PEER-REVIEW REPORTS

Radiation-Induced Malignant Gliomas: A Current Review Aladine A. Elsamadicy1, Ranjith Babu1, John P. Kirkpatrick2, David Cory Adamson1,3,4

Key words Anaplastic astrocytoma - Glioblastoma - Malignant gliomas - Radiation-induced malignant gliomas - Radiotherapy - Reirradiation -

Abbreviations and Acronyms ALL: Acute lymphoblastic leukemia GBM: Glioblastoma multiforme RIMG: Radiation-induced malignant glioma RT: Radiotherapy From the 1Division of Neurosurgery, Department of Surgery, Duke University Medical Center; and 2Department of Radiation Oncology, Duke Cancer Institute, and 3 Neurosurgery Section, Durham VA Medical Center, 4 Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, USA To whom correspondence should be addressed: David Cory Adamson, M.D., Ph.D. [E-mail: [email protected]] Citation: World Neurosurg. (2015) 83, 4:530-542. http://dx.doi.org/10.1016/j.wneu.2014.12.009 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter Published by Elsevier Inc.

- OBJECTIVE:

Radiation-induced malignant gliomas (RIMGs) are known uncommon risks of brain irradiation. We describe 4 cases of RIMG that occurred at our institution and conduct the largest comprehensive review of the literature to characterize RIMGs better.

- METHODS:

Patients were identified through the PubMed database. Pearson R linear correlation test was used to evaluate the correlation between radiotherapy (RT) dose and age and latency period. Student t test was used to evaluate differences between latency periods for original tumor lesions. A normalized biologic equivalent dose analysis was performed to indicate the minimum and maximum radiation threshold for neoplasia. A Kaplan-Meier analysis was used to illustrate the overall survival curves.

- RESULTS:

The analysis included 172 cases from the PubMed database and 4 cases occurring at our institution. The median RT dose administered was 35.6 Gy, with the most common dosage ranges being 21e30 Gy (31%) and 41e50 Gy (21.5%). Median latency period was 9 years until diagnosis of RIMG, and RIMG occurred within 15 years in 82% of the patients. There was no correlation between the age of the patient at the time RT was administered (R2 [ 0.00081) or amount of RT (R2 [ 0.00005) and latency period for RIMG. The mean biologic equivalent dose for neoplasia of a RIMG was 63.3 Gy. The median survival of patients with RIMG improved over time (P [ 0.004), with median survival of 9 months before 2007 and 11.5 months after 2007.

- CONCLUSIONS:

INTRODUCTION Radiotherapy (RT) is commonly used to treat various brain lesions. Although RT has proven to be a successful technique, side effects can occur owing to the radiation exposure, such as radiation necrosis, delayed cognitive changes, local scalp irritation, and radiation-induced malignant gliomas (RIMGs) (59, 80, 91). Although RIMGs are considered rare, many reports describe malignant gliomas (World Health Organization grade III or IV) arising after RT of histologically different tumors or lesions. Because of the rarity of these events, various characteristics, such as the latency time and correlation with radiation dosage or patient characteristics, have not been fully explored. We performed a comprehensive review of the literature to characterize RIMGs better. Because RT has greatly evolved in recent years, we set out to determine if the occurrence of RIMG has changed over time.

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The risk of RIMG appears to be the same for all age groups, histologies, and RT dosages. Although the risk is low, patients should be aware of RIMG as a possible complication of brain irradiation.

MATERIALS AND METHODS Identification A systematic review through a PubMed search was performed for articles related to RIMGs using key word phrases in combination to maximize the amount of related articles. “GBM,” “malignant glioma,” “glioblastoma,” “brain tumor,” and “anaplastic astrocytoma” were searched in combination with “after radiation,” “radiation-induced,” “radiosurgery-induced,” “radiotherapy-induced,” “SRS-induced,” and “SRT-induced.” Articles that presented cases involving patients undergoing RT for a brain tumor or lesion who were later diagnosed with a grade III or grade IV malignant glioma, including glioblastoma multiforme (GBM), anaplastic astrocy-

toma, anaplastic oligodendroglioma, and anaplastic oligoastrocytoma, were reviewed. We identified 172 published cases from 1960e2013 (Table 1), and we added 4 cases identified at our institution (2013). Various factors were collected, including patient age at initial diagnosis of brain lesion, age at second diagnosis of malignant tumor, gender, latency period from the time of RT to the second diagnosis of the malignant glioma, and the total RT dosage directed toward the lesion site. For analyses, we divided patients into 2 groups—before and after 2007. Patients who received their diagnosis in 2007 were included in the “after 2007” group. We chose 2007 because that seemed to be the most consistent time point to evaluate

