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Original Article |
Departments of Internal Medicine, Division of Diabetology and Endocrinology (E.M.E., B.B., K.O.), Occupational and Environmental Medicine (Z.M., J.B., L.H.), Neurology (B.N.), and Radiation Physics (G.S.-T.), University Hospital, S-221 85 Lund, Sweden
Address all correspondence and requests for reprints to: Dr. Eva Marie Erfurth, Department of Internal Medicine, Division of Diabetology and Endocrinology, University Hospital, S-221 85 Lund, Sweden. E-mail: eva_marie.erfurth{at}med.lu.se.
Abstract
Vascular mortality, especially cerebrovascular disease (CVD), are the most pronounced cause of mortality in women with hypopituitarism. In a cohort of 342 patients operated and irradiated for pituitary tumors, 31 died from CVD (CVD patients) between 1952 and 1996. The study assessed whether the radiation regimens and duration of symptoms of hypopituitarism before operation differed between the 31 CVD patients and the 62 matched patients from the same cohort who had not died from CVD (control patients). Furthermore, the infarction/hemorrhage ratio, type of clinical stroke syndrome, and time to death after stroke were investigated in the CVD patients and in matched controls from the general population who had died from CVD (population controls).
No significant differences in maximum or centrally absorbed dose, maximum or central biological equivalent dose, field size, or number of fraction were recorded between CVD and control patients. A significant difference in the duration of symptoms of hypopituitarism before operation was recorded, but only in women (P = 0.01). There were no significant differences in the infarction/hemorrhage ratio (P > 0.3) of lacunar or posterior circulation syndrome compared with middle cerebral artery syndrome with cortical features (P = 0.22) or the proportion of patients who died within the first month after stroke onset (60% vs. 59%, respectively) between CVD patients and population controls.
In conclusion, no significant effect on CVD deaths could be detected for any radiation parameter. A long history of unsubstituted pituitary insufficiency may be a contributing factor to the very high CVD mortality among women. There were no indications of significant differences in type of stroke, clinical stroke syndromes, or stroke fatality between the CVD patients and the population controls.
VASCULAR COMPLICATIONS occasionally follow irradiation of pituitary tumors (1, 2, 3, 4). The most dramatic reports are of children who suffered stroke after irradiation and had clear arteriographic changes within the radiation fields (5). Human and animal studies have shown that therapeutic radiation can induce arterial injury and lead to an atherosclerosis-like occlusive disease (6). In the cerebral vasculature, capillaries and endothelial cells seem to be the most radiosensitive (7).
Hypopituitarism is a well documented consequence of irradiation of pituitary adenomas or other brain tumors (8, 9). Information on hypopituitarism has been missing in previous studies reporting stroke after radiotherapy for cerebral tumors (1, 2, 3, 4). Increased vascular mortality is now well documented in patients with hypopituitarism (10, 11, 12). Furthermore, we recently reported that cerebrovascular disease (CVD) mortality was the most striking cause, especially in females in whom a 5-fold risk increase for CVD deaths was recorded (11). Only 12% of the pituitary tumor patients were not irradiated, so an assessment of whether cranial irradiation contributed to the increase in CVD deaths was not possible (11). In a recent large study radiotherapy was not a factor determining mortality outcome in pituitary adenoma patients with hypopituitarism (12). On the other hand, a 4-fold risk increase for CVD accidents was suggested in patients irradiated for a pituitary adenoma (4). Thus, whether radiotherapy is a causal factor for the increased CVD mortality in hypopituitary patients with pituitary tumors is still a matter of debate.
The aim of the present study was to assess whether the radiation regimens differed between patients who died from CVD compared with controls from the same cohort who had not died from this disease and whether localization of the stroke area in the brain correlated with the volume of radiation treatment. Other aims were to investigate whether the patients who died of stroke already suffered from increased vascular morbidity at operation of the pituitary tumor and whether they had had a history of longer duration of symptoms of hypopituitarism before operation compared with those patients who had not died from stroke. Finally, we investigated whether the proportions of ischemic and hemorrhagic stroke, type of clinical stroke syndrome, and time to death after stroke differed between patients operated and irradiated for pituitary tumor and nonirradiated referents from the general population who also died from CVD.
