Subsequent neoplasms in survivors of childhood central nervous system tumors: risk after modern multimodal therapy.
BACKGROUND
Multimodal therapy has improved survival for some childhood CNS tumors. However, whether risk for subsequent neoplasms (SNs) also increases is unknown. We report the cumulative incidence of, and risk factors for, SNs after a childhood primary CNS tumor and determine whether treatment that combines radiation therapy (RT) with chemotherapy increases risk for SNs.


METHODS
Analyses included 2779 patients with a primary CNS tumor treated at St Jude Children's Research Hospital between 1985 and 2012. Cumulative incidence and standardized incidence ratios (SIRs) were estimated for SNs confirmed by pathology report. Cumulative incidence among the 237 five-year medulloblastoma survivors treated with multimodal therapy (RT + chemotherapy) was compared with a historical cohort of 139 five-year survivors treated with RT but no chemotherapy in the Childhood Cancer Survivor Study.


RESULTS
Eighty-one survivors had 97 SNs. The cumulative incidence of first SN was 3.0% (95% CI: 2.3%-3.9%) at 10 years, and 6.0% (95% CI: 4.6%-7.7%) at 20 years from diagnosis. Risks were highest for subsequent glioma, all grades (SIR = 57.2; 95% CI: 36.2-85.8) and acute myeloid leukemia (SIR = 31.8; 95% CI: 10.2-74.1). Compared with RT alone, RT + chemotherapy did not increase risk for SNs (hazard ratio: 0.64; 95% CI: 0.38-1.06). Among five-year survivors of medulloblastoma treated with multimodal therapy, cumulative incidence of SN was 12.0% (95% CI: 6.4%-19.5%) at 20 years, no different than survivors treated with RT alone (11.3%, P = .44).


CONCLUSIONS
The cumulative incidence of SNs continues to increase with time from treatment with no obvious plateau, but the risk does not appear to be higher after exposure to multimodal therapy compared with RT alone. Continued follow-up of survivors as they age is essential.
Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee (K.T., A.B., A.G., C.W.); Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee (C.L., D.S.); Department of Radiological Sciences, St Jude Children's Research Hospital, Memphis, Tennessee (L.E.K., T.E.M.); Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee (D.W.E., B.A.O.); Department of Surgery, St Jude Children's Research Hospital, Memphis, Tennessee (F.A.B., P.K.); Semmes-Murphey Neurologic and Spine Institute, Memphis, Tennessee (F.A.B., P.K.); Department of Neurosurgery, University of Tennessee Health Science Center, Memphis, Tennessee (F.A.B., P.K.); University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee (J.R.); Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee (L.L.R., G.T.A.).
Karen
K
Tsui
Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee (K.T., A.B., A.G., C.W.); Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee (C.L., D.S.); Department of Radiological Sciences, St Jude Children's Research Hospital, Memphis, Tennessee (L.E.K., T.E.M.); Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee (D.W.E., B.A.O.); Department of Surgery, St Jude Children's Research Hospital, Memphis, Tennessee (F.A.B., P.K.); Semmes-Murphey Neurologic and Spine Institute, Memphis, Tennessee (F.A.B., P.K.); Department of Neurosurgery, University of Tennessee Health Science Center, Memphis, Tennessee (F.A.B., P.K.); University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee (J.R.); Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee (L.L.R., G.T.A.).
Amar
A
Gajjar
Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee (K.T., A.B., A.G., C.W.); Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee (C.L., D.S.); Department of Radiological Sciences, St Jude Children's Research Hospital, Memphis, Tennessee (L.E.K., T.E.M.); Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee (D.W.E., B.A.O.); Department of Surgery, St Jude Children's Research Hospital, Memphis, Tennessee (F.A.B., P.K.); Semmes-Murphey Neurologic and Spine Institute, Memphis, Tennessee (F.A.B., P.K.); Department of Neurosurgery, University of Tennessee Health Science Center, Memphis, Tennessee (F.A.B., P.K.); University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee (J.R.); Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee (L.L.R., G.T.A.).
