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Risk of Second Brain Tumor after Conservative Surgery and Radiotherapy for Pituitary Adenoma: Update after an Additional 10 Years

Neuro-Oncology Unit (G.M., D.T., A.G., M.B.), Computing Department (S.A.), The Royal Marsden NHS Foundation Trust, and Academic Unit of Radiotherapy and Oncology, The Institute of Cancer Research (D.T., M.B.), Sutton, Surrey SM2 5PT, United Kingdom

Address all correspondence and requests for reprints to: Dr. Michael Brada, Institute of Cancer Research and Royal Marsden National Health Service Trust, Downs Road, Sutton, Surrey, United Kingdom SM2 5PT. E-mail: michael.brada{at}icr.ac.uk.

	Abstract

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We assessed the risk of second brain tumors in a cohort of patients with pituitary adenoma treated with conservative surgery and external beam radiotherapy. Four hundred and twenty-six patients (United Kingdom residents) with pituitary adenomas received radiotherapy at the Royal Marsden Hospital (RMH) between 1962 and 1994. They were followed up for 5749 person-years. The cumulative incidence of second intracranial tumors and systemic malignancy was compared with population incidence rates through the Thames Cancer Registry and the National Health Service Central Register (previously OPCS) to record death and the potential causes. Eleven patients developed a second brain tumor, including five meningiomas, four high grade astrocytomas, one meningeal sarcoma, and one primitive neuroectodermal tumor. The cumulative risk of second brain tumors was 2.0% [95% confidence interval (CI), 0.9–4.4%] at 10 yr and 2.4% (95% CI, 1.2–5.0%) at 20 yr, measured from the date of radiotherapy. The relative risk of second brain tumor compared with the incidence in the normal population was 10.5 (95% CI, 4.3–16.7). The relative risk was 7.0 for neuroepithelial and 24.3 for meningeal tumors. The relative risks were 24.2 (95% CI, 4.8–43.5), 2.9 (95% CI, 0–8.5), and 28.6 (95% CI, 0.6–56.6) during the intervals 5–9, 10–19, and more than 20 yr after radiotherapy (four cases occurred >20 yr after treatment). There was no evidence of excess risk of second systemic malignancy. An additional 10-yr update confirmed our previous report of an increased risk of second brain tumors in patients with pituitary adenoma treated with surgery and radiotherapy. The 2.4% risk at 20 yr remains low and should not preclude the use of radiotherapy as an effective treatment option. However, an increased risk of second brain tumors continues beyond 20 and 30 yr after treatment.

	Introduction

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CONVENTIONAL EXTERNAL BEAM radiotherapy is effective in achieving control of tumor growth and hormonal hypersecretion in patients with pituitary adenoma. Despite its effectiveness, there is concern about late effects of radiation, with second radiation-induced brain tumor a particularly feared complication. It is recognized that radiation is associated with the development of intracranial tumors after therapeutic cranial irradiation for acute lymphoblastic leukemia (1), tinea capitis (2, 3), and intracranial tumors (4, 5, 6), and criteria for radiation-induced tumors have been formulated (7). Increased risk of second brain tumors has also been demonstrated in animals exposed to radiation (8).

We previously reported an actuarial cumulative risk of developing a second brain tumor in patients with pituitary adenoma treated with surgery and radiotherapy of 1.0% at 10 yr and 1.9% at 20 yr after treatment, with a relative risk compared with the normal population of 10.5 (9). The results were confirmed by some investigators (10), although other series reported a lower incidence (11, 12). Although there is a debate about the relative and actuarial risks of developing a second brain tumor, it must be acknowledged that the relationship between radiotherapy and second brain tumor remains putative, with no clear demonstration of one treatment factor as the only cause. The reason for singling out radiation as the most likely culprit is the evidence for radiotherapy as the main determinant in other conditions and the relative lack of evidence of association between pituitary adenoma and second malignancy.

Regardless of the debate about causation, we continued detailed follow-up of the cohort of patients with pituitary adenoma reported previously. In this report we assessed the potential change in the actuarial incidence and relative risk of second tumor with additional 10 yr of follow-up in an enlarged cohort containing the previously reported series.