Subjects and Methods
Pituitary tumor cohort
During the period 1946–1988, 477 subjects from the South Medical Region of Sweden were operated for a pituitary tumor at Department of Neurosurgery, Lund University Hospital. One hundred thirty-five of these patients were excluded from the study base due to acromegaly (n = 27), Cushing’s disease (n = 6), death during the first postoperative month (n = 20), missing records or not fully identified (n = 21), death before 1952 (n = 6), or not subjected to radiation therapy (n = 55). The tumor type and gender distribution of the remaining cohort of 342 patients (females; n = 130) are shown in Table 1
. Except for 38 patients, the cohort was the same as that in the report by Bulow et al. (11). Radiation therapy was administered within 6 months after surgery for a pituitary tumor in all but 4 cases. Ninety-five percent of the operations were transcranial, and the rest transsphenoidal. Reoperations were performed in 61 (17.8%) patients. Pituitary insufficiency was diagnosed in 64.2% within 6 months after surgery, in 72.4% within 1 yr, in 76.8% within 2 yr, and in 82.1% within 5 yr.
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The follow-up started in 1952 when the Swedish Cause-of-Death Register was established. On an individual basis patients were followed from the onset of postoperative irradiation until December 31, 1995, or until death or emigration, whichever occurred first. At the end of the follow-up, 206 of 342 patients (60.2%) were dead, 1 had emigrated, and the remaining 135 were still alive and living in Sweden. The median time of follow up was 14 yr (range, 0.2–43 yr). Causes of death were retrieved from the Swedish National Bureau of Statistics. The death certificates were coded according to the eighth revision of the International Classification of Diseases. Death certificates were based on autopsies for 42% of the cohort compared with 46.1% in the general population in the same geographical area during the same observation period. Thirty-one of the patients had died of CVD during the follow-up. Detailed information for 20 of the deceased CVD patients from the pituitary cohort for whom relevant medical records could be retrieved is presented in Table 2.
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For the female CVD patients the median age at death was 69 yr (range, 46–82), and the median age at operation or irradiation was 56 yr (range, 35–67 yr). The median times from operation/radiation and from pituitary insufficiency to death in CVD patients were 10 yr (range, 6–40) and 10 yr (range, 5–40), respectively. For the male CVD patients the median age at death was 74 yr (range, 56–83), and the median age at operation or irradiation was 55 yr (range, 40–79 yr). The median times from operation/radiation and from pituitary insufficiency, to death in CVD patients were 21 yr (range, 2–33) and 15 yr (range, 2–33), respectively.
Radiation dosimetry
During the first two decades almost all of the 121 patients were treated with 4 fields of 200-kV x-rays. The most common technique is shown in Fig. 1. Because only 1 of the 4 fields was treated each day (field dose, 4–5 Gy), the difference in biological equivalent dose (BED) between the central volume and the lateral hotspots will be even higher than the corresponding difference in absorbed dose (13). Thus, the maximum BED was higher in the temporal lobes than in the pituitary. When calculating the radiation doses for this group of patients, correction was made for attenuation in bone, for conversion from roentgens (R) to Gray units (Gy), and for the higher biological effect of orthovoltage compared with high voltage radiation (14). These corrections and the calculations of BED are all made to make the old treatments compatible with modern radiotherapy. A more detailed exposure assessment was made for 48 of 121 patients. They had been treated with a median of 46 Gy (range, 34–59), with 1.6 Gy/fraction (range, 1.5–2.1).
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). A more detailed exposure assessment was made for 45 of 212 patients. They had been treated with a median of 41 Gy (range, 37–50), with 2.0 Gy/fraction (range, 1.8–2.3). Of the remaining 9 patients in the cohort, 7 had been treated on 2 occasions (2 with 200 kV and 5 with mV), and 2 patients had yttrium installation.
