Subsequent Malignant Neoplasms in the Childhood Cancer Survivor Study: Occurrence of Cancer Types in Which Human Papillomavirus is an Established Etiologic Risk Factor

Background: Human papillomavirus (HPV)-associated subsequent malignant neoplasms (SMN ) in childhood cancer survivors are poorly understood.

Methods: The cumulative risk of SMN was assessed among 24,363 Childhood Cancer Survivor Study participants. Standardized incidence ratios (SIRs) and absolute excess risk were calculated using age-matched, sex-matched, and calendar year rates from the Surveillance, Epidemiology, and End Results program. Poisson regression models identified SMN risk factors, evaluating relative SIRs (rSIR) and 95% confidence intervals (95% CIs).

Results: In total, 46 survivors developed an SMN (median age, 31 years [range, 10-56 years]; median time from primary cancer, 21 years [range, 9-35 years]). SMN sites included oropharynx (N = 44), anorectum (N = 6), uterine cervix (N = 2), and vulva (N = 2). The 33-year cumulative incidence was 0.3% (95% CI, 0.2%-0.4%), and the SIR was nearly 3-fold that of the general population (SIR, 2.86; 95% CI, 2.05-4.00). Female survivors were not at increased risk of cervical or vulvar cancers compared with the general population. All survivors had an elevated risk of oropharyngeal SMN (males: SIR, 4.06; 95% CI, 2.37-6.97; females: SIR, 8.44; 95% CI 4.88-14.61) and anorectal SMN (males: SIR, 13.56; 95% CI, 5.09-36.13; females: SIR, 9.15; 95% CI, 2.29-36.61). Males (vs females: rSIR, 1.99; 95% CI, 1.00-3.94); head, neck, and pelvic radiotherapy doses >3000 centigray (vs none: rSIR, 2.35; 95% CI, 1.11-4.97); and cisplatin-equivalent doses >400 mg/m (vs none: rSIR, 4.51; 95% CI, 1.78-11.43) were associated with increased SMN SIRs in multivariable analysis.

Conclusions: Childhood cancer survivors are at increased risk for SMN in sites susceptible to HPV-associated malignancies. Further research examining HPV in the etiology of SMN and the promotion of HPV vaccination and surveillance guidelines for SMN in cancer survivors is warranted.