Cancer Causes Control (2014) 25:659–668 DOI 10.1007/s10552-014-0367-5
ORIGINAL PAPER
Risk of second benign brain tumors among cancer survivors in the surveillance, epidemiology, and end results program Alina Kutsenko • Amy Berrington de Gonzalez Rochelle E. Curtis • Preetha Rajaraman
•
Received: 28 October 2013 / Accepted: 12 March 2014 / Published online: 30 March 2014 Ó Springer International Publishing Switzerland (outside the USA) 2014
Abstract Purpose To assess risk of developing a second benign brain tumor in a nationwide population of cancer survivors. Methods We evaluated the risk of developing second benign brain tumors among 2,038,074 1-year minimum cancer survivors compared to expected risk in the general population between 1973 and 2007 in nine population-based cancer registries in the NCI’s surveillance, epidemiology, and end results program. Excess risk was estimated using standardized incidence ratios (SIRs) for all second benign brain tumors and specifically for second meningiomas and acoustic neuromas diagnosed during 2004–2008. Results 1,025 patients were diagnosed with a second primary benign brain tumor, of which second meningiomas composed the majority (n = 745). Statistically significant increases in risk of developing a second meningioma compared to the general population were observed following first cancers of the brain [SIR = 19.82; 95 % confidence interval (CI) 13.88–27.44], other central nervous system (CNS)
Electronic supplementary material The online version of this article (doi:10.1007/s10552-014-0367-5) contains supplementary material, which is available to authorized users. A. Kutsenko (&) A. Berrington de Gonzalez R. E. Curtis P. Rajaraman Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, NCI/NIH, 9609 Medical Center Drive, MSC 9778, Bethesda, MD 20892, USA e-mail:
[email protected] A. Berrington de Gonzalez e-mail:
[email protected] R. E. Curtis e-mail:
[email protected] P. Rajaraman e-mail:
[email protected] (SIR = 9.54; CI 3.10–22.27), thyroid (SIR = 2.05; CI 1.47–2.79), prostate (SIR = 1.21; CI 1.02–1.43), and acute lymphocytic leukemia (ALL) (SIR = 42.4; CI 23.18– 71.13). Statistically significant decreases in risk were observed following first cancers of the uterine corpus (SIR = 0.63; CI 0.42–0.91) and colon (SIR = 0.56; CI 0.37–0.82). Differences in risk between patients initially treated with radiotherapy versus non-irradiated patients were statistically significant for second meningioma after primary cancers of the brain (pHet \ 0.001) and ALL (pHet = 0.02). No statistically significant increased risks were detected for second acoustic neuromas (n = 114) following any first primary tumor. Conclusions Risk of second benign brain tumors, particularly meningioma, is increased following first primary cancers of the brain/CNS, thyroid, prostate, and ALL. Radiation exposure likely contributes to these excess risks. Keywords Meningioma Radiotherapy SEER Brain neoplasm Second primary neoplasm
Introduction The number of cancer survivors in the United States has increased rapidly during the past decade. In January 2008, there were approximately 12 million people alive with a history of cancer [1]. Cancer survivors are at higher risk for a number of morbidities, one of the most serious being increased incidence of new malignancies, which account for about 16 % of all cancers reported to the National Cancer Institute’s (NCI) Surveillance, Epidemiology, and End Results (SEER) Program [2]. A previous examination of malignant brain tumors in cancer survivors found excess risks following first cancers of the brain and central
123
660
nervous system, prostate, and acute lymphoblastic leukemia (ALL) [3]. In this analysis, we focus solely on second benign malignancies of the brain and central nervous system. Data on benign brain malignancies began to be comprehensively collected starting in 2004 by the SEER Program of population-based cancer registries. Almost 200,000 brain tumors were diagnosed in the United States between 2004 and 2007. Approximately two-thirds of these were tumors of benign and borderline malignancy [4]. Although histologically benign, these tumors can cause serious morbidity and have the potential to cause cognitive changes, seizures, and focal neurologic deficits [5]. The two most common benign brain tumor subtypes are meningiomas and acoustic neuromas, which together make up approximately 23 % of all intracranial tumors [6]. The only identified risk factors for benign brain tumors to date are moderate to high-dose cranial irradiation; a history of prior cancers of the brain, central nervous system (CNS), and acute lymphocytic leukemia (ALL); and possession of a few rare hereditary syndromes such as neurofibromatosis [7, 8]. Cranial irradiation has been shown to significantly increase the incidence of meningiomas and acoustic neuromas even at moderate doses [9–12]. In this study, we use data from the SEER Program to examine the standardized incidence ratio (SIR) of second benign brain tumors among 1-year minimum cancer survivors diagnosed with a first primary malignant tumor from 1973 to 2007 compared to risk of benign brain tumors in the general population. We further assess the potential role of cranial radiotherapy in this risk. While studies have evaluated risk factors for second malignant brain tumors in SEER, this is the first study to our knowledge to assess populationbased risk estimates of second benign brain tumors.