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RIMG: A CURRENT REVIEW

Table 1. All Patients with a Diagnosis of Radiation-Induced Malignant Glioma from 1960e2013 Author, Year

Age (years)/Sex

Original Tumor

RT Dose (Gy)

Abedalthagafi and Bakhshwin, 2012 (1)

43/F

Clear cell renal cell carcinoma

unk

Ahn and Kim, 2012 (2)

4/F

EN rhabdomyosarcoma

Amene et al., 2012 (3)

7/F

Juvenile pilocytic astrocytoma

Anderson and Treip, 1984 (4)

3/F

ALL

45

Latency (years) 5

RIMG GBM

13

sGBM

9

sGBM

25

6

MG/III/IV

unk

Bachman and Ostrow, 1978 (6)

1/F

Ependymoma

39.6

5

GBM

Balasubramaniam et al., 2007 (7)

60/F

Acoustic neuroma

50

5

GBM

Barnes et al., 1982 (8)

17/F

MB

40

6

GBM

Berman et al., 2007 (9)

34/F

AVM

15

9

GBM

Brat et al., 1999 (10)

18/F

Craniopharyngioma

55

11

GBM

20/M

ALL

36

7

AA

9/M

Rhabdomyosarcoma

54

11

GBM

60/M

Pituitary adenoma

45

15

GBM

28/F

Ependymoma

54

7

AA

19/F

Lymphoblastic lymphoma

30

5

GBM

45

31/F

Hodgkin disease

34/M

Pineal tumor

13/M

ALL

45.7 24

8

AA

23

GBM

8

GBM

Chung et al., 1981 (12)

2/M

ALL

Clifton et al., 1980 (13)

21/M

Hodgkin disease

24

5

GBM

49.7

6

sGBM

Dierssen et al., 1988 (15)

28/F

Pituitary adenoma

6

GBM

Donson et al., 2007 (16)

14/M

Burkitt lymphoma

unk

7

GBM

11/M

MB

unk

3

GBM

19/M

Low-grade astrocytoma

unk

15

GBM

23/F

Ependymoma

unk

12

GBM

unk

10

GBM

22

AO

66

14/F

ALL

Enchev et al., 2009 (18)

18/F

Craniopharyngioma

49.3

Flickinger et al., 1989 (19)

55/M

Pituitary adenoma

47.5

Fontana et al., 1987 (20)

6/M

ALL

24

11

GBM

3/M

ALL

24

10

GBM

7.5

GBM

6/M

ALL

24

10

GBM

Furuta et al., 1998 (22)

8/M

MB

40

15

AA

Gessi et al., 2008 (23)

7/M

MB

59.8

8

GBM

Grabb et al., 1996 (24)

20/F

Medullomyoblastoma

30

17

AA

Gutjahr and Dieterich, 1979 (25)

4/F

Craniopharyngioma

60

8

GBM

Hamasaki et al., 2010 (26)

5/M

MB

40

35

GBM

Hope et al., 2006 (27)

15/M

MB

40

23

AA

Huang et al., 1987 (28)

26/M

Pituitary adenoma

66

12

AO

RT, radiotherapy; RIMG, radiation-induced malignant glioma; F, female; unk, unknown; GBM, glioblastoma multiforme; EN, embryonal nasopharyngeal; s, spinal; ALL, acute lymphoblastic leukemia; MG/III/IV, malignant glioma World Health Organization grade 3 or 4; MB, medulloblastoma; AVM, arteriovenous malformation; M, male; AA, anaplastic astrocytoma; AO, anaplastic oligodendroglioma; c, cerebellar; VHL, von Hippel-Lindau; MG/3, malignant glioma World Health Organization grade III; AML, acute myelogenous leukemia; VS, vestibular schwannomas. Continues

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Table 1. Continued Author, Year

Age (years)/Sex

Original Tumor

Hufnagel et al., 1988 (29)

33/M

Pituitary adenoma

Joh et al., 2011 (31)

17/F

ALL

RT Dose (Gy)

Latency (years)

RIMG

55

8

MG/III/IV

19.5

6

GBM MG/III/IV

Judge et al., 1984 (33)

3/F

ALL

24

9

Kaido et al., 2001 (34)

14/M

AVM

60

6.5

Kawanabe et al., 2012 (35)

18/M

Testicular seminoma

30.6

37

GBM sAA

Kikkawa et al., 2013 (36)

