Abstract
We analysed the incidence of second primary intracranial tumours in patients with pituitary adenomas treated with radiotherapy compared to the risk of patients not exposed to irradiation and to the general population. Materials and methods. This retrospective cohort study includes 298 patients with pituitary adenomas that received radiotherapy to the pituitary from 1960 to 2007. The patients were recruited from the Cancer Registry of northern Sweden and the local radiotherapy-registry of the University Hospital in Umeå. Only patients with ≥12 months follow-up after diagnosis of pituitary adenoma were included. A cohort of 131 patients with pituitary adenomas not treated with radiotherapy was used as reference. Standard incidence ratios (SIR) between observed and expected number of second primary intracranial tumours were calculated. Results. The median observation time after diagnosis of pituitary adenoma in 298 patients treated with radiotherapy was 14 years, and the total number of person-years at risk was 4 784. Six (2.0%) of the patients developed second primary intracranial tumours between 7 and 31 years after radiotherapy. Two patients had gliomas and four had meningiomas. The expected number of intracranial tumours was 1.15 giving a SIR of 5.20 (95% CI 1.90–11.31). No significant correlations were found between radiation technique or administered dose and the risk of developing a second primary intracranial tumour. The cumulative risk for second intracranial tumours at 10 and 20 years was 1.3%. Patients not treated with radiotherapy were followed 1 601 years and no second primary intracranial tumour occurred. Discussion. The results indicate an increased risk of second primary intracranial tumours in patients treated with radiotherapy for pituitary adenomas, compared to patients not exposed to irradiation and to the general population. Meningiomas were more frequent than gliomas and the median time interval between radiotherapy and second intracranial tumour was 17 years.
Exposure to ionising radiation (x-rays) is considered a risk-factor for the development of intracranial tumours [Citation1], especially at young age, and it is one of a few known environmental risk-factors for tumours in the brain and the meninges [Citation2–4]. Of particular interest has been the development of second primary intracranial tumours after radiotherapy [Citation1,Citation2,Citation5–8]. Particularly meningiomas may arise many years, even decades, after radiotherapy, even after exposure to low doses [Citation7,Citation8]. The considerable time span between exposure and tumour development makes prospective studies of the subject hard to manage.
Pituitary adenomas are slowly growing benign tumours that can either be hormonally secreting or non-secreting. The annual incidence of pituitary adenomas in Sweden reported to the Cancer Registry of the Swedish National Board of Health and Welfare is 1.2/100 000 for men and 1.0/100 000 for women [Citation9].
The prevalence of pituitary adenomas in autopsy studies is about 10–14% [Citation10], but clinically significant adenomas are more rare, although the prevalence has been reported as high as 94/100 000 according to a recent Belgian study [Citation11].
Postoperative radiotherapy for pituitary adenomas used to be a standard therapy to reduce the risk of relapse in GH- and ACTH-secreting adenomas as well as in large non-secreting adenomas [Citation12,Citation13]. Nowadays postoperative radiotherapy has kept its place in the therapy arsenal as a way to minimise the risk of relapse or to inhibit the growth of an inoperable pituitary adenoma [Citation12,Citation13].
Stereotactic radiotherapy and in some cases gamma-knife or proton irradiation are means to increase tumour dose and reduce exposure of irradiation to surrounding normal tissue. A common long-term adverse effect of radiotherapy to the pituitary is a decrease of pituitary function [Citation14,Citation15]. Another potential long-term side-effect is late cerebrovascular morbidity [Citation16]. There have also been reports of a low risk of optic neuropathy and late development of second primary intracranial tumours [Citation5,Citation17–22]. Brada et al. reported a cumulative risk of second brain tumours of 1.9% over 20 years, in patients treated with conservative surgery and radiotherapy for pituitary adenomas [Citation17].
In this study we identified patients with pituitary adenomas from 1960 to 2007 who received radiotherapy at the University Hospital in Umeå, Sweden. The aim was to assess the incidence of second primary intracranial tumours compared to patients with pituitary adenomas that were not irradiated and to the general population of northern Sweden. We also wanted to assess whether a second primary intracranial tumour could be related to the radiotherapy technique or the administered dose.
Materials and methods
All patients with pituitary adenomas registered in the Cancer Registry of northern Sweden (ICD-7 195.3) between 1960 and 2007 (n=572) were examined retrospectively. All patients that received radiotherapy to the pituitary region and had a follow-up time ≥ 12 months after diagnosis of the pituitary adenoma were included in the study (n=286).