Methods We used SEER Program data to examine 2,038,074 1-year minimum cancer survivors, of whom 1,025 were diagnosed with a second primary benign brain tumor between the years of 2004 and 2007. The SEER program, which collects population-based data on cancer incidence and survival in the United States, covers approximately 28 % of the US population and accrues data on demographics, tumor morphology and topography, and initial cancer treatment. SEER added non-malignant CNS tumors to its case definitions starting on January 1, 2004, thus only recently allowing investigators the opportunity to analyze comprehensive nationwide data on benign brain cancers [13]. Patients eligible for inclusion in this study were reported to one of nine SEER population-based cancer registries (San Francisco-Oakland SMSA, Connecticut, Detroit,
123
Cancer Causes Control (2014) 25:659–668
Hawaii, Iowa, New Mexico, Seattle, Utah, and Atlanta) between the years of 1973 and 2008. Race was specified as white (including white, other unspecified [1991?], and unknown patients), black, or other (including American Indian/AK Native, Asian/Pacific Islander patients). Data analyses were restricted to patients who survived a minimum of 12 months after their primary cancer diagnosis (to minimize the probability of including primary metastases or recurrence) and had an attained age of \85 years. Person-years (PY) of observation were cumulated during the calendar years 2004–2008 from 12 months after initial cancer diagnosis until date of death, date last known alive, or end of the study (12/21/2008), whichever occurred first. We examined the risk of developing any second benign brain tumor, as well as risk of the two most common subtypes: meningioma and acoustic neuroma. Second benign brain tumors were defined as benign/borderline tumors in the brain or CNS with ICD-O-3 topography codes for meninges, brain, and spinal cord, cranial nerves, and other parts of the CNS (C70, C71, and C72). Intracranial meningiomas were tumors with ICDO-3 morphology codes 9,530–9,539 and ICDO-3 topography codes for cerebral and unspecified meninges (C70.0 and C70.9) excluding the spinal meninges (C70.1). Second acoustic neuromas were defined by ICD-O-3 morphology code 9,560 and ICDO-3 topography codes for acoustic nerve and unspecified cranial nerves (C72.4 and C72.5). Over 98 % of the data for the second cancers were microscopically confirmed, indicating the high reliability of the SEER database and the low likelihood that metastases would be reported as new primary tumors. Standardized incidence ratios (SIRs) were calculated for all benign brain tumors, meningioma and acoustic neuroma using the MP-SIR SEER*Stat Program [14]. Expected numbers of new benign brain tumors were calculated based on the accumulated PYR and on gender, age, race, and calendar time-specific SEER incidence rates in the general reference population for 2004–2008. SIRs were calculated as the observed (O) divided by the expected (E) number of second cancers. Exact two-sided 95 % confidence intervals (CIs) were calculated based on the assumption that the observed number of subsequent tumors followed a Poisson random distribution. Tests of heterogeneity (pHet) were conducted as described by Breslow [15]. In addition to overall SIRs, we also calculated SIRs stratified by time since and age at first primary diagnosis, gender, and race. In order to evaluate the effects of treatment with cranial irradiation on the risk of second benign brain tumors, we stratified risk for first primary sites (oral cavity and pharynx, eye and orbit, brain, other CNS, and ALL) that were likely to receive cranial radiotherapy based on standard treatment practices by reported initial radiotherapy use and latency (time since first cancer diagnosis)
Cancer Causes Control (2014) 25:659–668
661
[16]. Of note, SEER Program does not specify location of radiation given as first course of cancer-directed therapy (total brain irradiation for hematopoietic stem cell transplantation is not distinguished separately). The SEER Program separately captured prophylactic cranial irradiation from 1988 to 1997 for patients with leukemia and lung cancer only (included in first course of radiotherapy from 1998 onwards). Evaluation of the effects of initial radiotherapy was restricted to patients who survived at least 5 years, under the typical assumption of a minimum 5-year latent period for radiation-related solid cancers [17]. For first primary tumors, which indicated a significant SIR with second benign brain tumor and radiotherapy, we stratified by histology where applicable.
Results A total of 2,038,074 1-year minimum cancer survivors were diagnosed with a first primary cancer between 1973 and 2007, at ages \85 years in the SEER data (Table 1). The majority of patients were white (85 %) and between the ages of 65–84 (46 %) at first cancer diagnosis. Patients had a mean age at diagnosis of 61.8 years and were Table 1 Selected characteristics of 1-year cancer survivors Characteristic
No. of patients
(%)
# 1-year survivors
2,038,074
–
Average age
61.8 years
–
Average follow-up
8.0 years
–
Male
1,024,578
50.3
Female
1,013,496
49.7
White
1,734,508
85.1
Black
172,546
8.5
Other
131,020
6.4
Sex
Race
Age at primary diagnosis \25 years
52,425
2.6
25–44 years
241,310
11.9
45–64 years
810,161
39.7
934,178
45.8
1973–84
493,194
24.2
1985–94
595,578
29.2
1995–03
642,175
31.5
2004–2008
307,127
15.1
Yes RT
664,033
68.3
No RT
1,391,227
31.6
Unknown RT
2,822
0.1
65–84 years Calendar year of diagnosis
Radiotherapy treatment
