade 0–3): grade 0: none or one lesion 6 9 mm; grade 1: single lesions 6 9 mm in diameter and areas of grouped lesions 6 20 mm in diameter; grade 2: one lesion of between 10 and 20 mm in diameter or areas of grouped lesions > 20 mm in diameter with no more than connecting bridges (i.e. no confluence of lesions) between each lesion; grade 3: single lesions and confluent areas of high signal intensities > 20 mm in diameter [13,14]. In all patients the presence of other possible (cardiovascular) risk factors for WMLs, cerebral atrophy and brain infarctions were assessed [15–19]. Cerebral atrophy (cortical, central or cortical and central) was determined by visual assessment as an increase in the peripheral CSF spaces with an increase in the width of the sulci and dilatation of CSF, loss of parenchyma, and dilatation of the ventricular system (lateral and third ventricles). The severity of the cerebral atrophy (i.e. sulcal and ventricular enlargement) was classified into no cerebral atrophy or presence of cortical, central, or cortical and central involvement. Cerebral atrophy was rated on T2 weighted MRI scans. Brain infarctions (silent and symptomatic) were rated as present or absent and defined as larger areas of T2 hyperintense gliosis or focal tissue loss with local substitution of CSF on T1 or T2 weighted MR images. Lastly, any MRI abnormalities of the temporal lobes and the hippocampi including atrophy or posttraumatic cortical and subcortical damage were rated on T2 weighted images as present or absent.
Statistical analysis In the time to event analysis of longitudinal follow-up, the age at start of follow-up must be taken into consideration, because there is an inverse correlation between age and life-expectancy. We used age instead of surviving time as the time base in the analyses [20], because age itself is related to other risk factors of lifeexpectancy. In this way, patients of the same age were compared and age at the event (i.e. brain abnormality) instead of surviving time was the outcome parameter. Statistics by the log-rank test was used with which the number of observed events and the calculated expected values (i.e. extent of exposure) were used to calculate relative risks (RRs). The RRs and 95% confidence intervals (CI) for cumulative incidence of MRI brain abnormalities were compared in NFA patients treated with or without RT by log-rank test. In the time to event analyses, differences in age and follow-up time between the two treatment groups were taken into account. Left-censoring was used because of differences in age at the start of MRI scan follow-up: the patient was only used in the analyses after reaching the age at start of MRI follow-up (i.e. age at pre-treatment MRI scan). Right-censoring was also applied due to differences in follow-up time: the patient does not participate in the analyses at ages higher than that at the end of MRI scan follow-up (i.e., age at the last post-treatment MRI scan or age at appearance of a brain abnormality). In case the date of first occurrence of any of the MRI brain abnormalities was unknown, the date on half of the MRI follow-up time was used. Categorical variables were analysed using chi-square test (v2 test) and continuous variables were analysed by the Mann–Whitney U test. Data are presented as median, frequencies or percentages when appropriate. Two-tail p-values of 50 Gy 3 Radiation fraction dose: 1.8 Gy 43 2.0 Gy 4 Hormonal substitution No. of hormone replacements (0/1/2/3/4/5) Glucocorticoids Thyroid hormone Growth hormone Sex hormones Desmopressin Cardiovascular risk factors Hypertension Atrial fibrillation Hypercholesterolemia Diabetes mellitus Coronary- or peripheral artery disease Prior stroke
0.49
– –
6/5/8/14/14/ 0 36 (77) 34 (72) 10 (21) 31 (66) 8 (17)
5/5/14/12/3/ 0 26 (67) 22 (56) 6 (15) 22 (56) 5 (13)
0.08
14 (30) 2 (4) 13 (28) 5 (11) 8 (17)
15 (38) 1 (3) 11 (28) 3 (8) 8 (21)
0.54 0.59 0.84 0.76 0.27
0
3 (8)
0.18
0.44 0.15 0.67 0.50 0.77
Abbreviations: RT+: patients with postoperative radiotherapy; RT : patients without postoperative radiotherapy; y: year; Gy: Gray. Data are given as absolute numbers, median (range) or number (percentage). * RT + versus RT by v2 test or Mann–Whitney U test.