The radiotherapy for pituitary adenomas in northern Sweden between the years 1960–2007 have been performed at the Department of Oncology at the University Hospital in Umeå. Therefore, all patients diagnosed with pituitary adenomas listed in the local radiotherapy-registry at the Department of Oncology at the University Hospital in Umeå were compared to the Cancer Registry of northern Sweden. This resulted in the inclusion of another 12 patients, making a total of 298 patients. One hundred and thirty-one patients with pituitary adenomas in the region not treated with radiotherapy were used as a reference group.
Pituitary adenomas in both registries were coded using the International Classification of Diseases (ICD-7 = 195.3). The included patients were also examined for other diagnoses in the Cancer Registry. Patients were followed to the time of death or the end of 2007, through connection to the Population Registry of Sweden. Medical records, histopathological tumour type and radiotherapy charts were studied for all patients.
The person-years at risk were calculated from the time of diagnosis of the pituitary adenoma to the time of diagnosis of a second primary tumour, death, or December 2007. The expected number was calculated by multiplying the sex-, age- and calendar-specific incidence rates in the reference population by the corresponding numbers of person-years in the cohort. The reference population contained all inhabitants, about 900 000, in the region, consisting of the counties of Norrbotten, Västerbotten, Västernorrland and Jämtland in northern Sweden. The ratio between observed and expected number of tumours was calculated giving the standard incidence ratio (SIR).
P-values regarding gender differences in outcome were calculated using a modified χ2 test with 2-sided p-values.
Part of the study population has been previously reported with a shorter follow-up in a study regarding cancer incidence in general in patients with pituitary adenomas [Citation22]. In the present study the aim was to evaluate radiotherapy in relation to the risk of developing of second primary intracranial tumours.
The study was approved by the Ethical Committee of Umeå University and has been conducted in accordance to the Helsinki Declaration.
Results
Two hundred and ninety-eight patients, 182 men and 116 women, with pituitary adenomas received fractionated external radiotherapy between the years 1960–2007. The mean follow-up time was 16.1±9.9 years, with a total of 4 784 person-years at risk. The median age at diagnosis of the pituitary adenoma was 55 years, ranging from 7–82 years. One hundred and forty patients (47%) were alive at the end of the study. Two hundred and sixty-four patients received post-operative radiotherapy, whereas the remaining 34 patients received radiotherapy without prior surgery. In 118 patients surgery was performed by a transsphenoidal approach, in 80 patients a frontal hemi-craniotomy was performed and in 66 patients the surgical procedure was unknown. A reference group of 131 patients with pituitary adenomas most of whom were treated with surgery, but not radiotherapy, was identified from the Cancer Registry of northern Sweden. and show patient characteristics.
Table Ia. Clinical material of the study group. Patients with pituitary adenomas that have received radiotherapy to the pituitary.
Table Ib. Clinical material of the reference group. Patients with pituitary adenomas that have not received radiotherapy to the pituitary.
On the basis of histopathological examination and/or clinical characteristics of endocrinological activity 213 patients (71%) had non-secreting pituitary adenomas, 49 (16%) had GH-secreting adenomas, 16 (5%) had prolactinomas, five (2%) had ACTH-secreting adenomas and in 15 patients (5%) the type of adenoma was unknown or not discernible upon evaluation.
The fractionated external radiotherapy was mainly given in three different ways following the local traditions in the clinic of the time. Fifty patients (17%) received pendulum treatment that was given through a singular beam focus that was mechanically rotated in a 180° arc around the target area. This treatment was mainly used in the first two decades of the study period. The median observation time for these patients was 25 years (range 3–43 years). Most patients, 157 (53%), were treated with two fixed opposite temporal beam foci, with a median observation time of 15 years (range 1–42 years). In the last two decades a third frontal field was added and 70 (23%) patients were treated with a three-field technique, with a median observation time of 10 years (range 1–35 years).
The target radiation doses and fractioning were similar for all three techniques although the absorbed tissue dose is slightly more uncertain regarding the pendulum treatment. With all three methods a mean dose of 2.0 Gy per fraction was given up to a mean target dose of 42.5 ± 3.5 Gy. Five of the remaining 21 patients received stereotactic radiotherapy and one patient received an older radiotherapy technique where two temporal and two sagittal fields alternately were used. In 15 patients neither the radiotherapy technique nor the delivered dose was known.