21/M

Lymphoblastic lymphoma

30

10

sGBM

Kitanaka et al., 1989 (37)

13/M

Pineal germinoma

54

7

MG/III/IV

7/F

Craniopharyngioma

60

16

MG/III/IV

Kleriga et al., 1978 (38)

1/M

MB

50

11

MG/III/IV

Komaki et al., 1977 (39)

28/M

Craniopharyngioma

24

6

GBM

Komatsu et al., 2011 (40)

10/M

Germ cell tumor

50

13

MG/III/IV

Kranzinger et al., 2001 (41)

14/F

Craniopharyngioma

4

AA

Lee et al., 2012 (42)

47/F

Meningioma

44

4.83

Lin et al., 2007 (43)

29/F

Nasopharyngeal carcinoma

63

3

MG/III/IV

Liwnicz et al., 1985 (44)

11/M

Craniopharyngioma

59

25

GBM

unk

GBM

2/M

Malignant ependymoma

35

14

GBM

2 weeks/M

Retinoblastoma

55

12

GBM

5/M

Burkitt lymphoma

18

5

GBM

Lubetzi et al., 1991 (45)

23/F

Meningioma

50

5

GBM

Maat-Schieman et al., 1985 (46)

5/M

Craniopharyngioma

60

14

MG/III/IV

Malone et al., 1986 (47)

6/F

ALL

24

5

MG/III/IV

Marus et al., 1986 (48)

10/M

ALL

32

7

MG/III/IV

19/F

Thyroid cancer

58

23.5

sAA

52/F

Pituitary microadenoma

45

6

MG/III/IV

2/F

Bilateral retinoblastoma

18

3.75

GBM

Matsumura et al., 1998 (49)

18/M

Giant cell astrocytoma

50

8

GBM

McIver and Pollock, 2004 (50)

38/F

Metastatic melanoma

30

5.3

cAA

McWhirter et al., 1986 (51)

2/M

ALL

24

Menon et al., 2007 (52, 53)

6/M

ALL

18

3

GBM

4/F

ALL

18

11 months

GBM

10

MG/III/IV

10/M

ALL

18

6

GBM

5/M

Craniopharyngioma

50

12

MG/III

Muzumdar et al., 1999 (55)

6/M

ALL

20

6

GBM

Myong and Park, 2009 (56)

25/M

VHL hemangioblastoma

50.4

7

GBM

Nakamizo et al., 2001 (57)

11/M

MB

30

9

MG/III/IV

18/F

MB

30

9

MG/III/IV

3

sGBM

12.5

AA

Ng et al., 2007 (58)

23/M

Hodgkin disease

Nishio et al., 1998 (59)

40/F

Pituitary adenoma

30.6

18/M

Pineal germinoma

30 þ 20

Ohba et al., 2011 (60)

72/M

Meningioma

unk

50

9.5

GBM

4

GBM Continues

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RIMG: A CURRENT REVIEW

Table 1. Continued Author, Year

Age (years)/Sex

Original Tumor

Okamoto et al., 1985 (61)

39/F

Pituitary adenoma

50

5

GBM

Pearl et al., 1980 (64)

5/M

MB

30

13

GBM

Pettorini et al., 2008 (65) Piatt et al., 1983 (66)

Prasad and Haas-Kogan, 2009 (67)

RT Dose (Gy)

Latency (years)

RIMG

8/F

Craniopharyngioma

49.3

22

MG/III

38/M

Pituitary adenoma

49

14

GBM

25/M

Pituitary adenoma

45

10

GBM

12/M

ALL

59.4

20

GBM

4/F

AML

18

10

GBM

Preissig et al., 1979 (68)

52/M

Chemodectoma

44.8

8

MG/III/IV

Raffel et al., 1985 (69)

13/M

ALL

24

7

MG/III/IV

7/F

Low-grade spine astrocytoma

40

14

GBM

Riffaud et al., 2006 (71)

30/M

Hodgkin disease

40

9

sMG/III/IV

Rimm et al., 1987 (72)

6/M

ALL

24

11

GBM

Rittinger et al., 2003 (73)

5/M

Craniopharyngioma

55

12

MG/III/IV

Robinson, 1978 (74)

10/M

Pineal teratoma

40

26

MG/III/IV

36/M

Meningioma

27.5

21

MG/III/IV

2/M

MB

26

7

GBM

7/F

MB

35.2

9

GBM

2/F

ALL

18

8

GBM

2/M

ALL

24

9

GBM

2/F

ALL

18

13

GBM

Rappaport et al., 1991 (70)