In this study we showed that the cumulative incidence of WMLs, cerebral atrophy, brain infarctions, abnormalities of the temporal lobes and hippocampi, and severity of WMLs and cerebral atrophy ratings on MRI were not increased in NFA patients treated with RT compared to patients treated with surgery-alone. To our knowledge, this is the first study investigating several radiological brain abnormalities in NFA patients. Pre- and posttreatment MRI scans were available for all patients. Furthermore, the incidence of brain abnormalities in irradiated patients was compared to patients treated with surgery-alone as a reference group. In irradiated primary brain tumour patients WMLs and cerebral atrophy are associated with larger RT treatment volumes, higher RT doses, and older age of the patient [5,21,22] and may also be influenced by (other) disease- (e.g., degree of malignancy, tumour recurrence, neurologic co-morbidity) and treatment-related (e.g., chemotherapy) factors relating to malignant brain disease. [22,23]. Other investigators have assessed and compared WMLs
Table 2 Relative risk and 95% confidence intervals for cumulative incidence of MRI abnormalities in NFA patients treated with and without postoperative radiotherapy. RT+
White-matter Lesions Cerebral atrophy Cortical Central Cortical & central Brain infarctions Temporal lobes Hippocampi
RT
Relative risk
95% CI
P (univariate)
10.62
0.49
(0.25–0.97)
0.042
20.84 20.68 17.18 5.57 5.83 4.49
0.65 0.73 0.61 0.87 0.73 0.84
(0.39–1.07) (0.43–1.22) (0.36–1.06) (0.28–2.68) (0.26–1.99) (0.27–2.63)
0.093 0.23 0.081 0.80 0.53 0.76
Obs
Exp
Obs
Exp
15 (32)
20.38
16 (41)
31 (66) 31 (66) 26 (55) 6 (13) 8 (17) 7 (15)
37.16 35.52 31.82 6.43 9.17 7.51
27 (69) 25 (64) 23 (59) 6 (15) 7 (18) 5 (13)
Abbreviations: Obs: observed numbers; Exp: expected numbers; CI: confidence interval. Other abbreviations as in Table 1.
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Fig. 1. Age at non-functioning pituitary macro-adenoma (NFA) diagnosis and age at white-matter lesions in patients treated with and without postoperative radiotherapy.
and cerebral atrophy and cognitive performance in low-grade glioma patients treated with or without RT [7,13]. The patient and treatment characteristics of these studies and this present study are shown in Table 3. The irradiated NFA patients in this study compared to irradiated primary brain tumour patients are treated with a lower RT fraction dose and a lower total RT dose, with focal RT to a fixed intracranial tumour position, and with smaller RT treatment volumes resulting in RT dose–volume differences within different areas of the brain, and NFA patients are not exposed to factors relating to malignant brain disease. Lastly, it has been shown that WMLs are often found on brain MRI scans of elderly people and the prevalence of WMLs increases with age [24]. The present study showed that the cumulative incidence of WMLs in NFA patients increases with age. Several limitations need to be addressed. Firstly, the coronal T2 weighted MR images used for the assessment provide a limited view of the cerebral hemispheres restricted to the frontal and temporal lobes. Although this can be acknowledged, complications which may be associated with surgical and/or RT for NFA patients would be expected in the frontal and temporal lobes, which were depicted as primary regions of interest on these images. Secondly, this study did not assess impairments in cognitive performance, so the clinical relevance of the observed radiological brain abnormalities could not be evaluated. However, we demonstrated that brain
abnormalities on MRI were not observed more frequently in treated NFA patients with impairments compared to NFA patients without impairments in verbal memory or executive functioning [25]. Conversely, the absence of brain abnormalities on MRI did not exclude impairments in cognition. The potential long-term side effects of RT to the brain in NFA patients are important in the determination of the risk versus benefit and relevant in clinical decision making. The use of more modern and precise RT treatment delivery techniques, such as stereotactic radiosurgery and stereotactic conformal RT, enabling to achieve a steeper dose gradient from the PTV to the normal surrounding brain tissues, may in the future translate into a further reduction of long-term side effects of RT to the brain. Furthermore, accurate delineation of the organs at risks (OARs) (e.g., temporal lobes, hippocampi, whole brain, optic nerves, chiasm, pituitary) is important in treatment planning to prevent overdosage and toxicity to the OARs. A uniform delineation guideline and recommendation for a contouring method and atlas of OARs for pituitary adenoma disease, such as recently published for nasopharyngeal carcinoma patients [26], will facilitate side-effect correlation studies and dosimetric research between different treatment institutes. Finally, in NFA patients with residual disease, the consequences of an active surveillance policy instead of RT, including frequent MRI scans, the possible (psychological) consequences of uncertainties
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Fig. 2. Age at NFA diagnosis and age at cerebral atrophy in patients treated with and without postoperative radiotherapy.