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Pituitary insufficiency was defined as deficiency of at least one axis of the anterior lobe. Endocrine evaluation varied over the years, and pituitary function was assessed according to current tests for each time period. This has previously been described in detail together with details on cortisone, thyroid, and gonadal hormone replacement (11). None of the CVD patients or controls had been treated with GH during follow-up. The estimated duration of hypopituitarism was based on symptoms of decreased libido, amenorrhea, dry hair, loss of body hair, and symptoms of polyuria, polydipsia, and tiredness. It is possible that some PRL-producing tumors were classified as nonfunctional tumors before the late 1970s, when serum PRL assays became available.
Cohort based case-control study
For each of the 31 patient who had died from CVD (CVD patients), 2 control patients from the same cohort were chosen, matched for gender, age at radiation, and time of follow-up, from those who had not died of CVD (control patients). The study design is outlined in Fig. 3. This matching resulted in a median age of 55 yr for both groups (Table 3). For all 31 CVD patients and 62 control patients information on tumor type, extension of tumor growth, recurrence, and operation regimens was available.
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Relevant hospital records or autopsy protocols could be retrieved for only 23 of 31 deceased CVD patients in the cohort. The records were scrutinized in a blinded fashion, and a neurologist used the available information to ascertain clinical criteria for stroke (acute focal neurological deficit lasting for >24 h or leading to death, with no cause other than CVD), and 20 of the 23 CVD patients fulfilled these criteria.
For 18 of these 20 remaining CVD patients, clinical features could be used to classify them into 4 clinical stroke syndromes according to the Oxfordshire Community Stroke Project classification (15): 1) total anterior circulation syndrome (TACS), both cortical and subcortical symptoms from anterior and middle cerebral artery territory; 2) partial anterior circulation syndrome (PACS), more restricted and predominantly cortical symptoms from the same arterial territories; 3) lacunar syndrome (LACS), pure motor stroke, pure sensory stroke, sensorimotor stroke, and ataxic hemiparesis; and 4) posterior circulation syndrome (POCS), vertebrobasilar or posterior cerebral artery symptoms (Table 2
). Nine CVD patients had been treated with 200 kV x-rays, which resulted in a median maximum absorbed dose of 50 Gy (range, 37–58), with 1.6 Gy/fraction (range, 1.3–2.1). In this treatment group there were 4 patients with POCS, 2 with PACS, and 2 with TACS stroke syndromes. For the other radiation regimen, 1 patient was treated with cobalt-60, and this patient had LACS. Furthermore, 10 patients had been treated with 8–33 mV, with a median maximum absorbed dose of 41 Gy (range, 40–51), with 2.0 Gy/fraction (range, 1.6–2.1). For 1 of these patients the clinical stroke syndrome could not be determined, and 2 patients each had LACS, POCS, and PACS.
The type of stroke (infarction or hemorrhage), based on computerized tomography, angiography, or autopsy findings, could be determined in 14 of the CVD patients (Table 2). Evaluation of type of stroke showed infarctions in all but 1 patient, who suffered a hemorrhage in a pituitary tumor.
Potential control patients who had died of CVD, matched for age, calendar year of death, gender, and hospital code, were randomly selected from the general population (population controls) using the Cause-of-Death Register (see study design in Fig. 3). Matching for hospital code ensured that they were recruited from the same population study base as the CVD patients.
The same procedure for retrieval and assessment of medical information that had been used for the CVD patients was applied for the population controls. Sixteen matched pairs could be established for comparisons with respect to clinical stroke syndromes. The corresponding figure for type of stroke was 13 matched pairs.
