Risk of secondary neoplasms after external-beam radiation therapy treatment of pediatric low-grade gliomas: a SEER analysis, 1973–2015

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  • 1 Department of Neurosurgery, Stanford School of Medicine, Stanford, California
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OBJECTIVE

Although past studies have associated external-beam radiation therapy (EBRT) with higher incidences of secondary neoplasms (SNs), its effect on SN development from pediatric low-grade gliomas (LGGs), defined as WHO grade I and II gliomas of astrocytic or oligodendrocytic origin, is not well understood. Utilizing a national cancer registry, the authors sought to characterize the risk of SN development after EBRT treatment of pediatric LGG.

METHODS

A total of 1245 pediatric patient (aged 0–17 years) records from 1973 to 2015 were assembled from the Surveillance, Epidemiology, and End Results (SEER) database. Univariable and multivariable subdistribution hazard regression models were used to evaluate the prognostic impact of demographic, tumor, and treatment-related covariates. Propensity score matching was used to balance baseline characteristics. Cumulative incidence analyses measured the time to, and rate of, SN development, stratified by receipt of EBRT and controlled for competing mortality risk. The Fine and Gray semiparametric model was used to estimate future SN risk in EBRT- and non–EBRT-treated pediatric patients.

RESULTS

In this study, 366 patients received EBRT and 879 did not. Forty-six patients developed SNs after an LGG diagnosis, and 27 of these patients received EBRT (OR 3.61, 95% CI 1.90–6.95; p < 0.001). For patients alive 30 years from the initial LGG diagnosis, the absolute risk of SN development in the EBRT-treated cohort was 12.61% (95% CI 8.31–13.00) compared with 4.99% (95% CI 4.38–12.23) in the non–EBRT-treated cohort (p = 0.013). Cumulative incidence curves that were adjusted for competing events still demonstrated higher rates of SN development in the EBRT-treated patients with LGGs. After matching across available covariates and again adjusting for the competing risk of mortality, a clear association between EBRT and SN development remained (subhazard ratio 2.26, 95% CI 1.21–4.20; p = 0.010).

CONCLUSIONS

Radiation therapy was associated with an increased risk of future SNs for pediatric patients surviving LGGs. These data suggest that the long-term implications of EBRT should be considered when making treatment decisions for this patient population

ABBREVIATIONS

CIF = cumulative incidence function; EBRT = external-beam radiation therapy; ICD-O-3 = International Classification of Diseases for Oncology, Third Edition; LGG = low-grade glioma; NOS = not otherwise specified; SEER = Surveillance, Epidemiology, and End Results; SHR = subhazard ratio; SMD = standardized mean difference; SN = secondary neoplasm.

Supplementary Materials

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Illustration from Seaman et al. (pp 260–267). Copyright Jane Whitney. Published with permission.

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Contributor Notes

Correspondence Gerald A. Grant: Stanford School of Medicine, Stanford, CA. ggrant2@stanford.edu.

INCLUDE WHEN CITING Published online June 18, 2021; DOI: 10.3171/2021.1.PEDS20859.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

  • 1

    Ries LAG, Smith MA, Gurney JG, et al. , eds.Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program 1975–1995. NIH Pub. No. 99-4649. National Cancer Institute, SEER Program; 1999. Accessed February 19, 2021. https://seer.cancer.gov/archive/publications/childhood/

    • Search Google Scholar
    • Export Citation
  • 2

    Ward E, DeSantis C, Robbins A, et al. Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin. 2014;64(2):83103.

  • 3

    Galloway TJ, Indelicato DJ, Amdur RJ, et al. Second tumors in pediatric patients treated with radiotherapy to the central nervous system. Am J Clin Oncol. 2012;35(3):279283.

    • Search Google Scholar
    • Export Citation
  • 4

    Nishio S, Morioka T, Inamura T, et al. Radiation-induced brain tumours: potential late complications of radiation therapy for brain tumours. Acta Neurochir (Wien). 1998;140(8):763770.