followed up for an average of 8.0 years. Approximately 32 % of 1-year minimum cancer survivors were treated with radiotherapy. Table 2 describes the risk of developing a second benign brain tumor compared to expected risk in the general population according to various risk factors for all benign brain tumors (n = 1,025), meningioma (n = 745), and acoustic neuroma (n = 114). Risk of developing any second benign brain tumor was higher for cancer survivors compared to the expected rates in the general population (SIR = 1.13). Risks were higher in males than in females for all benign brain tumors (SIR = 1.25 vs. 1.06) and for second meningiomas (SIR = 1.29 vs. 1.07) (pHet = 0.01). SIRs for all second benign brain tumors appeared to differ by race with higher increases in risk seen for blacks and other races (pHet = 0.02). Young age at initial diagnosis (age \25 years) was associated with markedly increased risks for all benign tumors combined (SIR = 7.57) and meningioma (SIR = 13.17) compared to diagnosis at older ages (pHet \ 0.001). Reported initial radiotherapy was associated with a higher risk of developing a second benign brain tumor (SIR RT = 1.21, SIR noRT = 1.09), and this difference was statistically significant for second meningioma (SIRRT = 1.36, SIRnoRT = 1.05, p \ 0.001). In contrast, there was no overall evidence of a risk associated with reported radiation for acoustic neuroma in these data but statistical power was limited. Observed SIRs for all second benign brain tumors combined by first primary sites were in general very similar to those for meningioma. Table 3 therefore presents detailed results for the risk of second meningioma alone by time since first primary cancer diagnosis and by type of first primary site. Statistically significant increases in risk of second meningioma compared to expected rates in the general population were observed following first cancers of the brain (SIR = 19.82; 95 % CI 13.88–27.44), other CNS (SIR = 9.54; 95 % CI 3.10–22.27), thyroid (SIR = 2.05; 95 % CI 1.47–2.79), prostate (SIR = 1.21; 95 % CI 1.02–1.43), and ALL (SIR = 42.4; 95 % CI 23.18–71.13). SIRs were also increased (but nonsignificantly) following a number of other first sites, including cancers of the salivary gland, nasopharynx, esophagus, stomach, liver, gallbladder, eye, and acute non-lymphocytic leukemia. Where increased risk of developing a second meningioma was observed, this risk generally increased with time since initial cancer diagnosis. Increased risk of developing a second meningioma compared to the general population was first observed in the period ten or more years following initial diagnosis with ALL (SIR = 66.75; 95 % CI 36.49–112.00). A modest increased SIR of meningioma after prostate cancer was observed overall, but risks were statistically significant only after a 10-year latency period. Risk of developing a second meningioma following first
123
662
Cancer Causes Control (2014) 25:659–668
Table 2 Risk of developing second benign brain tumors during 2004–2008 among 2,038,074 SEER 1-year cancer survivors Characteristics
All benign brain
Meningioma
No. of patients
%
SIR
1,025
100
1.13*
Male
412
40.2
1.25*
Female
613
59.8
1.06
All patients
pHet
Acoustic neuroma
No. of patients
%
SIR
745
72.7
1.14*
279
37.4
1.29*
466
62.6
1.07
pHet
No. of patients
%
SIR
114
11.1
1.05
59
51.8
1.07
55
48.2
1.03
pHet
Gender 0.01
0.01
0.85
Race White
861
84
1.10*
Black Other
88 76
8.6 7.4
1.24 1.44*
12–35 mo
169
13.7
1.11
36–59 mo
134
10.9
1.03
0.02
618
83
1.13*
74 53
9.9 7.1
1.23 1.36*
120
13.3
1.13
93
10.3
1.01
0.03
96
84.2
0.97
3 15
2.6 13.2
0.99 2.36*
21
16
1.03
14
10.7
0.82
\0.001
Latency \0.001
\0.001
60–119 mo
298
24.1
1.17*
208
23
1.14
37
28.2
1.18
120? mo
424
34.4
1.15*
324
35.8
1.20*
42
32.1
1.06
0.51
Age at primary diagnosis \25 years
6
7.57* \0.001
49
6.6
2
1.8
1.26
25–44 years
129
12.6
1.23*
71
9.5
1.07
25
21.9
1.39
45–64 years
482
47
1.09
351
47.1
1.13*
57
50
0.94
65–84 years
352
34.3
1
274
36.8
1.02
30
26.3
1.05
Yes
356
34.7
1.21*
287
38.5
1.36* \0.001
28
24.6
0.81
No
669
65.3
1.09*
458
61.5
1.05
86
75.4
1.17
62
13.17* \0.001
0.37
Radiotherapy 0.12
0.09
pHet = p value for heterogeneity * Statistically significant (p \ 0.05)
cancers of the uterine corpus (SIR = 0.63; 95 % CI 0.42–0.91) and colon (SIR = 0.56; 95 % CI 0.37–0.82) was significantly lower than expected rates based on the general population. Observed SIRs for all second benign brain tumors combined were very similar to those for meningioma, with the exception of increased SIRs for all benign brain tumors following cancers of the nasopharynx (SIR = 3.87; 95 % CI 1.05–9.91) and kidney (SIR = 1.72; 95 % CI 1.17–2.43). We further examined the patterns of the SIRs for second meningioma according to the age at first cancer diagnosis, gender, and race (Table 4). Excess risk of developing a second meningioma compared to the general population following cancers of the brain (SIR = 114.06; 95 % CI 74.51–167.13), other CNS tumors (SIR = 73.86; 95 % CI 8.95–266.82), and ALL (SIR = 90.16; 95 % CI 48.01–154.18) was greatest in patients diagnosed with a primary tumor at age 25 years or younger. The highest risk of meningioma occurred after prostate cancers diagnosed in the youngest age group for this cancer site of 45–64 years (SIR = 1.46; 95 % CI 1.12–1.88). Analyses stratified by gender indicated higher risks of developing second meningioma compared to general population expected rates among male patients as compared to female
123