Statistical methods
Data are presented as medians and ranges. Comparisons between the CVD patients and the 2 control patients (here referred to as control 1 and control 2) in each matched triplet were made by a Monte Carlo simulated extension of the ordinary Wilcoxon matched pair, signed rank test (16). In short, the rank sum of the positive differences was calculated for the original data by contrasting patient vs. control 1 and patient vs. control 2 in each of the k triplets, thereby producing 2k differences. The two-sided P value associated with this rank sum was then obtained as half its percentile rank in a distribution of 1000 rank sums generated under the null hypothesis of no difference between patients and controls. In each replication, a rank sum of the positive differences was calculated in 4 steps: 1) 1 of the 3 subjects in each of the k triplets was randomly selected as patient; 2) the difference between the patient and each of the remaining 2 subjects selected as controls was calculated; 3) the absolute value of the 2k differences was ranked (excluding ties); and 4) the rank sum for the positive differences was calculated and standardized such that the overall rank sum of the replication equaled the rank sum for the original data.
Comparisons between the CVD patients from the cohort and the population controls regarding stroke type and clinical stroke syndromes were made by a binomial test for the numbers of discordant pairs. Significance was defined as P < 0.05.
Results
Cohort-based case-control study
There were no significant differences in maximum or centrally absorbed dose, maximum or central BED, field size, or number of fractions between CVD and control patients (Table 4). Only maximum BED tended to be higher among the CVD patients (P = 0.07). The type of radiotherapy did not differ between CVD and control patients. There was a significantly longer duration of symptoms of hypopituitarism before diagnosis among the CVD patients compared with the control patients (P = 0.05). When stratifying for gender, the difference in symptom duration, but in no other potential risk factor, became more pronounced for females (median, 12 months; range, 6–156; P = 0.01), whereas it disappeared for males (median, 12 months; range, 0–120; P = 0.73; Table 5). However, there was no significant correlation between duration of symptoms of hypopituitarism before diagnosis and survival among the females in the cohort (P = 0.51).
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In all CVD patients the estimated stroke localization was within the volume of irradiation.
Evaluation of stroke in CVD patients from the pituitary tumor cohort and population controls with CVD
Six of 16 matched pairs were discordant with respect to clinical stroke syndrome. In 5 pairs the CVD patients had LACS or POCS, whereas the population controls had TACS or PACS; in the remaining discordant pair the relation was the opposite (P = 0.22). Three of 13 matched pairs were discordant with respect to type of stroke. In 2 pairs the CVD patients had infarction, whereas the population controls had hemorrhage; in the remaining discordant pair the relation was the opposite (P > 0.3). There was no difference in the proportion of patients who died within the first month after stroke onset (60% vs. 59%, respectively) between CVD patients and population controls.
Discussion
This is the first detailed study of stroke deaths in patients with operated and irradiated pituitary tumors. There are previous stroke incidence studies on this type of patient (1, 2, 3, 4, 17). However, except for the study by Flickinger et al. (2), a detailed dosimetry of radiotherapy has not been given in these studies. Although a very detailed dosimetry of irradiation was provided in the present study, no significant difference in dose, fractionation, or type of irradiation was recorded between CVD patients and controls, even after gender stratification. Corrections for the older techniques, used on 38% of the cohort, making them compatible to modern radiotherapy was made in the calculations of BED. Furthermore, the older and newer techniques were equally represented in both patient groups. Thus, it was probably not the old radiation technique that caused the CVD deaths, which is also illustrated by the fact that the CVD deaths appeared during all decades of observation.
Furthermore, we found no difference in type of pituitary tumor, recurrence rate, operation regimens, or extension of tumor growth in CVD patients compared with controls. Thus, there was no indication that differences in tumor characteristics or treatment could explain the CVD deaths. The present cohort was based on a consecutive case series from a well defined geographical area of patients operated and irradiated for a pituitary tumor in one hospital department. A selection bias is therefore unlikely to be present.