	Subjects and Methods

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Four hundred and twenty-six patients (247 males and 179 females) with pituitary adenomas resident in the United Kingdom received radiotherapy at the Royal Marsden Hospital (RMH) between 1962 and 1994. Part of the present series includes the previous cohort of 334 patients reported in 1992 (9). The remaining 92 patients were treated in our institution between 1987 and 1994. The patient and treatment characteristics are shown in Table 1. On the basis of clinical characteristics and endocrinological assessment, 263 patients had nonfunctioning adenoma, and 135 had secreting pituitary adenoma. In 28 patients the secretory status was not known. Three hundred and forty-one patients had surgery before radiotherapy, and 72 patients had no prior surgery. The diagnosis of adenoma was confirmed histologically in 334 patients, and in 92 the diagnosis was based on endocrinological and/or radiological features.

The median follow-up for the entire series was 12 yr, ranging from 0–38.4 yr; 126 patients were followed for more than 20 yr. At the time of analysis, 214 of 426 patients died. Of the surviving patients, 28 had not been seen since January 1, 1990, and 26 were last seen between 1990 and 1995. Data were censored at the last follow-up or at death from another cause. The total follow-up consisted of 5749 person-years.

Statistical considerations

The risk to patients of a second brain tumor was estimated by the Kaplan-Meier survival method (13), and the time of the event was measured from the beginning of radiotherapy. Predictors of risk of second tumor were analyzed in a univariate analysis by the log-rank test (14). The second tumor data were compared with the expected numbers of tumors in the general population using national age- and sex-specific incidence rates (Office for National Statistics, England and Wales 1992). All P values were two-sided and based on the Poisson distribution (15).

	Results

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Incidence of second tumors

Eleven of the 426 patients developed a second intracranial tumor after surgery and radiotherapy for pituitary adenoma (Table 2). Five patients had meningioma, four had high grade astrocytoma, one had meningeal sarcoma, and one had primitive neuroectodermal tumor (PNET). The diagnosis was confirmed histologically in all but one subject, in whom the presence of a meningioma was diagnosed by computed tomographic imaging. In all cases tumors were identified within the region of entry of radiation fields, and in one case the tumor was in the pituitary fossa. Tumors were diagnosed 6–34 yr after radiotherapy, with a mean ± SD of 6.7 ± 1.7 yr for astrocytoma and 20.8 ± 10.0 yr for meningeal tumors. Age, sex, pituitary adenoma type, radiation dose (Table 3), tumor extent, and medical treatment were not found to be predictive of the development of second tumors on univariate analysis. Thirty-seven patients developed a second tumor at peripheral sites during the follow-up (Table 4).

The cumulative risk of second brain tumors was 2.0% [95% confidence interval (CI), 0.9–4.4%] at 10 yr, 2.4% (95% CI, 1.2–5.0%) at 20 yr, and 8.5% (95% CI, 3.1–21.8%) at 30 yr, measured from the date of radiotherapy (Fig. 1). Compared with an age- and sex-matched normal population, this represented an increased risk of brain tumors (relative risk, 10.5; 95% CI, 4.3–16.7). The relative risk of developing a brain tumor was 7.0 for glial and 24.3 for meningeal tumors (Table 5). After stratification for interval between treatment and the presence of a second tumor, the relative risk was 24.2 between 5 and 10 yr and 28.6 after 20 yr, with an apparently low relative risk between 10 and 19 yr, reflecting the different timing of development of glial and meningeal tumors (Table 6).

View larger version (7K): [in this window] [in a new window]   FIG. 1. Cumulative actuarial probability of developing a second brain tumor. Error bars represent 95% CIs.

	Discussion

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We demonstrated an increased risk of second brain tumors in patients with pituitary adenoma treated with surgery and external beam radiotherapy. Second tumors diagnosed were meningiomas and malignant neuroepithelial tumors, particularly high grade astrocytomas. The actuarial cumulative incidence of second brain tumors was 2.4% at 20 yr, with a relative risk of 10.5 compared with the general population.