patients following primary cancers of the brain, other CNS, ALL, and thyroid, although the differences were only statistically significant after a first other CNS cancer (pHet = 0.01). In general, risk of second meningioma was more increased among black patients, particularly following primary malignant cancers of the brain (pHet = 0.001). SIR deficits were observed for second meningioma following primary cancers of the uterine corpus and colon regardless of age, race, or gender. In order to assess the effects of cranial irradiation on risk of second benign brain tumors, we further examined primary sites that were likely to receive cranial radiotherapy (oral cavity and pharynx, eye and orbit, brain, other CNS, and ALL), stratified by reported use of radiotherapy (Table 5). Increased risk of developing a second meningioma compared to the general population was increased for all of these sites. A higher magnitude of excess risk for individuals reporting use of radiotherapy was generally observed for each of the included primary sites, but this difference was only statistically significant for meningioma after first primary cancers of the brain (SIRRT = 41.81; 95 % CI 28.21–59.69, SIRnoRT = 3.57; 95 % CI 0.43–12.90, pHet \ 0.001) and ALL (SIRRT = 93.18; 95 %
Cancer Causes Control (2014) 25:659–668
663
Table 3 Standardized incidence ratios for second meningiomas by primary site and time since first cancer diagnosis 12–35 Months
36–59 Months
60–119 Months
120? Months
Total
Observed
SIR
Observed
SIR
Observed
SIR
Observed
SIR
Observed
SIR
1.20*
745
95 % CI
120
1.13
93
1.01
208
1.14
324
1.14*
1.06–1.23
Salivary gland
1
3.88
0
N/A
0
N/A
2
2.01
3
1.58
0.33–4.61
Nasopharynx
1
9.95
0
N/A
0
N/A
1
3.15
2
3.01
0.36–10.88
Esophagus
1
2.39
0
N/A
1
3.08
1
4.35
3
2.46
0.51–7.18
Stomach
2
2.22
1
1.68
3
3.19
0
N/A
6
1.63
0.6–3.55
Small intestine
0
N/A
0
0
1
2.03
1
1.84
2
1.12
0.14–4.05
Colon Rectum and rectosigmoid
5 3
0.59 0.92
2 6
0.29 2.14
12 4
0.94 0.72
7 5
0.39* 0.62
26 18
0.56* 0.92
0.37–0.82 0.54–1.45
Liver
2
4.84
0
N/A
1
5.4
0
N/A
3
3.37
0.7–9.86
Gallbladder
0
N/A
1
15.32
0
N/A
0
N/A
1
2.25
0.06–12.52
Nose, nasal cavity and middle ear
0
N/A
0
N/A
0
N/A
0
N/A
0
N/A
0–5.07
Lung and bronchus
4
0.64
4
1.13
4
0.77
5
0.95
17
0.84
0.49–1.35
Bones and joints
0
N/A
0
N/A
1
4.67
0
N/A
1
1.04
0.03–5.8
Soft tissue including heart
1
1.92
1
2.49
1
1.27
1
0.57
4
1.16
0.32–2.96
Melanoma of the skin Female breast
4
0.9
7
1.82
8
37
1.37
22
0.86
52
1
19
1.15
38
0.93
85
0.96
196
1.16
0.82–1.59
1
0.86–1.14
Uterine cervix
1
1.21
0
N/A
2
0.93
13
1.44
16
1.25
0.72–2.04
Uterine corpus
6
1.12
2
0.41
10
0.93
10
0.43*
28
0.63*
0.42–0.91
Ovary
3
1.64
2
1.51
1
0.42
8
1.42
14
1.26
0.69–2.11
1
21
1.03
53
1.27
47
1.38*
142
1.21*
1.02–1.43
0.22
4
1.05
10
1.39
14
1.29
29
1.1
0.73–1.57 0.73–2.07
Prostate Urinary bladder
21 1
Kidney
4
1.48
1
0.48
8
2.3
3
0.7
16
1.28
Eye and orbit
0
N/A
0
N/A
1
3.42
1
1.81
2
1.66
Brain
3
8.99*
1
5.01
3
7.72*
29
32.43*
36
19.82*
13.88–27.44
Other CNS Thyroid
0 3
N/A 1.23
0 5
N/A 2.39
2 10
15.82* 2.44*
3 22
11.65* 2.03*
5 40
9.54* 2.05*
3.1–22.27 1.47–2.79
Hodgkin lymphoma
0
N/A
0
N/A
0
N/A
3
1.22
3
0.78
0.16–2.29
Non-hodgkin lymphoma
5
1.09
6
1.58
8
1.23
12
1.63
31
1.39
0.95–1.98
Myeloma
0
N/A
0
N/A
3
3.43
0
N/A
3
0.87
Acute lymphocytic leukemia (ALL)
0
N/A
0
N/A
0
N/A
14
Chronic lymphocytic leukemia (CLL)
3
2.1
3
2.62
4
2.27
Acute non-lymphocytic leukemia (ANLL)
1
4.34
0
N/A
0
Acute myeloid leukemia (AML)
1
4.75
0
N/A
Acute monocytic leukemia
0
N/A
0
Chronic myeloid leukemia (CML)
1
3.58
0
0.2–5.98
0.18–2.53
66.75*
14
42.40*
23.18–71.13
1
0.59
11
1.82
0.91–3.26
N/A
2
5.11
3
2.98
0.61–8.7
0
N/A
0
N/A
1
1.1
0.03–6.13
N/A
0
N/A
0
N/A
0
0
N/A
0
N/A
0
N/A
1
1.04
0–74.07 0.03–5.78
* Statistically significant (p \ 0.05)
123
664
Cancer Causes Control (2014) 25:659–668
Table 4 Selected standardized incidence ratios for second meningioma stratified by age at primary diagnosis, gender, and race
Primary sites Brain O
Other CNS
SIR
O
PHet
ALL
SIR
PHet
O
0.01
Prostate SIR
PHet
0.04
O
SIR
PHet
0.07
Age at primary diagnosis \25 years
114.06* \0.001
2
73.86*
13
90.16*
0
N/A
25–44 years
4
5.76*
2
14.65*
1
14.07
0
N/A
45–64 yr
5
7.35*
1
4.15
0
N/A
61
1.46*
65–84 yrs
1
4.69
0
N/A
0
N/A
81
1.07
4 1
27.39* 2.65
0.01
7 7
60.65* 32.59*
0.29
142 0
1.21* N/A
N/A
0.46
0.25
111
1.18
0.64
24
1.36
7
1.24
26
Gender Male Female
14 22
25.26* 17.43*
0.27
0.001
Race White
26
16.01*
4
8.96*
12
43.10*
Black
5
47.24*
1
21.52
2
121.41*
Other
5
57.75*
0
N/A
0
N/A
Primary sites Thyroid O
SIR
Colon PHet
O
SIR
PHet
0.94
Uterine corpus
All primary sites
O
O
SIR
PHet
0.71
SIR
PHet
\0.001
Age at primary diagnosis \25 years
0
N/A
0
N/A
0
N/A
49
13.17*
25–44 years
14
1.97*
0.33
1
0.55
2
0.68
71
1.07
45–64 years
17
1.90*
11
0.56*
16
0.59*
351
1.13*
65–84 years
9
3.25*
14
0.57*
10
0.72
274
1.02
Gender Male
7
2.99*
33
1.92*
White
35
2.15*
Black
3
Other
2
Female
0.29
6
0.40*
20
0.64*
19
0.51*
2.4
4
1
3
0.31
0
N/A
28
0.63*
N/A
279
1.29*
466
1.07
26
0.66*
618
1.13*
0.74
2
0.91
74
1.23
0.85
0
N/A
53
1.36*
0.01
Race
* Statistically significant (p \ 0.05)
0.35
CI 44.68–171.35, SIRnoRT = 25.78; 95 % CI 7.02–66.01, pHet = 0.02). Increased risks of second meningioma after other central nervous system cancers, thyroid cancer, and cancer of the oral cavity/pharynx were quite similar regardless of reported radiotherapy. Since primary cancers of the brain and CNS are a heterogeneous group characterized by distinct differences in age of onset, invasiveness, and etiology, we stratified the aforementioned sites at increased for cranial radiotherapy in the brain and CNS by specific histology. When subdivided by histology, increased risk of developing a second meningioma compared to the general population was observed after first primary diagnoses of malignant glioma, astrocytoma NOS, gemistocytic astrocytoma, pilocytic astrocytoma, oligodendroglioma, and medulloblastoma (Online resource 1). Increased risk of meningioma was