Numerous case reports implicate radiotherapy of the brain in the development of cerebrovascular injury (7). Bowen and Paulsen (1) presented 2 cases of cerebral infarction, 13 and 20 yr after cranial irradiation for pituitary tumors, and suggested that pituitary radiation increases the risk of a subsequent stroke. Hashimoto et al. (3) investigated 139 patients with a pituitary adenoma who received a radiation dose of 40–60 Gy. Ten patients suffered cerebral ischemic events, 3 of which were considered to be caused by radiation angiopathy because of their atypical occlusive patterns. Strokes occurred 5, 7, and 8 yr after irradiation. The studies mentioned have been mostly descriptive, and no appropriate groups for comparison have been provided. Brada et al. (4) reported a 4-fold risk for cerebrovascular accidents in patients irradiated for a pituitary adenoma compared with the general population. The risk was higher in women than in men. The conclusions from this study can be questioned, however, because the expected incidence used for comparison was calculated from a different calendar-year period than that for the cohort. Moreover, patients with acromegaly were included in the cohort. These patients have an increased cerebrovascular mortality regardless of irradiation (18). In contrast to the results presented by Brada et al. (4), Tomlinson et al. (12) reported that radiotherapy was not a factor determining mortality outcome in a large cohort of patients with hypopituitarism.
The results from the present study suggest that factors other than irradiation were of importance for the CVD deaths. However, it has to be taken into account that the variation in the radiation dose was rather small, which decreases the possibility of recording a dose-dependent risk for CVD. Our findings are in contrast to those of Brada et al. (4), who suggested that an increasing dose of radiotherapy, measured in Gray units, was associated with increasing risk for cerebrovascular accidents. However, because detailed dosimetry or dose per fraction were not provided in the study by Brada et al. (4), a reliable and comparable assessment is difficult. The present result is consistent with the report by Flickinger et al. (2), who studied 156 patients after irradiation for a pituitary adenoma and recorded an increased incidence of cerebral infarction (observed 7 cases vs. expected 3.5). As in the present study, the equivalent dose, which more accurately reflects the neural tissue tolerance, was calculated, and in a multivariate analyses the increased incidence of stroke was associated with age, but not with equivalent dose of irradiation.
Hypopituitarism is another possible explanation for the CVD deaths. A novel observation in the present study was that among the female CVD patients, who also had the highest standardized mortality ratios for CVD deaths, a significantly longer duration of symptoms for hypopituitarism before operation was recorded. No such difference was seen among the males. Thus, it is possible that unsubstituted pituitary insufficiencies before operation, e.g. gonadal insufficiencies, were not only of longer duration, but also were more harmful for females than for males. This is in accordance with a recent finding that untreated gonadotropin deficiency is an independent significant factor affecting mortality in patients with hypopituitarism (12). Another possibility is that symptoms of amenorrhea in females are easier to detect than decreased in libido in males. However, more gender-unspecific symptoms of hypopituitarism were also recorded. Whether CVD and control patients differed in GH deficiency at the time of surgery can unfortunately not directly be assessed because GH testing was not performed preoperatively during the inclusion period 1946–1988. However, there are good reasons to assume that postoperative GH deficiency was comparable between CVD and control patients due to similarities in tumor size, tumor extension, type of surgery, and radiation therapy.
There are numerous reports of an increase in cardiovascular risk factors in patients with hypopituitarism receiving conventional hormone treatment and with unsubstituted GH deficiency (19). These factors include lipid abnormalities, high waist hip ratio, and insulin resistance. Furthermore, endothelial dysfunction (20), suggested to be an early event in the pathogenesis of atherosclerosis, has been recorded in this patient group, and GH treatment has been shown to reverse these early atherosclerotic changes (21). None of the CVD or control patients had been treated with GH during follow-up. However, these risk factors alone cannot explain the very high stroke risk among the women. An attractive hypothesis is an interaction between the long-standing consequences of unsubstituted hypopituitarism before diagnosis or inadequately substituted pituitary insufficiencies or GH deficiency and the effect of radiotherapy, which affects the cerebrovasculature to cause an increased stroke risk. Moreover, the smaller vessel diameter in females might be of importance for the higher stroke risk for females in the present cohort. This idea has been suggested as an explanation for the increased risk of complications after carotid surgery in females compared with males (22). In the present study vascular diseases were not more prevalent at operation in the CVD patients than in the control patients, which means that vascular risk factors must have been manifested later. A caveat with this hypothesis, however, is that no significant correlation was seen between the duration of symptoms of hypopituitarism before diagnosis and survival among the females.