The study largely confirms the results reported previously in a smaller cohort of 334 patients with a shorter follow-up (9). The present data report a larger number of patients with additional cases of second brain tumor and an additional 10 yr of follow-up and therefore provide a greater confidence in the results. It is of interest that the magnitude of risk of developing a second brain tumor remains unchanged. The new, and perhaps not unexpected, finding is the occurrence of second tumors more than 20 and 30 yr after treatment, with a broadly similar relative risk in the later period.

The results are in keeping with the reported cumulative risk of secondary glioma after radiation of 2.7% at 15 yr in a cohort of 305 patients with pituitary adenomas, and a relative risk of malignant brain tumor of 16 (16). However, other studies reported only a moderate or no increased risk of second brain tumors after irradiation of pituitary adenomas (12, 17, 18). In a more recent study, Erfurth et al. (19) reported a cohort of 325 patients irradiated with a median dose of 40 Gy (<2 Gy/fraction) with three cases of intracranial tumor (two astrocytomas and one meningioma) with a relative risk of second brain tumor of 2.7 compared with the normal population. As the latency period for the development of meningiomas is decades after radiotherapy (20), the different lengths of follow-up in the reported studies may in part account for the apparent discrepancy. The lower dose used may also be associated with a lower risk. In addition, meningiomas may be asymptomatic, and the lower incidence in some studies (11, 12, 18) could be an underestimate if patients were lost to follow-up, and cause of death was not reported.

The question arises of whether the limitations of long-term follow-up lead to an underestimation of the risk. Assuming a median latency for the development of gliomas as 5 yr, 53 patients had died and 42 were still alive in the first 5 yr. Assuming 20 yr as the median latency for the development of meningioma, 157 patients died and 163 were still alive within the 20-yr period. Although only a proportion of the population were therefore at risk of developing a second brain tumor, the use of actuarial methodology and standardized mortality ratio, which provide a comparison with the general population, mean that early death due to other causes or loss to follow-up do not bias the results in either direction.

The results reported here may also overestimate the risk. Pituitary adenoma population is under close scrutiny with frequent recourse to imaging, and asymptomatic benign meningiomas are more likely to be noted than in the normal population. Although the actuarial risk is not disputed, the denominator in the calculation of relative risk may underrepresent the real situation; therefore, the true relative risk may be somewhat lower.

It is generally assumed that ionizing radiation is responsible for inducing second tumors in the brain (3), and it remains the only recognized environmental causative factor in the development of meningioma (20, 21, 22, 23) occurring after high and low dose radiation. The relative risk of developing meningioma in patients irradiated in childhood for tinea capitis has been reported to be 9.5 after a mean dose of 1.4 Gy (3).

The relative risk of developing of glioma after prophylactic cranial irradiation for leukemia is reported to be 22–23 (1). This corresponds to a 10- to 20-yr cumulative risk of 0.5–1.5% among survivors of childhood acute lymphoblastic leukemia. A higher incidence of 12.8% has also been reported (24). Individual case reports have suggested an increased risk of a second brain tumor after irradiation of other primary brain tumors (5, 6, 18, 25, 26, 27). However, the relative risk is not reported because there is no information on the size of the denominator (cohort of patients studied).

There is debate about the incidence of second brain tumors in patients with pituitary adenoma treated with surgery alone. Although there are recognized inherited syndromes associated with increased risk of developing brain tumors, such a link has not been described for patients with pituitary tumors. However, individual cases of brain tumors, especially meningioma, have been reported in previously untreated pituitary adenoma patients (18, 28). Overall, there is no clear evidence of increased incidence of brain tumors regardless of the type of adenoma (11). The only apparent association between malignant disease and pituitary adenoma is the slightly elevated risk of colon cancer in patients with acromegaly (29). Our conclusion remains that although the role of irradiation remains unproven, radiation is likely to be a contributing factor in the development of second brain tumors in patients with pituitary adenoma treated with conservative surgery and radiotherapy.