Romeike et al., 2007 (75)

Saenger et al., 1960 (77)

3/F

ALL

24

10

GBM

4/M

ALL

12

8

GBM

5/M

ALL

18

14

GBM

5/M

ALL

12

10

GBM

11/M

Cervical adenitis

4

11

GBM

Safneck et al., 1992 (78)

2/M

MB

44

11

AA

Saiki et al., 1997 (79)

29/M

Testicular cancer

50

10

GBM

Salvati et al., 2003 (82)

40/M

MB

30

11

GBM

43/F

Scalp hemangioma

30

20

GBM

40/M

Scalp hemangioma

30

12

GBM

66/F

Cavernous angioma

30

13

GBM

10/F

ALL

24

12

GBM

41/M

Tinea capitis

3

25

GBM

12/M

ALL

24

6

GBM

10/F

ALL

24

11

GBM

8/M

Tinea capitis

3

26

GBM

16/M

Tinea capitis

3

25

GBM

RT, radiotherapy; RIMG, radiation-induced malignant glioma; F, female; unk, unknown; GBM, glioblastoma multiforme; EN, embryonal nasopharyngeal; s, spinal; ALL, acute lymphoblastic leukemia; MG/III/IV, malignant glioma World Health Organization grade 3 or 4; MB, medulloblastoma; AVM, arteriovenous malformation; M, male; AA, anaplastic astrocytoma; AO, anaplastic oligodendroglioma; c, cerebellar; VHL, von Hippel-Lindau; MG/3, malignant glioma World Health Organization grade III; AML, acute myelogenous leukemia; VS, vestibular schwannomas. Continues

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Table 1. Continued Author, Year Salvati et al., 1994 (81)

Age (years)/Sex

Original Tumor

RT Dose (Gy)

Latency (years)

RIMG

42/M

Tinea capitis

3

25

GBM

19/M

ALL

24

6

GBM

21/F

ALL

24

11

GBM

34/M

Tinea capitis

3

26

GBM

41/M

Tinea capitis

3

25

GBM

Sanders et al., 1982 (84)

4/F

ALL

Sarkar et al., 2013 (85)

25/F

Cushing disease

Schmidbauer et al., 1987 (86)

13/M

Shah and Rajshekhar, 2004 (87)

11/M

Shamisa et al., 2001 (88)

50/F

VS

Shapiro et al., 1989 (89)

27/M

Pituitary adenoma

95

22

GBM

3/M

ALL

48

7

MG/III/IV

2/F

ALL

24

9

MG/III/IV

5/F

ALL

24

6

AA

4/M

ALL

24

4

AA

Shimizu et al., 1994 (90) Simmons and Laws, 1998 (92)

24

5

GBM

50.4

6

GBM

MB

60

6

GBM

ALL

18

5

GBM

17.1

7.5

GBM

6/F

ALL

24

4

GBM

25/F

Optic glioma

60

4

GBM

20/M

Craniopharyngioma

60

16

Grade III

23/F

Pituitary macroadenoma

45

18

GBM

17/M

Pituitary macroadenoma

50

11

GBM

Snead et al., 1982 (93)

9/F

Retinoblastoma

Soffer et al., 1990 (94)

2/F

Tinea capitis

Sogg et al., 1978 (95)

5/F

Craniopharyngioma

28

6

GBM

61

GBM

60

6

MG/III/IV

unk

Stavrou et al., 2001 (96)

5/M

MB

39

8

GBM

Stragliotto et al., 1998 (97)

5/unk

ALL

18

3

GBM

5/unk

ALL

24

3

GBM

9.5/unk

ALL

24

2.5

GBM

5/unk

ALL

24

13

GBM

5/unk

MB

36

7

GBM

5/unk

MB

36

8

GBM

6/unk

ALL

18

7

Suda et al., 1989 (99)

38/F

Pituitary adenoma

50

4.5

MG/III/IV

GBM

Symss et al., 2006 (101)

4/M

ALL

12

2.83

GBM

Tada et al., 1997 (102)

6/F

Germ cell tumor

50

10

GBM

Tamura et al., 1992 (103)

43/F

Pituitary adenoma

60

14

AA

Tsang et al., 1993 (104)

34/F

Pituitary adenoma

42.5

10

GBM

15

42/M

Pituitary adenoma

50

8/F

Malignant germ cell tumor

50

Ushio et al., 1987 (106)

2/F

Craniopharyngioma

Van Calenbergh et al., 1999 (107)

2/M

MB

Tsutsumi et al., 2009 (105)