In all CVD patients the estimated stroke localization was within the volume of irradiation. There was no indication that stroke type or stroke fatality differed between CVD patients and population controls. A nonsignificant overrepresentation of the clinical stroke syndromes LACS and POCS was noted among the CVD patients. The loss of patients and controls due to lack of retrievable medical information is unlikely to have resulted in any selection bias or differential misclassification, because a very careful matching was made for gender, age, and hospital code. The main problem when interpreting the results is that the few cases and controls available gave a low statistical power, which excludes detection of differences that were not large.
The present study did not permit a detailed assessment of stroke mechanisms with respect to intracranial arterial diseases vs. extracranial large artery or cardiac embolic sources. An external cause of stroke, emanating from an embolus from a plaque-affected cardiac or carotid artery, may theoretically have contributed to the increased CVD mortality, which is in accordance with the results reported by Markussis et al. (23). However, in a recent cross-sectional study of all women with hypopituitarism recruited from the same cohort as the present study base, no increase in intima media thickening, number of plaques in the carotid arteries, or major cardiac abnormalities was recorded (24). This would argue against an external cause and more in favor of a local cause for stroke in the present study group.
Another possible explanation for the CVD deaths in the present study is the surgical trauma, because significant vascular changes have been documented in children operated for craniopharyngiomas (25). This is also in agreement with the finding of a higher risk for CVD accidents after debulking surgery in patients irradiated for pituitary adenomas (4). We do not believe that this is as a probable explanation in the present study, because of the very similar extension of pituitary tumor growth, histological tumor diagnoses, and surgical approach in CVD and control patients. A comparison between operation regimens was not possible in the present study, as practically all operations were performed by the transcranial route, an operation technique that previously was more frequent than today even in macroadenomas. However, it was recently shown that operation regimens had no significant impact on the increased mortality in patients with hypopituitarism (12). Furthermore, occlusive arteriopathy may also occur as a result of a compression of the circle of Willis by a slowly growing basal pituitary tumor (17). The stroke deaths in the present study occurred at least 2 and a median of 15 yr after operation, which at least excludes immediate postoperative vascular complications. It should be born in mind that a long follow-up as in the present study (median, 14 yr) is needed to evaluate long-term outcomes of specific treatments. Without knowledge of the results of previous therapeutic policies, we will not have a baseline allowing us to evaluate newer treatments.
In conclusion, in this, the largest and most detailed assessment of its kind, no significant effects on CVD deaths could be detected for any radiation parameter. A long history of unsubstituted pituitary insufficiency may be a contributing factor to the very high CVD mortality among females. There was no indication of significant differences in type of stroke, clinical stroke syndromes, or stroke fatality at 1 month between the CVD patients and the population controls. An attractive hypothesis is a possible interaction between the long-standing consequences of unsubstituted hypopituitarism before diagnosis or inadequately substituted pituitary insufficiencies or GH deficiency together with the effect of radiotherapy affecting the cerebrovasculature, causing an increased risk for stroke.
Acknowledgments
Footnotes
This work was supported by the Swedish Research Council (Grant K1999-27X013074-01A) and the Medical Faculty, Lund University (Lund, Sweden).
Abbreviations: BED, Biological equivalent dose; CVD, cerebrovascular disease; LACS, lacunar syndrome; PACS, partial anterior circulation syndrome; POCS, posterior circulation syndrome; TACS, total anterior circulation syndrome.
Received April 3, 2002.
Accepted July 22, 2002.
References
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