Table 3 Comparison of patient- and treatment characteristics between studies that investigated white-matter lesions and cerebral atrophy in patients treated with or without radiotherapy for primary brain tumours.
Basic characteristics Tumour type Number Number RT+ / RT Brain imaging modality RT total dose (Gy) RT fraction dose (Gy) Focal RT Whole brain RT Age at time of diagnosis RT+ / RT Follow-up duration RT+ / RT (y) White-matter lesions Observed number RT+ / RT Expected number RT+ / RT Cerebral atrophy Observed number RT+ / RT Expected number RT+ / RT
(y)
Postma et al. [7]
Douw et al. [13]
NFA 86 47/39 MRI 45 (45–50.4) 1.8 (1.8–2) 47 0 51 (23–76)/53 (27–81) 13 (2–24)/9 (2–22)
Low-grade glioma 39 23/16 CT/MRI 54 (45–64) 2 (1.8–2.5) 19 4 – 5 (1–19)/4 (1–10)
Low-grade glioma 65# 32/33 MRI 56.6 (30–69)* 1.9* 30 2 32.3/31.4* 12 (6–28)*
15 (32)/16 (41) 20.38/10.62
6 (26)/0 –
–
26 (55)/23 (59) 31.82/17.18
14 (61)/1 (6) –
–
Abbreviations: NFA: non-functioning pituitary macro-adenoma. Other abbreviations as in Table 1. Data are given as absolute numbers, median (range) or number (percentage). # WMLs were rated on 35 MRI scans (20 RT+/15 RT ). Global Cortical Atrophy was rated on 37 MRI scans (23 RT+/14 RT ). Complete MRI scans were available for only 6 RT+ and 7 RT patients. * Mean.
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regarding local control to the patient, and the risk of a second or even multiple operations in case of symptomatic recurrent disease and finally RT, should not be underestimated. In conclusion, this study demonstrated that brain abnormalities on MRI are not observed more frequently in NFA patients treated with postoperative RT compared to patients treated with surgery-alone. Furthermore, RT was not associated with an increased severity of WMLs and cerebral atrophy in this cohort of patients. The results of the present study are of importance for clinical decision making and contribute to the discussion of the safety of RT in NFA patients. Conflict of interest statement No conflict of interest for all authors. Role of the funding source No funding source. Acknowledgement No acknowledgements.
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16] [17] [18] [19]
References [20] [1] Gittoes NJ, Bates AS, Tse W, et al. Radiotherapy for non-function pituitary tumours. Clin Endocrinol (Oxf) 1998;48:331–7. [2] Park P, Chandler WF, Barkan AL, et al. The role of radiation therapy after surgical resection of nonfunctional pituitary macroadenomas. Neurosurgery 2004;55:100–6. [3] van den Bergh AC, van den Berg G, Schoorl MA, et al. Immediate postoperative radiotherapy in residual nonfunctioning pituitary adenoma: beneficial effect on local control without additional negative impact on pituitary function and life expectancy. Int J Radiat Oncol Biol Phys 2007;67:863–9. [4] Erridge SC, Conkey DS, Stockton D, et al. Radiotherapy for pituitary adenomas: long-term efficacy and toxicity. Radiother Oncol 2009;93:597–601. [5] Constine LS, Konski A, Ekholm S, McDonald S, Rubin P. Adverse effects of brain irradiation correlated with MR and CT imaging. Int J Radiat Oncol Biol Phys 1988;15:319–30. [6] Surma-aho O, Niemela M, Vilkki J, et al. Adverse long-term effects of brain radiotherapy in adult low-grade glioma patients. Neurology 2001;56:1285–90. [7] Postma TJ, Klein M, Verstappen CC, et al. Radiotherapy-induced cerebral abnormalities in patients with low-grade glioma. Neurology 2002;59:121–3. [8] van Beek AP, van den Bergh AC, van den Berg LM, et al. Radiotherapy is not associated with reduced quality of life and cognitive function in patients