Chenghong
C
Li
Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee (K.T., A.B., A.G., C.W.); Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee (C.L., D.S.); Department of Radiological Sciences, St Jude Children's Research Hospital, Memphis, Tennessee (L.E.K., T.E.M.); Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee (D.W.E., B.A.O.); Department of Surgery, St Jude Children's Research Hospital, Memphis, Tennessee (F.A.B., P.K.); Semmes-Murphey Neurologic and Spine Institute, Memphis, Tennessee (F.A.B., P.K.); Department of Neurosurgery, University of Tennessee Health Science Center, Memphis, Tennessee (F.A.B., P.K.); University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee (J.R.); Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee (L.L.R., G.T.A.).
Deokumar
D
Srivastava
Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee (K.T., A.B., A.G., C.W.); Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee (C.L., D.S.); Department of Radiological Sciences, St Jude Children's Research Hospital, Memphis, Tennessee (L.E.K., T.E.M.); Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee (D.W.E., B.A.O.); Department of Surgery, St Jude Children's Research Hospital, Memphis, Tennessee (F.A.B., P.K.); Semmes-Murphey Neurologic and Spine Institute, Memphis, Tennessee (F.A.B., P.K.); Department of Neurosurgery, University of Tennessee Health Science Center, Memphis, Tennessee (F.A.B., P.K.); University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee (J.R.); Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee (L.L.R., G.T.A.).
Alberto
A
Broniscer
Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee (K.T., A.B., A.G., C.W.); Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee (C.L., D.S.); Department of Radiological Sciences, St Jude Children's Research Hospital, Memphis, Tennessee (L.E.K., T.E.M.); Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee (D.W.E., B.A.O.); Department of Surgery, St Jude Children's Research Hospital, Memphis, Tennessee (F.A.B., P.K.); Semmes-Murphey Neurologic and Spine Institute, Memphis, Tennessee (F.A.B., P.K.); Department of Neurosurgery, University of Tennessee Health Science Center, Memphis, Tennessee (F.A.B., P.K.); University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee (J.R.); Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee (L.L.R., G.T.A.).
Cynthia
C
Wetmore
Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee (K.T., A.B., A.G., C.W.); Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee (C.L., D.S.); Department of Radiological Sciences, St Jude Children's Research Hospital, Memphis, Tennessee (L.E.K., T.E.M.); Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee (D.W.E., B.A.O.); Department of Surgery, St Jude Children's Research Hospital, Memphis, Tennessee (F.A.B., P.K.); Semmes-Murphey Neurologic and Spine Institute, Memphis, Tennessee (F.A.B., P.K.); Department of Neurosurgery, University of Tennessee Health Science Center, Memphis, Tennessee (F.A.B., P.K.); University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee (J.R.); Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee (L.L.R., G.T.A.).
Larry E
LE
Kun
Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee (K.T., A.B., A.G., C.W.); Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee (C.L., D.S.); Department of Radiological Sciences, St Jude Children's Research Hospital, Memphis, Tennessee (L.E.K., T.E.M.); Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee (D.W.E., B.A.O.); Department of Surgery, St Jude Children's Research Hospital, Memphis, Tennessee (F.A.B., P.K.); Semmes-Murphey Neurologic and Spine Institute, Memphis, Tennessee (F.A.B., P.K.); Department of Neurosurgery, University of Tennessee Health Science Center, Memphis, Tennessee (F.A.B., P.K.); University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee (J.R.); Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee (L.L.R., G.T.A.).
Thomas E
TE
Merchant
Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee (K.T., A.B., A.G., C.W.); Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee (C.L., D.S.); Department of Radiological Sciences, St Jude Children's Research Hospital, Memphis, Tennessee (L.E.K., T.E.M.); Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee (D.W.E., B.A.O.); Department of Surgery, St Jude Children's Research Hospital, Memphis, Tennessee (F.A.B., P.K.); Semmes-Murphey Neurologic and Spine Institute, Memphis, Tennessee (F.A.B., P.K.); Department of Neurosurgery, University of Tennessee Health Science Center, Memphis, Tennessee (F.A.B., P.K.); University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee (J.R.); Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee (L.L.R., G.T.A.).
David W
DW
Ellison
Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee (K.T., A.B., A.G., C.W.); Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee (C.L., D.S.); Department of Radiological Sciences, St Jude Children's Research Hospital, Memphis, Tennessee (L.E.K., T.E.M.); Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee (D.W.E., B.A.O.); Department of Surgery, St Jude Children's Research Hospital, Memphis, Tennessee (F.A.B., P.K.); Semmes-Murphey Neurologic and Spine Institute, Memphis, Tennessee (F.A.B., P.K.); Department of Neurosurgery, University of Tennessee Health Science Center, Memphis, Tennessee (F.A.B., P.K.); University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee (J.R.); Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee (L.L.R., G.T.A.).