A total administered dose > 45.0 Gy were given to 41 patients (14%). In two patients radiotherapy was aborted prematurely resulting in administered doses < 30.0 Gy. Five patients were at some point during follow-up treated with Leksell's gamma-knife in other hospitals in Sweden. Four patients received radiotherapy at two separate occasions during follow-up due to relapse of the pituitary adenoma. The radiotherapy technique of choice varies over time as seen in .
Figure 1. Number of patients receiving radiotherapy over time. Subdivided according to the radiotherapy technique used.
During follow-up, six patients (2%, five men and one woman) developed second primary intracranial tumours seven to 31 years after radiotherapy. Two patients developed gliomas and four developed meningiomas. The expected number of intracranial tumours was 1.15, giving a SIR value of 5.20 (95% CI 1.90–11.31). The expected number of intracranial tumours for men was 0.69 and for women 0.46 giving SIR values of 7.23 (95% CI 2.33–16.87) for men, and 2.16 (95% CI 0.03–12.01) for women, respectively. The number of patients years at risk for those with pituitary adenoma not treated with radiotherapy was 1 601. None of these patients developed an intracranial tumour during the observation time.
No significantly increased incidence was seen for gliomas. Due to the registration procedure of meningiomas in the Cancer Registry, SIR-values for meningiomas were not possible to calculate separately.
All second primary intracranial tumours developed within the previously irradiated volume, and were verified with histology. Two patients had GH-secreting pituitary adenomas and four non-secreting adenomas. Four patients had been receiving radiotherapy by two opposite temporal fields and two patients by pendulum treatment. The radiation doses for the patients that developed second primary intracranial tumours did not different from that of patients that did not develop second tumours (). The cumulative risk of developing a second intracranial tumour at 10, 20 and 30 years was 1.3%, 1.3% and 4.8%, and the number of patients at risk at 10, 20 and 30 years after radiotherapy was 211, 97, and 33, respectively.
Table II. Characteristics of patients who received radiotherapy for pituitary adenoma and subsequently developed a second primary intracranial tumour within the irradiated volume.
During follow-up 36 patients (12%) developed second primary tumours outside the central nervous system, 28 tumours in men and 10 in women. Among the patients in the reference group, not treated with radiotherapy, there was a similar frequency of second primary extra cranial tumours. There was no significantly increased risk of any other type of second primary tumour in general or after subdivision to gender or to the hormonal status of the pituitary adenoma (). The number of second primary tumours outside the nervous system was 7.9 and 8.7 per 1000 person-years at risk, for patients treated with and without radiotherapy, respectively.
Table III. Second tumours outside the central nervous system in the study group (n=298) compared to the reference group (n=131)
Discussion
One of the reported late side effects of radiotherapy to the pituitary is the risk of second primary intracranial tumours [Citation17,Citation18]. In this study we present a cohort of patients with pituitary adenomas who have received fractionated external radiotherapy in northern Sweden the last 47 years with a total follow-up time of 4 784 person-years. In this cohort six patients (2%) developed second primary intracranial tumours. The frequency of second primary intracranial tumours in the study population corresponds well to previous studies where it has been reported to be between 0.6–2.4% [Citation17–19,Citation21]. In the study by Brada et al. the risk of developing a second primary brain tumour was 1.3% after 10, and 1.9% after 20 years, respectively [Citation17].
A significantly increased incidence of second primary intracranial tumours, compared to the general population of northern Sweden, was seen in men, SIR 7.23 (95% CI 2.33–16.87), but not in women SIR 2.16 (95% CI 0.03–12.01). We have not found any previous reports of gender differences concerning the risk of developing second primary intracranial tumours after radiotherapy. As only one second tumour was found among women the risk is not significantly increased. The difference in risk between genders observed in this study is probably explained by the limited number of patients with second primary tumours.
There were four meningiomas and two gliomas diagnosed among the patients that were treated with radiotherapy. Unfortunately due to a different registration process to the Cancer Registry before the year 1984, the incidence of meningiomas was not possible to calculate separately from other intracranial tumours. It is, however, reasonable to assume that the increased incidence in men for developing second primary intracranial tumours in general is also true for meningiomas alone.