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treated for nonfunctioning pituitary adenoma. Int J Radiat Oncol Biol Phys 2007;68:986–91. Brummelman P, Elderson MF, Dullaart RP, et al. Cognitive functioning in patients treated for nonfunctioning pituitary macroadenoma and the effects of pituitary radiotherapy. Clin Endocrinol (Oxf) 2011;74:481–7. Brummelman P, Sattler MG, Meiners LC, et al. Cognitive performance after postoperative pituitary radiotherapy: a dosimetric study of the hippocampus and the prefrontal cortex. Eur J Endocrinol 2012;166:171–9. Sattler MG, van Beek AP, Wolffenbuttel BH, et al. The incidence of second tumours and mortality in pituitary adenoma patients treated with postoperative radiotherapy versus surgery alone. Radiother Oncol 2012;104:125–30. Sattler MG, Vroomen PC, Sluiter WJ, et al. Incidence, causative mechanisms, and anatomic localization of stroke in pituitary adenoma patients treated with postoperative radiation therapy versus surgery alone. Int J Radiat Oncol Biol Phys 2013;87:53–9. Douw L, Klein M, Fagel SS, et al. Cognitive and radiological effects of radiotherapy in patients with low-grade glioma: long-term follow-up. Lancet Neurol 2009;8:810–8. Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA. MR signal abnormalities at 1.5 T in Alzheimer’s dementia and normal aging. AJR Am J Roentgenol 1987;149:351–6. de Leeuw FE, de Groot JC, Bots ML, et al. Carotid atherosclerosis and cerebral white matter lesions in a population based magnetic resonance imaging study. J Neurol 2000;247:291–6. de Leeuw FE, de Groot JC, Oudkerk M, et al. Atrial fibrillation and the risk of cerebral white matter lesions. Neurology 2000;54:1795–801. de Leeuw FE, de Groot JC, Oudkerk M, et al. Hypertension and cerebral white matter lesions in a prospective cohort study. Brain 2002;125:765–72. Heijer T, Skoog I, Oudkerk M, et al. Association between blood pressure levels over time and brain atrophy in the elderly. Neurobiol Aging 2003;24:307–13. Elkind MS, Sacco RL. Stroke risk factors and stroke prevention. Semin Neurol 1998;18:429–40. Korn EL, Graubard BI, Midthune D. Time-to-event analysis of longitudinal follow-up of a survey: choice of the time-scale. Am J Epidemiol 1997;145:72–80. Swennen MH, Bromberg JE, Witkamp TD, Terhaard CH, Postma TJ, Taphoorn MJ. Delayed radiation toxicity after focal or whole brain radiotherapy for lowgrade glioma. J Neurooncol 2004;66:333–9. Lawrence YR, Li XA, el Naqa I, et al. Radiation dose–volume effects in the brain. Int J Radiat Oncol Biol Phys 2010;76:S20–7. Armstrong CL, Hunter JV, Ledakis GE, et al. Late cognitive and radiographic changes related to radiotherapy: initial prospective findings. Neurology 2002;59:40–8. de Leeuw FE, de Groot JC, Achten E, et al. Prevalence of cerebral white matter lesions in elderly people: a population based magnetic resonance imaging study. The Rotterdam Scan Study. J Neurol Neurosurg Psychiatry 2001;70:9–14. Brummelman P, Sattler MG, Meiners LC. Cognition and brain abnormalities on MRI in pituitary patients. Eur J Radiol 2015;84:295–300. Sun Y, Yu XL, Luo W, et al. Recommendation for a contouring method and atlas of organs at risk in nasopharyngeal carcinoma patients receiving intensitymodulated radiotherapy. Radiother Oncol 2014;110:390–7.