New techniques of radiotherapy, such as radiosurgery and fractionated stereotactic radiotherapy, which reduce the volume of normal brain receiving high radiation doses (for details, see Refs.30 and 31), have been considered to lead to a reduction in the incidence of second tumors. Although no cases of second tumor after fractionated stereotactic radiotherapy or radiosurgery for pituitary adenomas have been reported to date, the occurrence of gliomas has been described after radiosurgery for meningioma (32) or other brain tumors (33, 34). On theoretical grounds, there is no reason to believe that radiation in any form will not be a future causative factor. The present lack of cases may simply be a reflection of the small number of patients treated and the lack of adequate long-term follow-up. Radiosurgery or stereotactic radiotherapy, which aim for more localized high dose irradiation, frequently irradiate larger volumes of normal brain compared with low doses and may increase the risk of second tumors. Intensity-modulated radiotherapy, which is a sophisticated technique of localized conformal radiotherapy, has, in fact, been predicted to increase the risk of radiation-induced second tumors (35). To demonstrate a change in the incidence of second brain tumors will require large cohorts of patients with follow-up in excess of 10 and 20 yr, and such data are currently not available.

As reported previously, astrocytomas occur earlier than meningiomas at a median time after irradiation of 6.7 ± 1.7 and 20.8 ± 10.0 yr, respectively, and this is in keeping with other studies (4, 20). A new finding is the occurrence of meningioma 30 yr after treatment, which suggests a continued need for surveillance. Meningiomas have been reported to occur up to 50 yr after irradiation, with a median time in the region of 19.5 yr based on reported cases (20).

One patient developed a PNET 5 yr after radiotherapy. The development of PNET after prophylactic craniospinal irradiation has been reported (20), and a recent publication suggests that it may be more common than previously suggested (36).

In summary, this study confirms the previous report of an increased risk of second brain tumors in patients with pituitary adenoma after surgery and radiotherapy. Although unproven, the circumstantial evidence points to the role of ionizing radiation in the development of second brain tumors. However, a potential genetic link between pituitary tumors, and gliomas and meningiomas cannot be excluded. Despite more cases noted with longer follow-up, the relative risk remains unchanged, and the actuarial incidence of 2.4% risk at 20 yr remains low. The contribution of second brain tumors to long-term mortality is minimal, with predominant risk of mortality from cerebrovascular events (37, 38, 39) of complex multifactorial etiology. The low incidence of second brain tumors should therefore not preclude the use of radiotherapy as an effective treatment modality in patients with otherwise uncontrolled pituitary adenomas.

	Footnotes

 
This work was supported in part by the Neuro-Oncology Research Fund, the Royal Marsden NHS Trust, and Cancer Research UK. The work was undertaken by the Royal Marsden NHS Trust, which received a proportion of its funding from the NHS Executive; the views expressed are those of the authors and are not necessarily those of the NHS Executive.

First Published Online November 23, 2004

Abbreviations: CI, Confidence interval; PNET, primitive neuroectodermal tumor.

Received June 22, 2004.