Brent A
BA
Orr
Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee (K.T., A.B., A.G., C.W.); Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee (C.L., D.S.); Department of Radiological Sciences, St Jude Children's Research Hospital, Memphis, Tennessee (L.E.K., T.E.M.); Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee (D.W.E., B.A.O.); Department of Surgery, St Jude Children's Research Hospital, Memphis, Tennessee (F.A.B., P.K.); Semmes-Murphey Neurologic and Spine Institute, Memphis, Tennessee (F.A.B., P.K.); Department of Neurosurgery, University of Tennessee Health Science Center, Memphis, Tennessee (F.A.B., P.K.); University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee (J.R.); Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee (L.L.R., G.T.A.).
Frederick A
FA
Boop
Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee (K.T., A.B., A.G., C.W.); Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee (C.L., D.S.); Department of Radiological Sciences, St Jude Children's Research Hospital, Memphis, Tennessee (L.E.K., T.E.M.); Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee (D.W.E., B.A.O.); Department of Surgery, St Jude Children's Research Hospital, Memphis, Tennessee (F.A.B., P.K.); Semmes-Murphey Neurologic and Spine Institute, Memphis, Tennessee (F.A.B., P.K.); Department of Neurosurgery, University of Tennessee Health Science Center, Memphis, Tennessee (F.A.B., P.K.); University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee (J.R.); Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee (L.L.R., G.T.A.).
Paul
P
Klimo
Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee (K.T., A.B., A.G., C.W.); Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee (C.L., D.S.); Department of Radiological Sciences, St Jude Children's Research Hospital, Memphis, Tennessee (L.E.K., T.E.M.); Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee (D.W.E., B.A.O.); Department of Surgery, St Jude Children's Research Hospital, Memphis, Tennessee (F.A.B., P.K.); Semmes-Murphey Neurologic and Spine Institute, Memphis, Tennessee (F.A.B., P.K.); Department of Neurosurgery, University of Tennessee Health Science Center, Memphis, Tennessee (F.A.B., P.K.); University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee (J.R.); Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee (L.L.R., G.T.A.).
Jordan
J
Ross
Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee (K.T., A.B., A.G., C.W.); Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee (C.L., D.S.); Department of Radiological Sciences, St Jude Children's Research Hospital, Memphis, Tennessee (L.E.K., T.E.M.); Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee (D.W.E., B.A.O.); Department of Surgery, St Jude Children's Research Hospital, Memphis, Tennessee (F.A.B., P.K.); Semmes-Murphey Neurologic and Spine Institute, Memphis, Tennessee (F.A.B., P.K.); Department of Neurosurgery, University of Tennessee Health Science Center, Memphis, Tennessee (F.A.B., P.K.); University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee (J.R.); Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee (L.L.R., G.T.A.).
Leslie L
LL
Robison
Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee (K.T., A.B., A.G., C.W.); Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee (C.L., D.S.); Department of Radiological Sciences, St Jude Children's Research Hospital, Memphis, Tennessee (L.E.K., T.E.M.); Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee (D.W.E., B.A.O.); Department of Surgery, St Jude Children's Research Hospital, Memphis, Tennessee (F.A.B., P.K.); Semmes-Murphey Neurologic and Spine Institute, Memphis, Tennessee (F.A.B., P.K.); Department of Neurosurgery, University of Tennessee Health Science Center, Memphis, Tennessee (F.A.B., P.K.); University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee (J.R.); Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee (L.L.R., G.T.A.).
Gregory T
GT
Armstrong
D000293:Adolescent; D000328:Adult; D001932:Brain Neoplasms / Q000188:drug therapy / Q000453:epidemiology* / Q000532:radiotherapy; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008527:Medulloblastoma / Q000188:drug therapy / Q000453:epidemiology* / Q000532:radiotherapy; D016609:Neoplasms, Second Primary / Q000453:epidemiology*; D012307:Risk Factors; D017741:Survivors; D055815:Young Adult
chemotherapy; childhood CNS tumor survivors; medulloblastoma; radiation; subsequent neoplasms