No second primary intracranial tumour was found in the reference group of patients with pituitary adenomas not treated with radiotherapy, a fact that suggests that exposure to irradiation is the etiologic factor for tumour development in the study group. It must, however, be considered that there are some differences between the study and the reference group. The median age was slightly lower and the gender ratio was more equal in the reference group compared to the study group. There were also a higher proportion of hormonally active adenomas in the reference group, 46% compared to 23%, in the study group. The reason why patients in the reference group were not offered radiotherapy is not possible to reconstitute retrospectively, but it is probably due to a less advanced tumour stage. The frequency of extracranial tumours among irradiated and non-irradiated patients is similar as shown in and .
One reason for an increased incidence of meningiomas in patients with pituitary adenomas may be the close follow-up that these patients are subject to, including frequent MRI-scannings of the brain. As meningiomas frequently are asymptomatic [Citation23] this may lead to over-diagnoses of small asymptomatic, clinically insignificant meningiomas, which under normal circumstances not necessarily would have been diagnosed. Thus it may lead to an over-estimation of the risk of second primary intracranial tumour development in retrospective studies.
No difference could be seen between the various radiation techniques and the risk of developing intracranial tumours. Although none of the patients that received radiotherapy with a three-field technique developed a second primary intracranial tumour, this is more likely due to a shorter follow-up for these patients, than to a lower risk. A longer follow-up for these patients are needed for an accurate assessment of the risk.
None of the patients that developed second primary intracranial tumours received higher than normal radiation doses, except for one patient with a meningioma who received radiotherapy at two separate occasions because of a late relapse of his pituitary adenoma. He developed a meningioma 24 years after the first, and one year after the second treatment.
It is unlikely that clinically significant second primary intracranial tumours remain undetected during follow-up, as all included patients have had their medical records until the end of 2007 examined in addition to the information received from the Cancer Registry. The accuracy of the cancer registration in Sweden has been evaluated and an underreporting of 3.7% of malignant tumours was found [Citation24]. Pituitary adenomas and meningiomas are mainly benign tumours but should still be reported to the Cancer Registry. One might consider a lower compliance in reporting patients not treated with surgery where no histopathologic verification of the tumour is present. Especially the reported incidence of prolactinomas in men could be lower than expected. This could be explained both by patients not being diagnosed due to a diffuse symptomatology or old age.
The relationship between the time of exposure to radiation and the time of diagnosis of the intracranial meningiomas in this study correlates well to the previous knowledge of the pathogenesis of meningiomas. Meningiomas tend to develop very late after radiotherapy [Citation4,Citation7,Citation8]. In this study the median time interval from exposure to diagnosis was 17 years (ranging 9–31 years).
In studies of childhood survivors of brain tumours or leukaemia, who had received radiotherapy to the brain, gliomas developed sooner after exposure than meningiomas [Citation24]. This is believed to be caused by the malignant nature of gliomas and their relatively higher cell proliferation. In this study one female patient developed a glioma as late as 26 years after radiotherapy. Although unusual, one cannot exclude this tumour from being potentially related to radiotherapy, which leads to a possibility that more malignant brain-tumours would be found with an even longer follow-up.
The long time-interval between exposure and the development of a second primary intracranial tumour makes any statistical interpretation of the risk harder to assess reliably, due to potential unknown confounding factors. However, even a slightly increased risk of late secondary tumour development must be taken into consideration when choosing the optimal treatment for patients with a benign disorder, such as pituitary adenomas.
With modern radiotherapy techniques such as fractionated stereotactic radiotherapy, it has been suggested that the risk of developing second primary intracranial tumours will be reduced even further, due to an optimised dose in the target volume with a lower dose outside the target volume. Although theoretically appealing this is still only a hypothesis, since long-time follow-up results regarding second intracranial tumour development have yet to be presented and will likely not be due for some years [Citation25]. There is also well established previous epidemiological knowledge that even low radiation doses to the brain, at least in children, give an excess risk of developing meningiomas [Citation7].
Conclusion
In this retrospective study with long follow-up of 298 patients with pituitary adenomas treated with radiotherapy, we present six patients with second primary intracranial tumours after radiotherapy to the pituitary. The SIR was 5.20 (95% CI 1.90–11.31). All intracranial tumours appeared within the irradiated volume. There was no correlation between radiotherapy technique and the risk of developing a second primary intracranial tumour. The cumulative risk at 10 and 20 years was 1.3%.
Acknowledgements
This study was supported by grants from Lions Research Foundation, Department of Oncology, Umeå University, and the Medical Faculty, Umeå University, Sweden. Björn Tavelin at the Oncologic Centre, Umeå University, is acknowledged for statistical support.
Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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