    • Search Google Scholar
    • Export Citation
  • 5

    Tsui K, Gajjar A, Li C, et al. Subsequent neoplasms in survivors of childhood central nervous system tumors: risk after modern multimodal therapy. Neuro Oncol. 2015;17(3):448456.

    • Search Google Scholar
    • Export Citation
  • 6

    You SH, Lyu CJ, Kim DS, Suh CO. Second primary brain tumors following cranial irradiation for pediatric solid brain tumors. Childs Nerv Syst. 2013;29(10):18651870.

    • Search Google Scholar
    • Export Citation
  • 7

    Neglia JP, Robison LL, Stovall M, et al. 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. 2006;98(21):15281537.

    • Search Google Scholar
    • Export Citation
  • 8

    Inskip PD, Sigurdson AJ, Veiga L, et al. Radiation-related new primary solid cancers in the childhood cancer survivor study: comparative radiation dose response and modification of treatment effects. Int J Radiat Oncol Biol Phys. 2016;94(4):800807.

    • Search Google Scholar
    • Export Citation
  • 9

    Packer RJ, Meadows AT, Rorke LB, et al. Long-term sequelae of cancer treatment on the central nervous system in childhood. Med Pediatr Oncol. 1987;15(5):241253.

    • Search Google Scholar
    • Export Citation
  • 10

    Relling MV, Rubnitz JE, Rivera GK, et al. High incidence of secondary brain tumours after radiotherapy and antimetabolites. Lancet. 1999;354(9172):3439.

    • Search Google Scholar
    • Export Citation
  • 11

    Friedman DL, Whitton J, Leisenring W, et al. Subsequent neoplasms in 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2010;102(14):10831095.

    • Search Google Scholar
    • Export Citation
  • 12

    Garwicz S, Anderson H, Olsen JH, et al. Second malignant neoplasms after cancer in childhood and adolescence: a population-based case-control study in the 5 Nordic countries. Int J Cancer. 2000;88(4):672678.

    • Search Google Scholar
    • Export Citation
  • 13

    Broniscer A, Ke W, Fuller CE, et al. Second neoplasms in pediatric patients with primary central nervous system tumors: the St. Jude Children’s Research Hospital experience. Cancer. 2004;100(10):22462252.

    • Search Google Scholar
    • Export Citation
  • 14

    Armstrong GT, Liu Q, Yasui Y, et al. Long-term outcomes among adult survivors of childhood central nervous system malignancies in the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2009;101(13):946958.

    • Search Google Scholar
    • Export Citation
  • 15

    Roddy E, Mueller S. Late effects of treatment of pediatric central nervous system tumors. J Child Neurol. 2016;31(2):237254.

  • 16

    Grier JT, Batchelor T. Low-grade gliomas in adults. Oncologist. 2006;11(6):681693.

  • 17

    Gilbert MR, Lang FF. Management of patients with low-grade gliomas. Neurol Clin. 2007;25(4):10731088, ix.

  • 18

    Prabhu VC, Khaldi A, Barton KP, et al. Management of diffuse low-grade cerebral gliomas. Neurol Clin. 2010;28(4):10371059.

  • 19

    Packer RJ, Pfister S, Bouffet E, et al. Pediatric low-grade gliomas: implications of the biologic era. Neuro Oncol. 2017;19(6):750761.

  • 20

    van den Bent MJ. Interobserver variation of the histopathological diagnosis in clinical trials on glioma: a clinician’s perspective. Acta Neuropathol. 2010;120(3):297304.

    • Search Google Scholar
    • Export Citation
  • 21

    Chaichana KL, McGirt MJ, Laterra J, et al. Recurrence and malignant degeneration after resection of adult hemispheric low-grade gliomas. J Neurosurg. 2010;112(1):1017.