Contents lists available at ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
MRI in pituitary adenoma
Brain abnormalities on MRI in non-functioning pituitary adenoma patients treated with or without postoperative radiotherapy Margriet G.A. Sattler a,b,⇑, Linda C. Meiners c, Wim J. Sluiter d, Gerrit van den Berg d, Johannes A. Langendijk a, Bruce H.R. Wolffenbuttel d, Alphons C.M. van den Bergh a, André P. van Beek d a Departments of Radiation Oncology, University of Groningen, University Medical Center Groningen; b Department of Radiation Oncology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam; c Department of Radiology, University of Groningen, University Medical Center Groningen; and d Department of Endocrinology and Metabolic Diseases, University of Groningen, University Medical Center Groningen, The Netherlands
a r t i c l e
i n f o
Article history: Received 31 August 2014 Received in revised form 27 December 2014 Accepted 3 January 2015 Available online 14 January 2015 Keywords: Non-functioning pituitary adenomas Postoperative radiotherapy Surgery Brain side effects MR imaging
a b s t r a c t Background and purpose: To assess and compare brain abnormalities on Magnetic Resonance Imaging (MRI) in non-functioning pituitary macro-adenoma (NFA) patients treated with or without postoperative radiotherapy (RT). Material and methods: In 86 NFA patients, treated between 1987 and 2008 at the University Medical Center Groningen, white-matter lesions (WMLs), cerebral atrophy, brain infarctions and abnormalities of the temporal lobes and hippocampi were assessed on pre- and post-treatment MRI scans in patients treated with (n = 47) or without RT. Results: The median MRI follow-up time for RT patients was 10 (range 1–22) years and 5 (range 1–21) years in patients treated without RT. In RT patients the cumulative incidence of WMLs was significantly lower compared to patients treated without RT (log-rank test RR 0.49, 95% CI 0.25–0.97, p = .042). The cumulative incidences of cerebral atrophy, brain infarctions, abnormalities of the temporal lobes and hippocampi, and the severity of WMLs and cerebral atrophy ratings were not significantly different between the two treatment groups. Conclusions: Brain abnormalities on MRI are not observed more frequently in NFA patients treated with RT compared to patients treated with surgery-alone. Furthermore, RT was not associated with an increased severity of WMLs and cerebral atrophy ratings in this cohort of NFA patients. Ó 2015 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 114 (2015) 239–244
In patients with non-functioning pituitary macro-adenoma (NFA), radiotherapy (RT) is usually applied as adjuvant treatment to prevent tumour progression after incomplete resection, or as salvage treatment in case of local recurrence after surgery, or as primary treatment in patients who are medically inoperable or refuse surgery. In NFA patients, RT results in excellent long-term local tumour control with reported rates of 90–97% at 10 years [1–4]. However, NFA are benign tumours, and therefore, concerns related to possible long-term side effects of RT to the brain are often used to delay or reject RT. Several studies have reported on long-term radiological brain effects in primary brain tumour patients treated with RT. Whitematter lesions (WMLs) and cerebral atrophy are well known radiological detectable abnormalities of the brain [5–7] and there appears to be a correlation with cognitive function [7]. ⇑ Corresponding author at: Department of Radiation Oncology, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. E-mail address: [email protected] (M.G.A. Sattler). http://dx.doi.org/10.1016/j.radonc.2015.01.003 0167-8140/Ó 2015 Elsevier Ireland Ltd. All rights reserved.
In NFA patients the long-term radiological brain effects of RT (i.e. WMLs and cerebral atrophy) are unknown and have not yet been investigated. Nevertheless, several studies reported on cognitive function [8–10]. Previously, we found no major influence of RT on cognition in NFA patients treated with RT compared to those treated with surgery-alone [8,9]. Furthermore, a dose–response relationship, by relating detailed radiation dosimetry to the temporal lobes, hippocampi and the prefrontal cortex, with cognition could not be established [10]. In addition, we showed that postoperative RT was not associated with an increased incidence of second tumours, stroke or mortality compared to pituitary adenoma patients treated with surgery-alone [11,12]. Lastly, we demonstrated that immediate postoperative RT in residual NFA has no additional negative impact on pituitary function compared to patients with residual disease and followed by an active surveillance policy [3]. In the light of our earlier results on the effects of postoperative RT, we postulated that RT has no additional adverse radiological brain effects. Therefore, our main objective is to assess and compare brain abnormalities on magnetic resonance imaging (MRI)