54.6 40

GBM

3.5

GBM

4

GBM

15

AA Continues

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RIMG: A CURRENT REVIEW

Table 1. Continued Author, Year

Age (years)/Sex

Original Tumor

15/M

ALL

24

9

GBM

2/F

ALL

24

9.8

MG/III

2.7/M

ALL

24

7.6

GBM

2/F

ALL

24

13.2

AA

3.8/M

ALL

24

7.6

MG/III

2/M

ALL

18

11

GBM

3/M

ALL

40

10.5

MG/III

2/F

ALL

24

8.5

AA

5/F

ALL

48

5.9

GBM

2/M

ALL

18

14.1

AO

Wu-Chen et al., 2009 (110)

39/M

Pituitary adenoma

54

23

AA

Yang et al., 2005 (111)

15/M

MB

36

10

GBM

Yaris et al., 2005 (112)

13/M

ALL

18

6

GBM

Yu et al., 2000 (113)

63/F

Meningioma

40

7

GBM

Zampieri et al., 1989 (114)

45/F

Pituitary adenoma

50

9

AA

Walters et al., 1998 (108)

11/M

Sarcoma

Zochodne et al., 1984 (115)

24/F

Scalp hemangioma

Zuccarello et al., 1986 (116)

42/M

Meningioma

Elsamadicy, 2013 (present study)

3/M

Anaplastic ependymoma

9/F

MB

8/M

MB

13/M

MB

RT Dose (Gy)

40 þ 16

Latency (years)

RIMG

8

AA

16.1

15

MG/III/IV

56

10

GBM

17

GBM

13

GBM

unk 55 unk 53.4

20

GBM

5

GBM

RT, radiotherapy; RIMG, radiation-induced malignant glioma; F, female; unk, unknown; GBM, glioblastoma multiforme; EN, embryonal nasopharyngeal; s, spinal; ALL, acute lymphoblastic leukemia; MG/III/IV, malignant glioma World Health Organization grade 3 or 4; MB, medulloblastoma; AVM, arteriovenous malformation; M, male; AA, anaplastic astrocytoma; AO, anaplastic oligodendroglioma; c, cerebellar; VHL, von Hippel-Lindau; MG/3, malignant glioma World Health Organization grade III; AML, acute myelogenous leukemia; VS, vestibular schwannomas.

patients in the era before temozolomide versus the era after temozolomide. A more recent study used a similar diagnosis period (32). This time point best represents the beginning of the current standard of care treatments for malignant gliomas (i.e., surgery resection followed by concurrent temozolomide with RT). This standard of care was defined in 2005 and likely took at least 1 year to become widespread (98). This time point has also been used by others when studying the concept of RIMG, such as Paulino et al. (63). Use of this time point makes it easier to draw comparisons between our survival results and results reported by others.

Statistical Analysis Pearson’s R linear correlation test was used to evaluate the correlation between RT dose and age with latency period. Student t test was used to evaluate differences between latency periods for original tumor lesions. A KaplanMeier analysis was used to illustrate the overall survival, and the log-rank test was used to evaluate the differences between survival curves. We calculated biologic equivalent dose (BED) in gray units using an alpha/beta ratio of 3 Gy and the formula: BED ¼ (total dose)  [1 þ (total dose)/ (number of doses  alpha/beta ratio)] or ¼ (total dose)  [1 þ (dose per fraction)/ (alpha/beta ratio)], based on the method described by Fowler (21).

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RESULTS Institutional Series At our institution, 4 patients were identified who underwent RT for brain lesions and were subsequently given a diagnosis of RIMG (Table 1). From 2003e2014, 4 patients were treated at Duke University Medical Center and were identified by searching an institutional database for patients with any brain tumor type. Of the 4 patients, 3 were male, and age range was 3e13 years. Medulloblastoma was the most common presenting tumor for which patients received RT, and all of these patients developed GBM 5e20 years after RT. Patient 1 received standard RT at age 3