Accepted November 16, 2004.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Neglia JP, Meadows AT, Robison LL, Kim TH, Newton WA, Ruymann FB, Sather HN, Hammond GD 1991 Second neoplasms after acute lymphoblastic leukemia in childhood. N Engl J Med 325:1330–1336[Abstract]
2. Sadetzki S, Flint-Richter P, Ben-Tal T, Nass D 2002 Radiation-induced meningioma: a descriptive study of 253 cases. J Neurosurg 97:1078–1082[Medline]
3. Ron E, Modan B, Boice Jr JD, Alfandary E, Stovall M, Chetrit A, Katz L 1988 Tumors of the brain and nervous system after radiotherapy in childhood. N Engl J Med 319:1033–1039[Abstract]
4. Kaschten B, Flandroy P, Reznik M, Hainaut H, Stevenaert A 1995 Radiation-induced gliosarcoma. Case report and review of the literature. J Neurosurg 83:154–162[Medline]
5. Liwnicz BH, Berger TS, Liwnicz RG, Aron BS 1985 Radiation-associated gliomas: a report of four cases and analysis of postradiation tumors of the central nervous system. Neurosurgery 17:436–445[Medline]
6. Simmons NE, Laws Jr ER 1998 Glioma occurrence after sellar irradiation: case report and review. Neurosurgery 42:172–178[CrossRef][Medline]
7. Cahan W, Woodard H, Higinbotham N, Stewart F, Coley B 1948 Sarcoma arising in irradiated bone. Report of 11 cases. Cancer 1:3–29
8. Lonser RR, Walbridge S, Vortmeyer AO, Pack SD, Nguyen TT, Gogate N, Olson JJ, Akbasak A, Bobo RH, Goffman T, Zhuang Z, Oldfield EH 2002 Induction of glioblastoma multiforme in nonhuman primates after therapeutic doses of fractionated whole-brain radiation therapy. J Neurosurg 97:1378–1389[Medline]
9. Brada M, Ford D, Ashley S, Bliss JM, Crowley S, Mason M, Rajan B, Traish D 1992 Risk of second brain tumour after conservative surgery and radiotherapy for pituitary adenoma. Br Med J 304:1343–1346
10. Tsang RW, Brierley JD, Panzarella T, Gospodarowicz MK, Sutcliffe SB, Simpson WJ 1994 Radiation therapy for pituitary adenoma: treatment outcome and prognostic factors. Int J Radiat Oncol Biol Phys 30:557–565[Medline]
11. Erfurth EM, Bulow B, Mikoczy Z, Hagmar L 2001 Incidence of a second tumor in hypopituitary patients operated for pituitary tumors. J Clin Endocrinol Metab 86:659–662[Abstract/Free Full Text]
12. Bliss P, Kerr GR, Gregor A 1994 Incidence of second brain tumours after pituitary irradiation in Edinburgh 1962–1990. Clin Oncol R Coll Radiol 6:361–363
13. Kaplan EL, Meier P 1958 Non parametric estimation from incomplete observations. J Am Stat Assoc 53:457–458[CrossRef]
14. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, Mantel N, McPherson K, Peto J, Smith PG 1977 Design and analysis of randomised clinical trials requiring prolonged observation of each patient. Part 2 analysis and examples. Br J Cancer 35:1–39[Medline]
15. Breslow NE, Day NE 1987 The design and analysis of cohort studies. Lyon: International Agency for Research on Cancer; 69
16. Tsang R, Laperriere N, Simpson W, Brierley J, Panzarella T, Smyth H 1993 Glioma arising after radiation therapy for pituitary adenoma: a report of four patients and estimation of risk. Cancer 72:2227–2233[CrossRef][Medline]
17. Erfurth EM, Bengtsson BA, Christiansen JS, Bulow B, Hagmar L 2001 Premature mortality and hypopituitarism. Lancet 357:1974[Medline]
18. Jones A 1991 Radiation oncogenesis in relation to the treatment of pituitary tumours. Clin Endocrinol (Oxf) 35:379–397[Medline]
19. Erfurth EM, Bulow B, Mikoczy Z, Svahn-Tapper G, Hagmar L 2001 Is there an increase in second brain tumours after surgery and irradiation for a pituitary tumour? Clin Endocrinol (Oxf) 55:613–616[CrossRef][Medline]
20. Harrison MJ, Wolfe DE, Lau TS, Mitnick RJ, Sachdev VP 1991 Radiation-induced meningiomas: experience at the Mount Sinai Hospital and review of the literature. J Neurosurg 75:564–574[Medline]