240
Pituitary adenoma and radiotherapy
(i.e. WMLs, cerebral atrophy, brain infarctions, abnormalities of the temporal lobes and hippocampi) in NFA patients treated with and without RT. Materials and methods Patients A total of 86 NFA patients underwent treatment between August 1987 and May 2008 at University Medical Center Groningen. The NFA diagnosis was based on the patient’s clinical history and presentation, endocrine evaluation, MRI outcome, and confirmed by postoperative histopathologic findings. To assure that acute and early-delayed post-treatment effects had resolved, RT patients and surgery-alone patients had an MRI follow-up of at least 6 months and 3 months, respectively. All patients were followed with MRI scans from the onset of diagnosis until November 2010 or date of death. Postoperative RT RT was indicated in case of residual disease after incomplete resection or as salvage treatment in patients with recurrent disease after surgery. All individual RT data were retrieved from the patient charts. The median total RT dose was 45 Gy (Gray) (range, 45–50.4 Gy) and most patients received 25 daily fractions of 1.8 Gy in 5 weeks. From 1987 to 2008 the RT patients (n = 47) were treated with linear accelerators with 4- to 18-MeV photons. The RT dose to the tumour was prescribed at the tumour encompassing isodose (n = 9) in the time period 1987–1990. From 1991 to 2008, the dose was prescribed at a central point in the tumour (n = 38) according to the recommendations of the International Commission on Radiation Units and Measurements (www.icru.org). In this time period, different conventional RT techniques were used: rotational (n = 1), 2 fields (n = 1), 2 fields and 3 fields (n = 6), 2 fields and 5 fields (n = 2), 3 fields (n = 22), 4 fields (n = 7) and 5 fields (n = 8). In the 1990s 3-dimensional (3D) RT treatment planning techniques were used. The gross tumour volume (GTV) is the grossly visible pituitary adenoma defined by Computed tomography (CT) or MRI. The planning target volume (PTV) was defined as the GTV plus a 1cm margin. MRI scans All MRI scans were all obtained from the Department of Radiology at the University Medical Center Groningen between July 1987 and November 2010. The MRI scans were primarily done for diagnosis and post-treatment NFA follow-up. MRI scanning was performed according to a standard NFA protocol. This protocol consisted of coronal T2 weighted images, and coronal and sagittal T1 weighted images without contrast, of the pituitary gland region, including the frontal and temporal lobes. The MRI scans were made on a 1 Tesla system using a regular head coil. All MRI scans (i.e. diagnosis and follow-up) were made on this same system during the study time period 1987–2010 in view of enabling comparison. The frontal and temporal lobes were assessed, as well as the frontal and temporal horns, central and peripheral cerebrospinal fluid (CSF) spaces and the hippocampi. Rating of MRI abnormalities MRI scans were presented randomly and rated by an experienced neuroradiologist (LM) blinded to clinical data and treatment. WMLs were defined as subcortical or periventricular focal or confluent areas of abnormal high signal intensity on T2 weighted
images in the white matter of the brain. The severity of WMLs was rated on a four point visual rating scale (Fazekas classification: grade 0–3): grade 0: none or one lesion 6 9 mm; grade 1: single lesions 6 9 mm in diameter and areas of grouped lesions 6 20 mm in diameter; grade 2: one lesion of between 10 and 20 mm in diameter or areas of grouped lesions > 20 mm in diameter with no more than connecting bridges (i.e. no confluence of lesions) between each lesion; grade 3: single lesions and confluent areas of high signal intensities > 20 mm in diameter [13,14]. In all patients the presence of other possible (cardiovascular) risk factors for WMLs, cerebral atrophy and brain infarctions were assessed [15–19]. Cerebral atrophy (cortical, central or cortical and central) was determined by visual assessment as an increase in the peripheral CSF spaces with an increase in the width of the sulci and dilatation of CSF, loss of parenchyma, and dilatation of the ventricular system (lateral and third ventricles). The severity of the cerebral atrophy (i.e. sulcal and ventricular enlargement) was classified into no cerebral atrophy or presence of cortical, central, or cortical and central involvement. Cerebral atrophy was rated on T2 weighted MRI scans. Brain infarctions (silent and symptomatic) were rated as present or absent and defined as larger areas of T2 hyperintense gliosis or focal tissue loss with local substitution of CSF on T1 or T2 weighted MR images. Lastly, any MRI abnormalities of the temporal lobes and the hippocampi including atrophy or posttraumatic cortical and subcortical damage were rated on T2 weighted images as present or absent.