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years for an anaplastic ependymoma located in the parietal lobe. At age 20, 17 years after RT, RIMG was diagnosed in the parietal lobe and histologically identified as a GBM. Patient 2 underwent craniospinal radiation with a focal boost to the posterior fossa (55 Gy) at age 9 years for a medulloblastoma in the cerebellum. At age 22, 13 years after RT, RIMG was diagnosed in the cerebellum and histologically identified as a GBM. Patient 3 received standard craniospinal radiation with a focal boost to the posterior fossa at age 8 years for a medulloblastoma in the cerebellum. At age 28, 20 years after RT, RIMG was diagnosed in the cerebellum and histologically identified as a GBM. Finally, patient 4 underwent craniospinal radiation with a focal boost to the posterior fossa (53.4 Gy) at age 13 years for a medulloblastoma in the cerebellum. At age 18, 5 years after RT, RIMG was diagnosed in the cerebellum and histologically identified as a GBM. Original Lesion, RT Dosage, and Minimum and Maximum RT Dosage Thresholds for RIMG The original lesion for which patients received RT consisted of several different types. The 5 most frequent original lesions for which patients underwent RT were acute lymphoblastic leukemia (ALL) (31.8%; n ¼ 56), medulloblastoma (13%; n ¼ 23), pituitary adenoma (10.8%; n ¼ 18), craniopharyngioma (8%; n ¼ 14), and tinea capitis (4%; n ¼ 7) (Figure 1). The RT dosage range groups of 21e30 Gy and 41e50 Gy were the most frequent dosage amounts applied toward the original tumor, accounting for 29.9% and 22% of all cases, respectively (Figure 2). The median RT dose given was 35.6 Gy. The minimum and maximum radiation thresholds for neoplasia of RIMG are 13.6 Gy and 110 Gy, respectively. Patients’ Gender and Age We identified 176 patients in whom a malignant glioma was diagnosed after RT, consisting of GBM, anaplastic astrocytoma, anaplastic oligodendroglioma, and anaplastic oligoastrocytoma. Of our cohort of patients, 96 (54.5%) were male, and 73 (41.5%) were female; gender was not specified in 7 patients (4%) (Table 1). The median age of patients receiving RT for their original tumor was 11 years (range, 2 weeks to 72 years). The most common

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Figure 1. The 5 most frequent original lesion types in patients in whom radiation-induced malignant gliomas were diagnosed. ALL, acute lymphoblastic leukemia; MB, medulloblastoma; PA, pituitary adenoma; CPG, craniopharyngioma; TC, tinea capitis; RT, radiotherapy.

age group for which RT was given was 9 years old (44.3%) (Figure 3). Latency Period Latency period was defined by the amount of time from when the patient received RT to the time a malignant glioma was diagnosed. The median latency period was 9 years for our cohort (Figure 4). RIMG occurred within 15 years in 82% of patients; in 18% of patients, RIMG developed >15 years after RT. The median latency period for ALL was 8 years; the median latency periods for medulloblastoma and pituitary adenoma were significantly different at 9.5 years (P ¼ 0.0012) and 10.5 years (P ¼ 0.0010), respectively. Age and RT Dose versus Latency Period Correlation tests were performed to determine whether age at which RT was

administered and RT dose were associated with the latency period of RIMG. No correlation was seen between patient age at the time of RT and the latency period for RIMG (R2 ¼ 0.00081) (Figure 5). Also, no correlation was found between the RT dose administered and the latency period (R ¼ 0.00005) (Figure 6). Reporting of RIMG and Survival Cases of RIMG as a result of RT for a primary brain lesion were first reported in the 1960s. Most cases of RIMG (94.8%) were published in the last 3 decades (Figure 7). There is clearly no downward trend in RIMG over time; however, this likely represents publication bias. There were 155 patients identified who had a reported survival period and were evaluable for the Kaplan-Meier analysis. The median survival of patients with RIMG has improved

Figure 2. Radiotherapy (RT) dose (Gy) range administered to patients with radiation-induced malignant glioma.

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Figure 3. Age when patients with radiation-induced malignant gliomas received radiotherapy (RT) for their original lesion.

over time (P ¼ 0.004), with median survival of 9 months before 2007 and 11.5 months after 2007. Examination of cases reported during and after 2007 revealed the median survival for grade III and IV RIMGs to be 16.5 months and 11.5 months, respectively. DISCUSSION RIMGs are fatal brain tumors and are an important rare risk factor in patients undergoing RT for other lesions. The common short-term risks of RT to the brain are diverse and include fatigue, short-term memory loss, and difficulty with visual motor processing (53). The common longterm risks of RT to the brain include brain necrosis, dysfunction of neurogenesis, and development of benign and malignant

tumors (54, 59, 61, 62). No risk factors have been conclusively identified to predict who may develop RIMG (61). Because RT has greatly evolved more recently with respect to normal brain exposure (movement from whole-brain to more focused RT) and amount of RT delivered to normal brain as a result of more conformal delivery strategies, we hypothesized that the number of RIMG cases should decrease. Cahan et al. (11) defined the parameters for identifying a radiation-induced tumor (67). These parameters are as follows: 1) The radiation-induced tumor must develop in the same region where RT was applied; 2) an adequate latency period, measured in years, must be observed between RT and diagnosis of the tumor; 3) the radiation-induced tumor must have a

Figure 4. Latency period (years) from after radiotherapy to diagnosis of radiation-induced malignant glioma.

