title: Stomach Cancer Following Hodgkin Lymphoma, Testicular Cancer and Cervical Cancer: A Pooled Analysis of Three International Studies with a Focus on Radiation Effects.
abstract: To further understand the risk of stomach cancer after fractionated high-dose radiotherapy, we pooled individual-level data from three recent stomach cancer case-control studies. These studies were nested in cohorts of five-year survivors of first primary Hodgkin lymphoma (HL), testicular cancer (TC) or cervical cancer (CX) from seven countries. Detailed data were abstracted from patient records and radiation doses were reconstructed to the site of the stomach cancer for cases and to the corresponding sites for matched controls. Among 327 cases and 678 controls, mean doses to the stomach were 15.3 Gy, 24.7 Gy and 1.9 Gy, respectively, for Hodgkin lymphoma, testicular cancer and cervical cancer survivors, with an overall mean dose of 10.3 Gy. Risk increased with increasing radiation dose to the stomach cancer site (P < 0.001) with no evidence of nonlinearity or of a downturn at the highest doses (≥35 Gy). The pooled excess odds ratio per Gy (EOR/Gy) was 0.091 [95% confidence interval (CI): 0.036-0.20] with estimates of 0.049 (95% CI: 0.007-0.16) for Hodgkin lymphoma, 0.27 (95% CI: 0.054-1.44) for testicular cancer and 0.096 (95% CI: -0.002-0.39) for cervical cancer (P homogeneity = 0.25). The EOR/Gy increased with time since exposure (P trend = 0.004), with an EOR/Gy of 0.38 (95% CI: 0.12-1.04) for stomach cancer occurring ≥20 years postirradiation corresponding to odds ratios of 4.8 and 10.5 at radiation doses to the stomach of 10 and 25 Gy, respectively. Of 111 stomach cancers occurring ≥20 years after radiotherapy, 63.8 (57%) could be attributed to radiotherapy. Our findings differ from those based on Japanese atomic-bomb survivors, where the overall EOR/Gy was higher and where there was no evidence of an increase with time since exposure. By pooling data from three studies, we demonstrated a clear increase in stomach cancer risk over a wide range of doses from fractionated radiotherapy with the highest risks occurring many years after exposure. These findings highlight the need to directly evaluate the health effects of high-dose fractionated radiotherapy rather than relying on the data of persons exposed at low and moderate acute doses.
authors.affiliation: a   Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Rockville, Maryland.
authors.forename: Ethel S
authors.initials: ES
authors.lastname: Gilbert
authors.affiliation: a   Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Rockville, Maryland.
authors.forename: Rochelle E
authors.initials: RE
authors.lastname: Curtis
authors.affiliation: b   Department of Epidemiology and Biostatistics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Michael
authors.initials: M
authors.lastname: Hauptmann
authors.affiliation: a   Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Rockville, Maryland.
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Kleinerman
authors.affiliation: c   Department of Epidemiology, University of Iowa, Iowa City, Iowa.
authors.forename: Charles F
authors.initials: CF
authors.lastname: Lynch
authors.affiliation: d   Department of Radiation Physics, University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Stovall
authors.affiliation: d   Department of Radiation Physics, University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Smith
authors.affiliation: d   Department of Radiation Physics, University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors.forename: Rita
authors.initials: R
authors.lastname: Weathers
authors.affiliation: e   Department of Oncology, Copenhagen University Hospital, Copenhagen, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Andersson
authors.affiliation: a   Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Rockville, Maryland.
authors.forename: Graça M
authors.initials: GM
authors.lastname: Dores
authors.affiliation: a   Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Rockville, Maryland.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Fraumeni
authors.affiliation: f   Department of Oncology, Oslo University Hospital and University of Oslo, Oslo, Norway.
authors.forename: Sophie D
authors.initials: SD
authors.lastname: Fossa
authors.affiliation: g   Clinical Epidemiology Unit, Department of Medicine, Karolinska Institute, Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Hall
authors.affiliation: h   Department of Radiation Oncology, University of Toronto, Toronto, Canada.
authors.forename: David C
authors.initials: DC
authors.lastname: Hodgson
authors.affiliation: i   Dalla Lana School of Public Health, University of Toronto, Toronto, Canada.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Holowaty
authors.affiliation: j   Department of Oncology, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Joensuu
authors.affiliation: k   Cancer Registry of Norway, Oslo, Norway.
authors.forename: Tom B
authors.initials: TB
authors.lastname: Johannesen
authors.affiliation: k   Cancer Registry of Norway, Oslo, Norway.
authors.forename: Froydis
authors.initials: F
authors.lastname: Langmark
authors.affiliation: l   Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Kaijser
authors.affiliation: m   Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland.|n   School of Health Sciences, University of Tampere, Tampere, Finland.
authors.forename: Eero
authors.initials: E
authors.lastname: Pukkala
authors.affiliation: a   Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Rockville, Maryland.
authors.forename: Preetha
authors.initials: P
authors.lastname: Rajaraman
authors.affiliation: Danish Cancer Society, Copenhagen, Denmark.
authors.forename: Hans H
authors.initials: HH
authors.lastname: Storm
authors.affiliation: j   Department of Oncology, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: Leila
authors.initials: L
authors.lastname: Vaalavirta
authors.affiliation: b   Department of Epidemiology and Biostatistics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Alexandra W
authors.initials: AW
authors.lastname: van den Belt-Dusebout
authors.affiliation: p   Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; and.
authors.forename: Berthe M
authors.initials: BM
authors.lastname: Aleman
authors.affiliation: q   Melvin and Bren Simon Cancer Center, Indianapolis University School of Medicine, Indianapolis, Indiana.
authors.forename: Lois B
authors.initials: LB
authors.lastname: Travis
authors.affiliation: a   Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Rockville, Maryland.
authors.forename: Lindsay M
authors.initials: LM
authors.lastname: Morton
authors.affiliation: b   Department of Epidemiology and Biostatistics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Flora E
authors.initials: FE
authors.lastname: van Leeuwen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D019583:Dose Fractionation, Radiation; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006689:Hodgkin Disease / Q000532:radiotherapy*; D006801:Humans; D038622:Internationality; D008297:Male; D008875:Middle Aged; D009381:Neoplasms, Radiation-Induced / Q000453:epidemiology / Q000209:etiology*; D013274:Stomach Neoplasms / Q000453:epidemiology / Q000209:etiology*; D013736:Testicular Neoplasms / Q000532:radiotherapy*; D002583:Uterine Cervical Neoplasms / Q000532:radiotherapy*