Statistical analysis In the time to event analysis of longitudinal follow-up, the age at start of follow-up must be taken into consideration, because there is an inverse correlation between age and life-expectancy. We used age instead of surviving time as the time base in the analyses [20], because age itself is related to other risk factors of lifeexpectancy. In this way, patients of the same age were compared and age at the event (i.e. brain abnormality) instead of surviving time was the outcome parameter. Statistics by the log-rank test was used with which the number of observed events and the calculated expected values (i.e. extent of exposure) were used to calculate relative risks (RRs). The RRs and 95% confidence intervals (CI) for cumulative incidence of MRI brain abnormalities were compared in NFA patients treated with or without RT by log-rank test. In the time to event analyses, differences in age and follow-up time between the two treatment groups were taken into account. Left-censoring was used because of differences in age at the start of MRI scan follow-up: the patient was only used in the analyses after reaching the age at start of MRI follow-up (i.e. age at pre-treatment MRI scan). Right-censoring was also applied due to differences in follow-up time: the patient does not participate in the analyses at ages higher than that at the end of MRI scan follow-up (i.e., age at the last post-treatment MRI scan or age at appearance of a brain abnormality). In case the date of first occurrence of any of the MRI brain abnormalities was unknown, the date on half of the MRI follow-up time was used. Categorical variables were analysed using chi-square test (v2 test) and continuous variables were analysed by the Mann–Whitney U test. Data are presented as median, frequencies or percentages when appropriate. Two-tail p-values of 50 Gy 3 Radiation fraction dose: 1.8 Gy 43 2.0 Gy 4 Hormonal substitution No. of hormone replacements (0/1/2/3/4/5) Glucocorticoids Thyroid hormone Growth hormone Sex hormones Desmopressin Cardiovascular risk factors Hypertension Atrial fibrillation Hypercholesterolemia Diabetes mellitus Coronary- or peripheral artery disease Prior stroke
0.49
– –
6/5/8/14/14/ 0 36 (77) 34 (72) 10 (21) 31 (66) 8 (17)
5/5/14/12/3/ 0 26 (67) 22 (56) 6 (15) 22 (56) 5 (13)
0.08
14 (30) 2 (4) 13 (28) 5 (11) 8 (17)
15 (38) 1 (3) 11 (28) 3 (8) 8 (21)
0.54 0.59 0.84 0.76 0.27
0
3 (8)
0.18
0.44 0.15 0.67 0.50 0.77
Abbreviations: RT+: patients with postoperative radiotherapy; RT : patients without postoperative radiotherapy; y: year; Gy: Gray. Data are given as absolute numbers, median (range) or number (percentage). * RT + versus RT by v2 test or Mann–Whitney U test.
In this study we showed that the cumulative incidence of WMLs, cerebral atrophy, brain infarctions, abnormalities of the temporal lobes and hippocampi, and severity of WMLs and cerebral atrophy ratings on MRI were not increased in NFA patients treated with RT compared to patients treated with surgery-alone. To our knowledge, this is the first study investigating several radiological brain abnormalities in NFA patients. Pre- and posttreatment MRI scans were available for all patients. Furthermore, the incidence of brain abnormalities in irradiated patients was compared to patients treated with surgery-alone as a reference group. In irradiated primary brain tumour patients WMLs and cerebral atrophy are associated with larger RT treatment volumes, higher RT doses, and older age of the patient [5,21,22] and may also be influenced by (other) disease- (e.g., degree of malignancy, tumour recurrence, neurologic co-morbidity) and treatment-related (e.g., chemotherapy) factors relating to malignant brain disease. [22,23]. Other investigators have assessed and compared WMLs
Table 2 Relative risk and 95% confidence intervals for cumulative incidence of MRI abnormalities in NFA patients treated with and without postoperative radiotherapy. RT+
White-matter Lesions Cerebral atrophy Cortical Central Cortical & central Brain infarctions Temporal lobes Hippocampi
RT
Relative risk
95% CI
P (univariate)
10.62
0.49
(0.25–0.97)
0.042
20.84 20.68 17.18 5.57 5.83 4.49
0.65 0.73 0.61 0.87 0.73 0.84
(0.39–1.07) (0.43–1.22) (0.36–1.06) (0.28–2.68) (0.26–1.99) (0.27–2.63)
0.093 0.23 0.081 0.80 0.53 0.76
Obs
Exp
Obs
Exp
15 (32)
20.38
16 (41)
31 (66) 31 (66) 26 (55) 6 (13) 8 (17) 7 (15)
37.16 35.52 31.82 6.43 9.17 7.51
27 (69) 25 (64) 23 (59) 6 (15) 7 (18) 5 (13)
Abbreviations: Obs: observed numbers; Exp: expected numbers; CI: confidence interval. Other abbreviations as in Table 1.