123
0.32
0.67
0.03
greatest after a first diagnosis of medulloblastoma or pilocytic astrocytoma, both of which are primarily childhood tumors (SIR = 275.44; 95 % CI 142.32–481.14 and SIR = 69.49; 95 % CI 8.42–251.03, respectively). Few significant associations or clear patterns were observed for development of second acoustic neuromas in cancer survivors compared to the general population except for increased risks of acoustic neuroma following cancer of the nasopharynx (all latencies combined, n = 2), but numbers were small (Online resource 2).
Discussion This report represents, to our knowledge, the first largescale population-based analysis of the risk of second
0.02 7.02–66.01 PHet was calculated for the total latency period
* Statistically significant (p \ 0.05)
44.68–171.35 93.18*
25.78* 4
10 51.85–198.86
9.31–87.51 34.18*
108.13* 10
4 N/A
N/A N/A 0
0
Yes RT
No RT
N/A
1.73–51.52 2.55–36.09
Acute lymphocytic leukemia (ALL)
3.57
14.26* 12.35* 2 3
2 N/A
0.26–57.47 1.51–45 10.32 12.46*
N/A 0
1 2 0.58–128.7 0.31–67.62
1.35–40.19 11.13*
23.10 12.14 1 1
2 No RT
Yes RT No RT
0.43–12.90
0.88
665
Other central nervous system
28.21–59.69 41.81* 30 34.18–81.78 56.95* 29 0.12–26.76 4.80 1 Yes RT Brain
0.90–26.87 7.44
N/A 0
2 0.19–41.22
N/A N/A
7.40 1
0 N/A
0.19–41.68
0
N/A
1
No RT
Eye and orbit
Yes RT
7.48
N/A
0.45 0.25–2.31
0.49–3.49 1.49
0.90 4
5 0.32–4.55
0.36–3.37 1.32
1.56 3
4 N/A
0.17–5.09 1.41 2
0
Yes RT
No RT
Oral cavity and pharynx
0.00
Observed O/E
95 % CI Observed
O/E
95 % CI
Observed
O/E
95 % CI
PHet Total 120? Months 60–119 Months Radiotherapy Primary site
Table 5 Risk of meningioma following cranial radiotherapy by latency
\0.001
Cancer Causes Control (2014) 25:659–668
benign brain tumors in the United States. Meningiomas comprised the majority of subsequent benign brain tumors and thus drove the observed associations. We noted significant excess risk of second meningioma compared to expected risk in the general population after primary cancers of the brain, other CNS, prostate, and ALL. Excess risks for these sites were generally higher in individuals diagnosed with a primary cancer at younger ages, in males, and in blacks. We also observed associations between second meningiomas and primary tumors of the breast, thyroid, and significant deficits of benign brain cancers after initial cancers of the uterine corpus and colon. Previous studies have examined risk of second malignant (as opposed to benign) brain tumors among cancer survivors. A SEER-based analysis of subsequent new malignant tumors of the brain and CNS observed an increased risk of subsequent brain cancer compared to the general population following first tumors of the brain, other CNS, ALL, thyroid, and testis [3]. These results are remarkably similar to the findings we observe for second benign tumors, although the magnitude of risk was much higher in our results for risk of second meningioma. The higher excess risk we observe for meningioma following these sites is consistent with prior studies, which have reported higher risks for meningioma than for glioma (the most common subtype for malignant brain tumors) following exposure to radiation [18–20]. This is expected since malignant and benign brain tumors are considered to be distinct in etiology. As with our results for second meningioma, higher SIRs for second malignant brain tumors were seen with earlier age at first diagnosis. Other studies have separately linked second brain cancers to first cancers of the brain, CNS, and ALL in childhood cancer survivors and have observed greater risks after longer latency periods [21–23]. The increased risk we detected among patients \25 years of age at primary diagnosis and with a long latency period is likely driven by the increased risks observed in ALL and childhood brain tumors. Genetic factors may also play an important role in the development of multiple malignancies. The increased rates of second cancers observed in younger patients may suggest a genetic susceptibility to developing cancer. However, it is important to note that latency may be a confounding factor in our data since we only analyzed second benign brain tumors diagnosed between 2004 and 2007. Late effects of radiotherapy exposure may contribute to the aforementioned associations observed between primary cancers and second meningiomas. Increased SIRs for meningioma compared to the general population were observed following all sites with potential exposure to cranial radiotherapy, and the magnitude of excess risk was generally higher in those with reported radiotherapy
123
666
