title: Second cancers among 104,760 survivors of cervical cancer: evaluation of long-term risk.
abstract: BACKGROUND
  Given the extended survival of patients diagnosed with cervical cancer, the large number of these women treated with radiotherapy, and the presence in this population of established cancer risk factors such as human papillomavirus (HPV) infection and cigarette smoking, it is important to clarify long-term trends in second cancer risk.
  
  
  METHODS
  Using data from 104,760 one-year survivors of cervical cancer reported to 13 population-based cancer registries in Denmark, Finland, Norway, Sweden, and the United States, we calculated standardized incidence ratios (SIRs) for second cancers overall and cancers at particular sites among women with cervical cancer, including cervical cancer patients who were treated or not treated with radiation, over more than 40 years of follow-up. Cox regression models were used to assess the time-varying association of radiotherapy with risk of second cancers and to assess the interaction of radiation treatment with age at diagnosis. All statistical tests were two-sided.
  
  
  RESULTS
  Among 104,760 one-year survivors of cervical cancer, the risk of all second cancers taken together was increased to a statistically significant extent (n = 12,496; SIR = 1.30; 95% confidence interval [CI] = 1.28 to 1.33). Compared with the general population, in both radiotherapy (N = 52,613) and no-radiotherapy groups (N = 27,382), risks for HPV-related cancers (of the pharynx, genital sites, and rectum/anus) and smoking-related cancers (of the pharynx, trachea/bronchus/lung, pancreas, and urinary bladder) were elevated to a statistically significant extent. Cervical cancer patients treated with radiotherapy, but not those who did not receive radiotherapy, were at increased risk for all second cancers and cancers at heavily irradiated sites (colon, rectum/anus, urinary bladder, ovary, and genital sites) beyond 40 years of follow-up compared with women in the general population. The association of radiotherapy with second cancer risk was modified by age at cervical cancer diagnosis for rectum/anus, genital sites, and urinary bladder, with higher hazard ratios for second cancer at younger ages of cervical cancer. After adjustment for competing mortality, the 40-year cumulative risk of any second cancer was higher among women diagnosed with cervical cancer before age 50 (22.2%; 95% CI = 21.5% to 22.8%) than among women diagnosed after age 50 (16.4%; 95% CI = 16.1% to 16.9%).
  
  
  CONCLUSIONS
  Cervical cancer patients treated with radiotherapy are at increased risk of second cancers at sites in close proximity to the cervix beyond 40 years of follow-up.
authors.affiliation: Viral Epidemiology Branch, Division of Cancer Epidemiology and Genetics, 6120 Executive Blvd, EPS 7072, Rockville, MD 20852, USA. chaturva@mail.nih.gov
authors.forename: Anil K
authors.initials: AK
authors.lastname: Chaturvedi
authors.forename: Eric A
authors.initials: EA
authors.lastname: Engels
authors.forename: Ethel S
authors.initials: ES
authors.lastname: Gilbert
authors.forename: Bingshu E
authors.initials: BE
authors.lastname: Chen
authors.forename: Hans
authors.initials: H
authors.lastname: Storm
authors.forename: Charles F
authors.initials: CF
authors.lastname: Lynch
authors.forename: Per
authors.initials: P
authors.lastname: Hall
authors.forename: Froydis
authors.initials: F
authors.lastname: Langmark
authors.forename: Eero
authors.initials: E
authors.lastname: Pukkala
authors.forename: Magnus
authors.initials: M
authors.lastname: Kaijser
authors.forename: Michael
authors.initials: M
authors.lastname: Andersson
authors.forename: Sophie D
authors.initials: SD
authors.lastname: Fosså
authors.forename: Heikki
authors.initials: H
authors.lastname: Joensuu
authors.forename: John D
authors.initials: JD
authors.lastname: Boice
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Kleinerman
authors.forename: Lois B
authors.initials: LB
authors.lastname: Travis
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D015986:Confounding Factors, Epidemiologic; D005260:Female; D005387:Finland / Q000453:epidemiology; D005500:Follow-Up Studies; D006801:Humans; D016014:Linear Models; D008875:Middle Aged; D016609:Neoplasms, Second Primary / Q000453:epidemiology* / Q000209:etiology* / Q000821:virology; D016017:Odds Ratio; D030361:Papillomavirus Infections / Q000150:complications / Q000453:epidemiology; D016016:Proportional Hazards Models; D011878:Radiotherapy / Q000009:adverse effects; D012042:Registries; D018570:Risk Assessment; D012307:Risk Factors; D018426:SEER Program; D012537:Scandinavian and Nordic Countries / Q000453:epidemiology; D012907:Smoking / Q000009:adverse effects / Q000453:epidemiology; D017741:Survivors / Q000706:statistics & numerical data*; D014412:Tumor Virus Infections / Q000150:complications / Q000453:epidemiology; D014481:United States / Q000453:epidemiology; D002583:Uterine Cervical Neoplasms / Q000453:epidemiology* / Q000532:radiotherapy