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Fig. 1. Age at non-functioning pituitary macro-adenoma (NFA) diagnosis and age at white-matter lesions in patients treated with and without postoperative radiotherapy.
and cerebral atrophy and cognitive performance in low-grade glioma patients treated with or without RT [7,13]. The patient and treatment characteristics of these studies and this present study are shown in Table 3. The irradiated NFA patients in this study compared to irradiated primary brain tumour patients are treated with a lower RT fraction dose and a lower total RT dose, with focal RT to a fixed intracranial tumour position, and with smaller RT treatment volumes resulting in RT dose–volume differences within different areas of the brain, and NFA patients are not exposed to factors relating to malignant brain disease. Lastly, it has been shown that WMLs are often found on brain MRI scans of elderly people and the prevalence of WMLs increases with age [24]. The present study showed that the cumulative incidence of WMLs in NFA patients increases with age. Several limitations need to be addressed. Firstly, the coronal T2 weighted MR images used for the assessment provide a limited view of the cerebral hemispheres restricted to the frontal and temporal lobes. Although this can be acknowledged, complications which may be associated with surgical and/or RT for NFA patients would be expected in the frontal and temporal lobes, which were depicted as primary regions of interest on these images. Secondly, this study did not assess impairments in cognitive performance, so the clinical relevance of the observed radiological brain abnormalities could not be evaluated. However, we demonstrated that brain
abnormalities on MRI were not observed more frequently in treated NFA patients with impairments compared to NFA patients without impairments in verbal memory or executive functioning [25]. Conversely, the absence of brain abnormalities on MRI did not exclude impairments in cognition. The potential long-term side effects of RT to the brain in NFA patients are important in the determination of the risk versus benefit and relevant in clinical decision making. The use of more modern and precise RT treatment delivery techniques, such as stereotactic radiosurgery and stereotactic conformal RT, enabling to achieve a steeper dose gradient from the PTV to the normal surrounding brain tissues, may in the future translate into a further reduction of long-term side effects of RT to the brain. Furthermore, accurate delineation of the organs at risks (OARs) (e.g., temporal lobes, hippocampi, whole brain, optic nerves, chiasm, pituitary) is important in treatment planning to prevent overdosage and toxicity to the OARs. A uniform delineation guideline and recommendation for a contouring method and atlas of OARs for pituitary adenoma disease, such as recently published for nasopharyngeal carcinoma patients [26], will facilitate side-effect correlation studies and dosimetric research between different treatment institutes. Finally, in NFA patients with residual disease, the consequences of an active surveillance policy instead of RT, including frequent MRI scans, the possible (psychological) consequences of uncertainties
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Fig. 2. Age at NFA diagnosis and age at cerebral atrophy in patients treated with and without postoperative radiotherapy.
Table 3 Comparison of patient- and treatment characteristics between studies that investigated white-matter lesions and cerebral atrophy in patients treated with or without radiotherapy for primary brain tumours.
Basic characteristics Tumour type Number Number RT+ / RT Brain imaging modality RT total dose (Gy) RT fraction dose (Gy) Focal RT Whole brain RT Age at time of diagnosis RT+ / RT Follow-up duration RT+ / RT (y) White-matter lesions Observed number RT+ / RT Expected number RT+ / RT Cerebral atrophy Observed number RT+ / RT Expected number RT+ / RT
(y)
Postma et al. [7]
Douw et al. [13]
NFA 86 47/39 MRI 45 (45–50.4) 1.8 (1.8–2) 47 0 51 (23–76)/53 (27–81) 13 (2–24)/9 (2–22)
Low-grade glioma 39 23/16 CT/MRI 54 (45–64) 2 (1.8–2.5) 19 4 – 5 (1–19)/4 (1–10)
Low-grade glioma 65# 32/33 MRI 56.6 (30–69)* 1.9* 30 2 32.3/31.4* 12 (6–28)*
15 (32)/16 (41) 20.38/10.62
6 (26)/0 –
–
26 (55)/23 (59) 31.82/17.18
14 (61)/1 (6) –
–
Abbreviations: NFA: non-functioning pituitary macro-adenoma. Other abbreviations as in Table 1. Data are given as absolute numbers, median (range) or number (percentage). # WMLs were rated on 35 MRI scans (20 RT+/15 RT ). Global Cortical Atrophy was rated on 37 MRI scans (23 RT+/14 RT ). Complete MRI scans were available for only 6 RT+ and 7 RT patients. * Mean.
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regarding local control to the patient, and the risk of a second or even multiple operations in case of symptomatic recurrent disease and finally RT, should not be underestimated. In conclusion, this study demonstrated that brain abnormalities on MRI are not observed more frequently in NFA patients treated with postoperative RT compared to patients treated with surgery-alone. Furthermore, RT was not associated with an increased severity of WMLs and cerebral atrophy in this cohort of patients. The results of the present study are of importance for clinical decision making and contribute to the discussion of the safety of RT in NFA patients. Conflict of interest statement No conflict of interest for all authors. Role of the funding source No funding source. Acknowledgement No acknowledgements.
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