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different histology than the original tumor; and 4) the patient should not have a pathology favoring the growth of tumors (e.g., Li-Fraumeni syndrome). The present study consists of 176 patients in whom a malignant glioma was diagnosed after RT, and it is the largest review of cases in the literature, with the second largest review article comprising 92 cases by Paulino et al. (63). The most frequent reason why patients in our series with RIMG received RT was for ALL (31.8%). Our study is consistent with older reports (32.6%e35.9%) (63, 83). The second most frequent reason, medulloblastoma (13%), occurred almost twice as often as in earlier reports (6.2%e8.7%) (63, 83). This difference may reflect a more aggressive treatment approach with RT for patients with medulloblastoma in current times. The median age of patients receiving RT was 11 years; 67.6% of patients were 19 years old. A median age of 10 years and 72.8% 19 years old were reported by Paulino et al. (63). Although there may be a slight increase in the age of patients receiving RT, our study is consistent with prior literature that demonstrates most patients who received RT and subsequently developed RIMG are still quite young. A previous study illustrated that ALL had the shortest latency period before the onset of RIMG compared with other nonmalignant tumors (63). In our study, the median latency period for ALL (8 years) was significantly shorter than the median latency period for medulloblastoma (9.5 years) and pituitary adenoma (10.5 years). There may be some predisposing feature such as less myelination in these patients because they tend to be younger (76). Nonetheless, we did not see a statistically significant correlation between latency period and age in our study despite having all age groups represented. An important finding in the present study is that there was no correlation between the RT dose and age of the patients receiving RT with latency period for RIMG. There was a weak correlation between the age of the patients receiving RT versus latency period for tinea capitis (R2 ¼ 0.405), although this may be due to a small sample size (n ¼ 7). RT was a standard care treatment for tinea capitis in accordance with the Adamson-Kienbock procedure, but it has now become an unfavorable treatment owing to other

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Figure 5. Age of patients when radiotherapy was administered versus the respective latency period to the onset of radiation-induced malignant glioma.

effective treatments, such as antifungal agents. The Adamson-Kienbock procedure averaged a total radiation dose of 4.75 Gy over 5 exposures at 10- to 20-minute intervals (91). A meaningful analysis of the question of why there is a lack of correlation between RT dose and latency period for RIMG would require detailed information on the dose and volume of treatment for each patient, which is unavailable in this study. One would think that a secondary malignant tumor formation would not occur in high-dose regions but would be more likely in lowdose regions. A retrospective study was done in France with 4581 pediatric patients with cancer treated with radiation, and results illustrated that most of the secondary malignancies occurred in the lower radiation dose areas (14). Consistent with that theory, our data show that secondary tumors are more common

after RT for tinea capitis (i.e., low dose, large volume) than after RT for pituitary adenoma (higher dose, smaller volume). Determining the optimal radiation dosage and its potential to cause RIMG should be taken into consideration when using RT at lower doses (e.g., hypofractionation schemes). We also calculated BED based on these data to help physicians counsel their patients better about risks (see earlier in Discussion). The median latency period for the whole cohort was 9 years from RT to the diagnosis of RIMG, which is a little less than twice the “5-year cure rule” often quoted among surgeons. This delayed latency is critical because it suggests that follow-up of patients after RT should be >5 years. We show that RIMGs have occurred in patients of all ages, of both genders, and with various original lesion types. This

Figure 6. Radiotherapy (RT) dose administered to patients versus the respective latency period to the onset of radiation-induced malignant glioma.