exposure compared to those without reported radiotherapy (although the difference was only statistically significant following primary diagnoses of the brain and ALL). 94 % of primary brain, 40 % of primary other CNS, and 71 % of primary ALL cases were reported to have received radiotherapy treatment; however, reporting of prophylactic RT for ALL is known to be incomplete in SEER before 1988. These cases had a significantly increased risk of developing a subsequent meningioma in our data. Our observed increased risk of second meningioma following exposure to radiotherapy is consistent with previous studies that have noted increased risk of meningioma in children therapeutically irradiated for treatment of tinea capitis [9, 19] and in childhood cancer survivors treated with radiotherapy [9, 18, 20]. In a cohort study of 10,834 Israeli patients irradiated for tinea capitis from 1948 to 1960, the relative risk and excess relative risk per gray (ERR/Gy) of developing meningiomas were 9.5 (95 % CI 3.5–25.7) and 4.63, respectively. Studies of childhood cancer survivors in Britain and the US have reported a strong linear relationship between radiation dose and risk of subsequent meningioma and radiation dose, with ERRs/Gy of 1.06 and 2.2, respectively [18, 20]. Although none of the three studies detected an effect of age at exposure on risk of meningioma following exposure to radiation, these studies were conducted on childhood cancer survivors and may have missed an age at exposure effect over a wider interval of age. Sporadic and radiation-induced meningiomas are distinct entities. Genes implicated in sporadic meningiomas include NF2, TP53, and PTEN, while radiation-induced meningiomas are characterized by genetic losses of parts of chromosome 22q [24]. It has been proposed that radiationassociated tumors may occur later than their sporadic counterparts. In our data, we observed a significantly increased risk of second meningiomas following radiotherapy treatment 12–35 months (SIR = 1.44; 95 % CI 1.08–1.87) and 120? months (SIR = 1.75; 95 % CI 1.45–2.08) after primary cancer diagnosis. Increased risk of second meningioma was observed in non-irradiated patients 60–119 months (SIR = 1.21; 95 % CI 1.01–1.42) after primary cancer diagnosis. Given that the increased risk of second meningioma detected in irradiated patients 12–35 months after primary cancer diagnosis may be attributable to surveillance bias, these data are difficult to interpret with respect to genetic disposition. Our large population-based sample of second meningiomas allowed us, unlike previous studies, to examine the risk of developing second meningiomas by specific histology of first primary brain tumor. Excess risk of second meningioma compared to the general population was highest after first primary medulloblastoma and pilocytic astrocytoma. This is consistent with particularly high
123
Cancer Causes Control (2014) 25:659–668
excess risks of malignant brain/CNS tumors compared to the general population after medulloblastoma (SIR = 18.9) [3], and high risks of second malignant tumors of any type observed after a first diagnosis medulloblastoma and astrocytoma or pilocytic astrocytoma in two other studies [3, 22, 25]. Both cancers mainly occur during childhood with the mean age at exposure being 14.1 and 18.8 years, respectively. Possible explanations for the particularly high observed increased risk of second neoplasms following these particular tumors could be young age of radiotherapy exposure, or an intrinsic quality of the tumor itself. Unlike primary diagnoses of meningioma, which is approximately twice as common in women compared with men [4], the excess risk of developing second meningioma compared to the general population was higher among male cancer survivors than female cancer survivors, suggesting that the sex difference in second meningioma rates is lower than in primary meningioma rates. A possible explanation for this difference is that a larger fraction of second meningioma cases in cancer survivors could be attributable to radiotherapy exposure, compared to meningiomas in the general population which may be attributable to a number of different factors, including hormonal influences [26]. Our finding of an association between thyroid cancer and meningioma has been reported in several studies, including a recent large case–control study of meningioma by Claus et al. [26–29]. While the mechanism underlying this association is not clear, one possible explanation is that the two cancers may be linked by common hormonal risk factors. Several previous studies report an association between meningioma and female breast carcinoma, while other studies found either no or only weak associations [26, 30, 31]. The cumulative observed rate of meningioma in female breast patients was 58 times the expected rate in a recent study conducted by Rao et al. [31]. In our analysis of 1-year minimum cancer survivors, breast cancer survivors did not have higher rates of meningioma than the general population beyond the first 12 months after primary diagnosis. This indicates a possible screening bias underlying the association, at least within our data. We observed significant deficits of second meningiomas after first cancers of the colon and uterine corpus. The deficits occurred in a small number of white males and females at later latencies. The etiology behind these associations is unclear, and these findings need to be replicated in other studies. Few primary sites were associated with an increased risk of developing a second acoustic neuroma compared to expected population risk. Previous studies have observed increased sensitivity to radiotherapy for acoustic neuroma compared with other benign brain tumors [9, 32]. In a study
Cancer Causes Control (2014) 25:659–668
