Margriet G.A. Sattler

The incidence of second tumours and mortality in pituitary adenoma patients treated with postoperative radiotherapy versus surgery alone

BACKGROUND AND PURPOSE To assess and compare the incidence of intra- and extracranial tumours and mortality in pituitary adenoma patients treated with postoperative radiotherapy and surgery alone. PATIENTS AND METHODS A total of 462 pituitary adenoma patients were treated between 1959 and 2008 at the University Medical Center Groningen in The Netherlands. Postoperative radiotherapy was administered on indication in 236 patients. RESULTS The median follow-up time was 14 (range 1-49) years in patients treated with radiotherapy and 6 (range 1-34) years in patients treated with surgery alone. Three radiotherapy patients developed an intracranial tumour compared to one patient treated with surgery alone. The numbers of extracranial tumours per follow-up year were 6.5 (95% CI 2.5-10.5) and 5.1 (95% CI 1.9-8.2) in patients treated with and without a technique with vertex field and central body axis irradiation and 7.1 (CI 95% 2.9-11.2) in surgery alone patients. Forty-five patients treated with radiotherapy died compared to twenty-four patients treated with surgery alone (log-rank test RR 1.26, 95% CI 0.77-2.08, p=0.36). CONCLUSION In this study postoperative radiotherapy and a radiotherapy treatment technique with vertex field and central body axis irradiation were not associated with an increased incidence of second tumours and mortality in pituitary adenoma patients.

Incidence, causative mechanisms, and anatomic localization of stroke in pituitary adenoma patients treated with postoperative radiation therapy versus surgery alone

PURPOSE To assess and compare the incidence of stroke and stroke subtype in pituitary adenoma patients treated with postoperative radiation therapy (RT) and surgery alone. METHODS AND MATERIALS A cohort of 462 pituitary adenoma patients treated between 1959 and 2008 at the University Medical Center Groningen in The Netherlands was studied. Radiation therapy was administered in 236 patients. The TOAST (Trial of ORG 10172 in Acute Stroke Treatment) and the Oxfordshire Community Stroke Project classification methods were used to determine causative mechanism and anatomic localization of stroke. Stroke incidences in patients treated with RT were compared with that observed after surgery alone. Risk factors for stroke incidence were studied by log-rank test, without and with stratification for other significant risk factors. In addition, the stroke incidence was compared with the incidence rate in the general Dutch population. RESULTS Thirteen RT patients were diagnosed with stroke, compared with 12 surgery-alone patients. The relative risk (RR) for stroke in patients treated with postoperative RT was not significantly different compared with surgery-alone patients (univariate RR 0.62, 95% confidence interval [CI] 0.28-1.35, P=.23). Stroke risk factors were coronary or peripheral artery disease (univariate and multivariate RR 10.4, 95% CI 4.7-22.8, P<.001) and hypertension (univariate RR 3.9, 95% CI 1.6-9.8, P=.002). There was no difference in TOAST and Oxfordshire classification of stroke. In this pituitary adenoma cohort 25 strokes were observed, compared with 16.91 expected (standard incidence ratio 1.48, 95% CI 1.00-1.96, P=.049). CONCLUSIONS In pituitary adenoma patients, an increased incidence of stroke was observed compared with the general population. However, postoperative RT was not associated with an increased incidence of stroke or differences in causative mechanism or anatomic localization of stroke compared with surgery alone. The primary stroke risk factor was pre-existent coronary or peripheral artery disease.

Cognitive performance after postoperative pituitary radiotherapy: a dosimetric study of the hippocampus and the prefrontal cortex

OBJECTIVE The hippocampus and prefrontal cortex (PFC) are important for memory and executive functioning and are known to be sensitive to radiotherapy (RT). Radiation dosimetry relates radiation exposure to specific brain areas. The effects of various pituitary RT techniques were studied by relating detailed dosimetry of the hippocampus and PFC to cognitive performance. METHODS In this cross-sectional design, 75 non-functioning pituitary macroadenoma (NFA) patients (61±10 years) participated and were divided into irradiated (RT+, n=30) and non-irradiated (RT-, n=45) groups. The RT+ group (who all received 25 fractions of 1.8 Gy; total dose: 45 Gy) consisted of three RT technique groups: three-field technique, n=10; four-field technique, n=15; and five-field technique, n=5. Memory and executive functioning were assessed by standardized neuropsychological tests. A reconstruction of the dose distributions for the three RT techniques was made. The RT doses on 30, 50, and 70% of the volume of the left and right hippocampus and PFC were calculated. RESULTS Cognitive test performance was not different between the four groups, despite differences in radiation doses applied to the hippocampi and PFC. Age at RT, time since RT, and the use of thyroid hormone varied significantly between the groups; however, they were not related to cognitive performance. CONCLUSION This study showed that there were no significant differences on cognitive performance between the three-, four-, and five-field RT groups and the non-irradiated patient group. A dose-response relationship could not be established, even with a radiation dose that was higher on most of the volume of the hippocampus and PFC in case of a four-field RT technique compared with the three- and five-field RT techniques.