21. Bondy ML, Wrensch MR 1996 Epidemiology of primary malignant brain tumours. In: Yung WKA, ed. Cerebral gliomas. London: Bailliere Tindall; 251–270
22. Longstreth Jr WT, Dennis LK, McGuire VM, Drangsholt MT, Koepsell TD 1993 Epidemiology of intracranial meningioma. Cancer 72:639–648[CrossRef][Medline]
23. Rubinstein AB, Shalit MN, Cohen ML, Zandbank U, Reichenthal E 1984 Radiation-induced cerebral meningioma: a recognizable entity. J Neurosurg 61:966–971[Medline]
24. Relling MV, Rubnitz JE, Rivera GK, Boyett JM, Hancock ML, Felix CA, Kun LE, Walter AW, Evans WE, Pui CH 1999 High incidence of secondary brain tumours after radiotherapy and antimetabolites. Lancet 354:34–39[CrossRef][Medline]
25. Salvati M, Frati A, Russo N, Caroli E, Polli FM, Minniti G, Delfini R 2003 Radiation-induced gliomas: report of 10 cases and review of the literature. Surg Neurol 60:60–67[CrossRef][Medline]
26. Cavin LW, Dalrymple GV, McGuire EL, Maners AW, Broadwater JR 1990 CNS tumor induction by radiotherapy: a report of four new cases and estimate of dose required. Int J Radiat Oncol Biol Phys 18:399–406[Medline]
27. Kitanaka C, Shitara N, Nakagomi T, Nakamura H, Genka S, Nakagawa K, Akanuma A, Aoyama H, Takakura K 1989 Postradiation astrocytoma. Report of two cases. J Neurosurg 70:469–474[Medline]
28. Abs R, Parizel PM, Willems PJ, Van de Kelft E, Verlooy J, Mahler C, Verhelst J, Van Marck E, Martin JJ 1993 The association of meningioma and pituitary adenoma: report of seven cases and review of the literature. Eur Neurol 33:416–422[Medline]
29. Orme SM, McNally RJ, Cartwright RA, Belchetz PE 1998 Mortality and cancer incidence in acromegaly: a retrospective cohort study. United Kingdom Acromegaly Study Group. J Clin Endocrinol Metab 83:2730–2734[Abstract/Free Full Text]
30. Brada M, Ajithkumar T, Minniti G 2004 Radiosurgery for pituitary adenomas; a review. Clin Endocrinol (Oxf) 61:531–543[CrossRef][Medline]
31. Ajithkumar TV, Brada M 2004 Stereotactic linear accelerator radiotherapy for pituitary tumours. Treat Endocrinol 3:211–216
32. Yu JS, Yong WH, Wilson D, Black KL 2000 Glioblastoma induction after radiosurgery for meningioma. Lancet 356:1576–1577[Medline]
33. Shamisa A, Bance M, Nag S, Tator C, Wong S, Noren G, Guha A 2001 Glioblastoma multiforme occurring in a patient treated with gamma knife surgery. Case report and review of the literature. J Neurosurg 94:816–821[Medline]
34. Kaido T, Hoshida T, Uranishi R, Akita N, Kotani A, Nishi N, Sakaki T 2001 Radiosurgery-induced brain tumor. Case report. J Neurosurg 95:710–713[Medline]
35. Hall EJ, Wuu CS 2003 Radiation-induced second cancers: the impact of 3D-CRT and IMRT. Int J Radiat Oncol Biol Phys 56:83–88[CrossRef][Medline]
36. Hader WJ, Drovini-Zis K, Maguire JA 2003 Primitive neuroectodermal tumors in the central nervous system following cranial irradiation: a report of four cases. Cancer 97:1072–1076[CrossRef][Medline]
37. Brada M, Burchell L, Ashley S, Traish D 1999 The incidence of cerebrovascular accidents in patients with pituitary adenoma. Int J Radiat Oncol Biol Phys 45:693–698[CrossRef][Medline]
38. Brada M, Ashley S, Ford D, Traish D, Burchell L, Rajan B 2002 Cerebrovascular mortality in patients with pituitary adenoma. Clin Endocrinol (Oxf) 57:713–717[CrossRef][Medline]
39. Tomlinson JW, Holden N, Hills RK, Wheatley K, Clayton RN, Bates AS, Sheppard MC, Stewart PM 2001 Association between premature mortality and hypopituitarism. West Midlands Prospective Hypopituitary Study Group. Lancet 357:425–431[CrossRef][Medline]

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