of 93,000 atomic bomb survivors, Preston et al. reported ERR per Sievert of 4.5 (95 % CI 1.9–9.2) for acoustic neuromas and 0.64 (95 % CI -0.01 to 1.8) for meningiomas [32]. It is possible that with our smaller numbers of acoustic neuroma, we had insufficient statistical power with which to detect underlying associations with radiotherapy for this tumor. Limitations of our study include the lack of detailed information regarding dose or location of radiation, chemotherapeutic agents, genetic conditions, or environmental factors that could be related to the development of second benign brain tumors. Although this is one of the largest studies to date of second benign brain tumors, these tumors were only comprehensively collected starting in 2004, resulting in a relatively small number of cases to date. The incidence rates of all benign brain and CNS tumors in the general population between the years of 2005–2008 were stable, thus making increased capture over calendar time unlikely [6]. However, the recent reporting date of second benign brain tumors adds a latency bias. Long-term survivors were primarily diagnosed in the earlier calendar years, and the increased risk observed in the first 5 years since primary diagnosis is only from the most recent decade. Further, this study may have overestimated the rates of second benign brain tumors compared to the rates in the general population. Given that most benign brain tumors are asymptomatic, more second benign brain tumors may have been detected in this study due to increased surveillance after the patient’s primary malignancy or CNS irradiation. Cancer survivors are also more likely to undergo imaging in the setting of vague symptoms when compared to the general population. Although some misclassification of race may have occurred in our data given that selfreported race can incorrectly describe or simplify a patient’s complex genetic background [33], this is unlikely to account for all of the risk differences between races in our data given the strong correlation between self-reported race/ethnicity and genetic cluster categories [34–36]. Additionally, reported race takes social factors into account that may be influencing the patient’s health outcomes. Despite these limitations, our study has the strength of a large-scale, population-based design. Despite the rarity of benign brain tumors, use of the nationwide SEER registry allowed us to assess an extensive number of cases representative of the United States. Additionally, we were able to extend previous literature on second benign brain tumors in childhood cancer survivors to include adults. Future studies will be needed to reassess possible associations and risk factors for second benign brain tumors once more data are collected. Conflict of interest of interest.
The authors declare that they have no conflict
667
References 1. Howlader NNA, Krapcho M, Neyman N, Aminou R, Waldron W, Altekruse SF, Kosary CL, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Chen HS, Feuer EJ, Cronin KA, Edwards BK (2011) SEER cancer statistics review, 1975–2008, National Cancer Institute http://seer.cancer.gov/csr/1975_2008/, based on November 2010 SEER data submission 2. Ng AK, Travis LB (2008) Subsequent malignant neoplasms in cancer survivors. Cancer J 14(6):429–434. doi:10.1097/PPO. 0b013e31818d87700130404-200811000-00014 3. Inskip PD (2003) Multiple primary tumors involving cancer of the brain and central nervous system as the first or subsequent cancer. Cancer 98(3):562–570. doi:10.1002/cncr.11554 4. Kohler BA, Ward E, McCarthy BJ, Schymura MJ, Ries LA, Eheman C, Jemal A, Anderson RN, Ajani UA, Edwards BK (2011) Annual report to the nation on the status of cancer, 1975–2007, featuring tumors of the brain and other nervous system. J Natl Cancer Inst 103(9):714–736. doi:10.1093/jnci/djr077 5. Shonka NA, Hsu SH, Yung W, Mahajan A, Prabhu S (2011) Chapter 37. Tumors of the central nervous system. In: Kantarjian HM, Wolff RA, Koller CA (eds) The MD Anderson manual of medical oncology, 2 edn. McGraw-Hill, New York 6. Dolecek TA, Propp JM, Stroup NE, Kruchko C (2012) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005–2009. Neurooncology 14(Suppl 5):v1–v49. doi:10.1093/neuonc/nos218 7. Wrensch M, Minn Y, Chew T, Bondy M, Berger MS (2002) Epidemiology of primary brain tumors: current concepts and review of the literature. Neurooncology 4(4):278–299 8. Bondy ML, Scheurer ME, Malmer B, Barnholtz-Sloan JS, Davis FG, Il’yasova D, Kruchko C, McCarthy BJ, Rajaraman P, Schwartzbaum JA, Sadetzki S, Schlehofer B, Tihan T, Wiemels JL, Wrensch M, Buffler PA (2008) Brain tumor epidemiology: consensus from the brain tumor epidemiology consortium. Cancer 113(7 Suppl):1953–1968. doi:10.1002/cncr.23741 9. Ron E, Modan B, Boice JD Jr, 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(16):1033–1039. doi:10.1056/NEJM198810203191601 10. Bondy M, Ligon BL (1996) Epidemiology and etiology of intracranial meningiomas: a review. J Neurooncol 29(3):197–205 11. Narod SA, Stiller C, Lenoir GM (1991) An estimate of the heritable fraction of childhood cancer. Br J Cancer 63(6):993–999 12. 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(19):1330–1336. doi:10.1056/NEJM199111073251902 13. Cahill KS, Claus EB (2011) Treatment and survival of patients with nonmalignant intracranial meningioma: results from the surveillance, epidemiology, and end results program of the National Cancer Institute. J Neurosurg 115(2):259–267. doi:10. 3171/2011.3.JNS101748 14. Surveillance Research Program, National Cancer Institute SEER*Stat software (http://seer.cancer.gov/seerstat) version 8.1.2 15. Breslow NE (1984) Elementary methods of cohort analysis. Int J Epidemiol 13(1):112–115 16. Berrington de Gonzalez A, Curtis RE, Kry SF, Gilbert E, Lamart S, Berg CD, Stovall M, Ron E (2011) Proportion of second cancers attributable to radiotherapy treatment in adults: a cohort study in the US SEER cancer registries. Lancet Oncol 12(4):353–360. doi:10.1016/S1470-2045(11)70061-4 17. Bhatia S (2005) Cancer survivorship–pediatric issues. Hematology/the Education Program of the American Society of
123
668
18.