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heterogeneity demonstrates that RIMG may be unrelated to the biology of the original tumor or lesion and is more likely due to the direct effects of RT on the brain. Despite evolving changes in how RT is delivered, there does not appear to be any decrease in the reports of RIMG in the modern era. However, from our study, the median survival of patients with RIMG may have improved slightly in the more current era since 2007. This slight improvement may possibly reflect more widespread and consistent use of temozolomide for malignant gliomas after 2005, but a larger sample size is needed to assess more accurately patient survival after RT. We were unable to ascertain what additional aspects of postsurgical adjuvant therapy may have affected survival. Some authors highlighted the more frequent use of immunomodulatory agents, whereas other authors focused on the more consistent use of alkylating agents targeting malignant glioma cells (17, 63, 100, 109). With the more widespread adoption of the use of concomitant temozolomide and RT in the modern era as part of the standard of care, these would likely be the most common agents used in these patients. Most of the patients who developed RIMG after 2007 would have received RT around 1998, which is likely too early to have experienced any significant changes in how RT was delivered compared with today. Changes in RT strategies continue to evolve (e.g., resection cavity focused RT has become more commonplace). Some institutions have reported great success with specific agents, such as bevacizumab, but none have altered standard of care yet. Although studies continue to advance understanding of the genomic, proteomic, and immunologic features of malignant gliomas, we are unaware of any data suggesting that tumor biology has changed over time except in response to therapies (e.g., temozolomideresistant mechanisms). Although RIMGs are important to consider when assigning treatment options for patients, they remain rare complications. For example, ALL is newly diagnosed in approximately 6000 patients each year, with most receiving some sort of RT (30). The incidence from 1960e2010 is approximately 0.0176% (53 per 300,000). However, RT is becoming much more common as a first-line treatment for various pathologies, such as vestibular

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metastatic to brain followed by primary brain glioblastoma. Gynecol Oncol 13:108-114, 1982. 9. Berman EL, Eade TN, Brown D, Weaver M, Glass J, Zorman G, Feigenberg SJ: Radiationinduced tumor after stereotactic radiosurgery for an arteriovenous malformation: case report. Neurosurgery 61:E1099; discussion E1099, 2007. 10. Brat DJ, James CD, Jedlicka AE, Connolly DC, Chang E, Castellani RJ, Schmid M, Schiller M, Carson DA, Burger PC: Molecular genetic alterations in radiation-induced astrocytomas. Am J Pathol 154:1431-1438, 1999. Figure 7. Published cases of radiation-induced malignant gliomas by decade.

schwannomas (5). With an increase of RT, rare complications may become more prevalent. We calculated normalized BED thresholds for RIMG. Based on reported data from the case reports published, we were able to report an estimated mean, median, minimum, and maximum radiation threshold for RIMG, of 63.3 Gy, 66.7 Gy, 13.6 Gy, and 110 Gy. This wide range illustrates the need for accurate reporting of the amount of radiation exposure dosed to individuals with a diagnosis of RIMG. By having a more accurate understanding of the minimum threshold of radiation for RIMG, clinicians in the future can counsel their patients better on the risk of RIMG and may consider dosing more conservatively in efforts to treat the patient, while reducing the probability of RIMG being diagnosed later. There are limitations to this review owing to the limitations of the information provided through the literature (publication bias) and the prognostic analysis we could do. Additionally, because most studies did not have molecular data, we are unable to characterize RIMGs conclusively and identify molecular prognostic factors. Nonetheless, we have summarized and analyzed all of the data present in the literature and have added 4 current cases from our personal experience. To the best of our knowledge, this review provides the most in-depth review and analysis of RIMGs to date. CONCLUSIONS Although RT is an effective therapy and is the standard of care for various brain lesions, it carries important risks. ALL is the most frequently reported reason for RT that leads to RIMG, and medulloblastoma

has become a more frequent reason. The risk of RIMG appears to be the same for all age groups, histologies, and RT dosages. The survival for patients with RIMG has improved since 2007, suggesting a positive effect of the current adjuvant treatment standard of care. Additionally, most patients who develop RIMG do not develop these tumors until a decade after initial RT, necessitating the need for close long-term follow-up. REFERENCES 1. Abedalthagafi M, Bakhshwin A: Radiationinduced glioma following CyberKnife treatment of metastatic renal cell carcinoma: a case report. J Med Case Rep 6:271, 2012. 2. Ahn SJ, Kim IO: Spinal cord glioblastoma induced by radiation therapy of nasopharyngeal rhabdomyosarcoma with MRI findings: case report. Korean J Radiol 13:652-657, 2012. 3. Amene CS, Yeh-Nayre LA, Crawford JR: Secondary glioblastoma multiforme in a child with disseminated juvenile pilocytic astrocytoma. Case Rep Oncol Med 2012:290905, 2012. 4. Anderson JR, Treip CS: Radiation-induced intracranial neoplasms: a report of three possible cases. Cancer 53:426-429, 1984. 5. Babu R, Sharma R, Bagley JH, Hatef J, Friedman AH, Adamson C: Vestibular schwannomas in the modern era: epidemiology, treatment trends, and disparities in management. J Neurosurg 119:121-130, 2013.

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Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Received 7 March 2014; accepted 9 December 2014; published online 16 December 2014

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