Brain abnormalities on MRI in non-functioning pituitary adenoma patients treated with or without postoperative radiotherapy

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.

Cognition and brain abnormalities on MRI in pituitary patients

PURPOSE The extent to which cognitive dysfunction is related to specific brain abnormalities in patients treated for pituitary macroadenoma is unclear. Therefore, we compared brain abnormalities seen on Magnetic Resonance Imaging (MRI) in patients treated for nonfunctioning pituitary macroadenoma (NFA) with or without impairments in cognitive functioning. METHODS In this cross-sectional design, a cohort of 43 NFA patients was studied at the University Medical Center Groningen. White matter lesions (WMLs), cerebral atrophy, (silent) brain infarcts and abnormalities of the temporal lobes and hippocampi were assessed on pre-treatment and post-treatment MRI scans. Post-treatment cognitive examinations were performed using a verbal memory and executive functioning test. We compared our patient cohort with large reference populations representative of the Dutch population. RESULTS One or more impairments on both cognitive tests were frequently observed in treated NFA patients. No treatment effects were found with regard to the comparison between patients with and without impairments in executive functioning. Interestingly, in patients with one or more impairments on verbal memory function, treatment with radiotherapy had been given more frequently (74% in the impaired group versus 40% in the unimpaired group, P=0.025). Patients with or without any brain abnormality on MRI did not differ in verbal memory or executive functioning. CONCLUSIONS Brain abnormalities on MRI are not observed more frequently in treated NFA patients with impairments compared to NFA patients without impairments in verbal memory or executive functioning. Conversely, the absence of brain abnormalities on MRI does not exclude impairments in cognition.

No negative impact of radiotherapy on the incidence of second tumours and mortality in pituitary adenoma patients

Purpose: Postoperative radiotherapy (PORT) results in excellent local tumour control and improvement of excessive hormonal secretion in pituitary adenoma patients where (repeated) surgery was unsuccessful. Despite this benefit, concerns related to possible long term side effects are often quoted to delay or reject this treatment. In previous studies. the incidence of second tumours and mortality in pituitary adenoma patients treated with PORT were compared with a normal reference population. For proper evaluation however, a direct comparison with similar patients treated with surgery alone should be made. The purpose of this study was to assess the impact of PORT on developing second tumours and mortality in pituitary adenoma patients by comparing the incidence with patients treated with surgery alone. Materials: A retrospective study was performed in 462 pituitary adenoma patients (non-functioning adenoma n=256. growth-hormone secreting n=139 and adrenocorticotropic-hormone secreting adenoma n= 67) treated between t959 and 2008 at the University Medical Center Groningen. PORT was performed in 236 pituitary adenoma patients. The different radiotherapy techniques used in this period were divided into techniques with (n=80) or without (n=153) a beam configuration directed into the central body axis of the patient. Most patients received a radiation fractionation scheme of 25 daily fractions of 1.8 Gy in 5 weeks.After pituitary adenoma diagnosis the incidence of tumours and death were investigated using median life expectancy (MLE). MLE was used to correct for year of birth and gender and with the application of years of follow up as a time base for a left-censored log-rank test. Results: Median age at diagnosis was 47 (range 10-83) years and median overall follow-up time was 9 (range 1-49) years. The median follow-up time of patients treated with PORT was 14 (range 1-49) years and 6 (range 134) years in patients treated with surgery alone. Four patients developed an intracranial tumour, 3 of them were treated with PORT. Twenty-one patients treated with PORT developed an extracranial tumour compared to 11 patients treated with surgery alone (RR 1.04 CI 95%, 0.50-2.17, P = 0.917). In 11 out of the 21 patients treated with PORT and diagnosed with an extracranial tumour a central body axis radiotherapy technique was used (RR 1.43 CI 95%, 0.60-3.41, P = 0.425).Forty-five patients treated with PORT died compared to 24 patients treated with surgery alone (RR 1.26 CI 95%, 0.77-2.08, P = 0.358). Conclusions: Postoperative radiotherapy did not increase the incidence of second tumours and mortality in pituitary adenoma patients. Central body axis radiotherapy technique was not associated with an increase in extracranlal tumours.