19.
20.
21.
22.
23.
24.
25.
26.
Cancer Causes Control (2014) 25:659–668 Hematology American Society of Hematology Education Program: 507–515. doi:10.1182/asheducation-2005.1.507 Neglia JP, Robison LL, Stovall M, Liu Y, Packer RJ, Hammond S, Yasui Y, Kasper CE, Mertens AC, Donaldson SS, Meadows AT, Inskip PD (2006) New primary neoplasms of the central nervous system in survivors of childhood cancer: a report from the childhood cancer survivor study. J Natl Cancer Inst 98(21):1528–1537. doi:10.1093/jnci/djj411 Sadetzki S, Chetrit A, Freedman L, Stovall M, Modan B, Novikov I (2005) Long-term follow-up for brain tumor development after childhood exposure to ionizing radiation for tinea capitis. Radiat Res 163(4):424–432 Taylor AJ, Little MP, Winter DL, Sugden E, Ellison DW, Stiller CA, Stovall M, Frobisher C, Lancashire ER, Reulen RC, Hawkins MM (2010) Population-based risks of CNS tumors in survivors of childhood cancer: the British childhood cancer survivor study. J Clin Oncol 28(36):5287–5293. doi:10.1200/JCO.2009.27.0090 Cardous-Ubbink MC, Heinen RC, Bakker PJ, van den Berg H, Oldenburger F, Caron HN, Voute PA, van Leeuwen FE (2007) Risk of second malignancies in long-term survivors of childhood cancer. Eur J Cancer 43(2):351–362. doi:10.1016/j.ejca.2006.10.004 Inskip PD, Curtis RE (2007) New malignancies following childhood cancer in the United States, 1973–2002. Int J Cancer 121(10):2233–2240. doi:10.1002/ijc.22827 Pui CH, Cheng C, Leung W, Rai SN, Rivera GK, Sandlund JT, Ribeiro RC, Relling MV, Kun LE, Evans WE, Hudson MM (2003) Extended follow-up of long-term survivors of childhood acute lymphoblastic leukemia. N Engl J Med 349(7):640–649. doi:10.1056/NEJMoa035091349/7/640 Shoshan Y, Chernova O, Juen SS, Somerville RP, Israel Z, Barnett GH, Cowell JK (2000) Radiation-induced meningioma: a distinct molecular genetic pattern? J Neuropathol Exp Neurol 59(7):614–620 Devarahally SR, Severson RK, Chuba P, Thomas R, Bhambhani K, Hamre MR (2003) Second malignant neoplasms after primary central nervous system malignancies of childhood and adolescence. Pediatr Hematol Oncol 20(8):617–625. doi:FYUQ1KULPWQ3AAUX Claus EB, Calvocoressi L, Bondy ML, Schildkraut JM, Wiemels JL, Wrensch M Family and personal medical history and risk of meningioma. J Neurosurg doi:10.3171/2011.6.JNS11129
123
27. Sughrue ME, Kane AJ, Shangari G, Parsa AT, Berger MS, McDermott MW Prevalence of previous extracranial malignancies in a series of 1228 patients presenting with meningioma. J Neurosurg 113 (5):1115–1121. doi:10.3171/2010.3.JNS091975 28. Lee E, Grutsch J, Persky V, Glick R, Mendes J, Davis F (2006) Association of meningioma with reproductive factors. Int J Cancer 119(5):1152–1157. doi:10.1002/ijc.21950 29. Davis F, Tavelin B, Grutsch J, Malmer B (2007) Second primary tumors following a diagnosis of meningioma in Sweden, 1958–1997. Neuroepidemiology 29(1–2):101–106. doi:10.1159/ 000109823 30. Custer BS, Koepsell TD, Mueller BA (2002) The association between breast carcinoma and meningioma in women. Cancer 94(6):1626–1635. doi:10.1002/cncr.10410 31. Rao G, Giordano SH, Liu J, McCutcheon IE (2009) The association of breast cancer and meningioma in men and women. Neurosurgery 65 (3):483–489; discussion 489. doi:10.1227/01. NEU.0000350876.91495.E000006123-200909000-00016 32. Preston DL, Ron E, Yonehara S, Kobuke T, Fujii H, Kishikawa M, Tokunaga M, Tokuoka S, Mabuchi K (2002) Tumors of the nervous system and pituitary gland associated with atomic bomb radiation exposure. J Natl Cancer Inst 94(20):1555–1563 33. Wilson JF, Weale ME, Smith AC, Gratrix F, Fletcher B, Thomas MG, Bradman N, Goldstein DB (2001) Population genetic structure of variable drug response. Nat Genet 29(3):265–269. doi:10.1038/ng761 34. Tang H, Quertermous T, Rodriguez B, Kardia SL, Zhu X, Brown A, Pankow JS, Province MA, Hunt SC, Boerwinkle E, Schork NJ, Risch NJ (2005) Genetic structure, self-identified race/ethnicity, and confounding in case-control association studies. Am J Hum Genet 76(2):268–275. doi:10.1086/427888 35. Risch N, Burchard E, Ziv E, Tang H (2002) Categorization of humans in biomedical research: genes, race and disease. Genome Biol 3 (7): comment 2007 36. Burchard EG, Ziv E, Coyle N, Gomez SL, Tang H, Karter AJ, Mountain JL, Perez-Stable EJ, Sheppard D, Risch N (2003) The importance of race and ethnic background in biomedical research and clinical practice. N Engl J Med 348(12):1170–1175. doi:10. 1056/NEJMsb025007