    • Search Google Scholar
    • Export Citation
  • 22

    Tsang DS, Murphy ES, Lucas JT Jr, et al. Pseudoprogression in pediatric low-grade glioma after irradiation. J Neurooncol. 2017;135(2):371379.

    • Search Google Scholar
    • Export Citation
  • 23

    de Blank P, Bandopadhayay P, Haas-Kogan D, et al. Management of pediatric low-grade glioma. Curr Opin Pediatr. 2019;31(1):2127.

  • 24

    Bandopadhayay P, Bergthold G, London WB, et al. Long-term outcome of 4,040 children diagnosed with pediatric low-grade gliomas: an analysis of the Surveillance Epidemiology and End Results (SEER) database. Pediatr Blood Cancer. 2014;61(7):11731179.

    • Search Google Scholar
    • Export Citation
  • 25

    Krishnatry R, Zhukova N, Guerreiro Stucklin AS, et al. Clinical and treatment factors determining long-term outcomes for adult survivors of childhood low-grade glioma: a population-based study. Cancer. 2016;122(8):12611269.

    • Search Google Scholar
    • Export Citation
  • 26

    Han SS, Rivera GA, Tammemägi MC, et al. Risk stratification for second primary lung cancer. J Clin Oncol. 2017;35(25):28932899.

  • 27

    Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94(446):496509.

  • 28

    Coviello E. STPEPEMORI: Stata module to test the equality of cumulative incidences across two groups in the presence of competing risks. S456899. Statistical Software Components. Boston College Department of Economics. Updated November 6, 2010. Accessed February 19, 2021. https://ideas.repec.org/c/boc/bocode/s456899.html

    • Search Google Scholar
    • Export Citation
  • 29

    Austin PC. Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples. Stat Med. 2009;28(25):30833107.

    • Search Google Scholar
    • Export Citation
  • 30

    Garrido MM, Kelley AS, Paris J, et al. Methods for constructing and assessing propensity scores. Health Serv Res. 2014;49(5):17011720.

  • 31

    Rombi B, Vennarini S, Vinante L, et al. Proton radiotherapy for pediatric tumors: review of first clinical results. Ital J Pediatr. 2014;40:74.

    • Search Google Scholar
    • Export Citation
  • 32

    Combs SE, Burkholder I, Edler L, et al. Randomised phase I/II study to evaluate carbon ion radiotherapy versus fractionated stereotactic radiotherapy in patients with recurrent or progressive gliomas: the CINDERELLA trial. BMC Cancer. 2010;10:533.

    • Search Google Scholar
    • Export Citation
  • 33

    Athar BS, Paganetti H. Comparison of second cancer risk due to out-of-field doses from 6-MV IMRT and proton therapy based on 6 pediatric patient treatment plans. Radiother Oncol. 2011;98(1):8792.

    • Search Google Scholar
    • Export Citation
  • 34

    Moteabbed M, Yock TI, Paganetti H. The risk of radiation-induced second cancers in the high to medium dose region: a comparison between passive and scanned proton therapy, IMRT and VMAT for pediatric patients with brain tumors. Phys Med Biol. 2014;59(12):28832899.

    • Search Google Scholar
    • Export Citation
  • 35

    Eaton BR, MacDonald SM, Yock TI, Tarbell NJ. Secondary malignancy risk following proton radiation therapy. Front Oncol. 2015;5:261.

  • 36

    Muskens IS, de Smith AJ, Zhang C, et al. Germline cancer predisposition variants and pediatric glioma: a population-based study in California. Neuro Oncol. 2020;22(6):864874.

    • Search Google Scholar
    • Export Citation
  • 37

    Sharif S, Ferner R, Birch JM, et al. Second primary tumors in neurofibromatosis 1 patients treated for optic glioma: substantial risks after radiotherapy. J Clin Oncol. 2006;24(16):25702575.

    • Search Google Scholar
    • Export Citation

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