Childhood cancer survivors face greater risks of subsequent malignant neoplasms from human papillomavirus
Authors: Mike Fillon
Journal: CA A Cancer Journal for Clinicians (2022)

“We know that childhood cancer survivors have suboptimal rates of HPV vaccination. … Improving these vaccination rates will be critical to reducing these rates [of subsequent malignant neoplasms due to human papillomavirus].” —Tara O. Henderson, MD, MPH A new study published in the journal Cancer (doi:10.1002/cncr.33922) has found that survivors of childhood cancers have a greater risk of subsequent malignant neoplasms associated with HPV infections and that survivors with these cancers are at increased risk of premature death. Although most HPV infections do not lead to cancer, several oncogenic types of HPV—most often HPV-16 and HPV-18—can cause cervical, vaginal, vulvar, anal, penile, and oropharyngeal cancer. Because of emerging evidence showing that childhood cancer survivors face an elevated risk of SMNHPVs, a group of researchers from several leading children's cancer centers investigated the factors that influence their risk of developing an SMNHPV. The researchers used data from the Childhood Cancer Survivor Study (CCSS) cohort, which includes 24,363 patients from 31 medical centers across North America. To be included in the CCSS, patients must have been alive at least 5 years after being diagnosed before the age of 21 years with one of the following diseases between January 1, 1970, and December 31, 1999: bone cancer, central nervous system malignancy, Hodgkin lymphoma, kidney cancer, leukemia, neuroblastoma, non-Hodgkin lymphoma, or soft tissue sarcoma. It is known from past research that HPV infection is involved in the pathogenesis of approximately 91% of cervical cancers, 75% of vaginal cancers, 69% of vulvar cancers, 91% of anal cancers, and 70% of oropharyngeal cancers. On the basis of these numbers, the researchers “assumed that most cervical, vaginal, vulvar, anal, and oropharyngeal second malignancies were associated with HPV,” even though information on the HPV status of individual cancers is not recorded in the CCSS. They also noted in their article that these figures are based largely on cancers diagnosed among adults and are likely to underestimate the role of HPV infection in CCSS cases because, in general, the HPV-associated forms of each malignancy occur at significantly younger ages than the non–HPV-associated forms. The researchers calculated standardized incidence ratios (SIRs) for each of these SMNHPVs by using age-matched, sex-matched, and calendar year–matched rates from the National Cancer Institute's Surveillance, Epidemiology, and End Results program. They used multivariable models to determine whether gender, race, primary diagnosis, age at primary diagnosis, smoking history, history of radiotherapy (by both body region and dosage), and history of chemotherapy (with alkylators, platinum agents, and anthracyclines considered separately) were significantly associated with developing each SMNHPV. There were 46 survivors in the data who had developed 1 or more SMNHPVs. Their tumors were found in the oropharynx (n = 44), anorectum (n = 6), uterine cervix (n = 2), and vulva (n = 2). The study authors found that the combination of all SMNHPVs was nearly 3 times more frequent among survivors of childhood cancer than the general population (SIR, 2.86; 95% CI, 2.05-4.00). When they considered SMNHPV sites individually, female survivors did not have an increased risk of cervical or vulvar cancers in comparison with the general population. Regardless of gender, survivors had an elevated risk of oropharyngeal SMNHPV (SIR for males, 4.06; 95% CI, 2.37-6.97; SIR for females, 8.44; 95% CI, 4.88-14.61) and anorectal SMNHPV (SIR for males, 13.56; 95% CI, 5.09-36.13; SIR for females, 9.15; 95% CI, 2.29-36.61). The researchers emphasized the importance of their discovery of high oropharyngeal cancer rates among female survivors of childhood cancers because females in the general population develop this tumor type less frequently than males. In multivariable analyses, males were more likely than females to develop an SMNHPV with a relative standardized incidence ratio (rSIR) of 2.23 (95% CI, 1.09-4.54). In comparison with survivors who did not receive any radiotherapy, the SMNHPV risk was higher among survivors who were exposed to more than 3000 cGy of head, neck, or pelvic radiotherapy (rSIR, 4.03; 95% CI, 2.50-6.50). Receiving >400 mg/m2 of platinum chemotherapy (in comparison with no exposure to platinum agents) also increased SMNHPV risk (rSIR, 4.71; 95% CI, 1.91-11.59). Being diagnosed with an SMNHPV (in comparison with no subsequent malignant neoplasm) increased the likelihood of premature death with a hazard ratio of 4.90 (95% CI, 1.83-13.14). The lead author of the study, Tara O. Henderson, MD, MPH, professor of pediatrics and director of the Childhood Cancer Survivors Center at the University of Chicago Comer Children's Hospital in Chicago, Illinois, says that although the outcomes of children have improved substantially—with current 5-year survival exceeding 85%—because of their previous cancer diagnosis and treatment, survivors unfortunately have high rates of premature mortality. “In examining large cohorts of survivors, we have learned that the second most frequent reason for early death is the development of new primary cancers (recurrence of their primary cancer is the leading cause). Therefore, it is critical to identify patients at risk for these other new cancers and implement early detection and prevention strategies to reduce this premature mortality.” “Importantly, we know that childhood cancer survivors have suboptimal rates of HPV vaccination,” says Dr. Henderson. “These data tell us that improving these vaccination rates will be critical to reducing these rates of cancers.” In an accompanying editorial appearing in Cancer (doi:10.1002/cncr.33920), a team of cancer prevention researchers led by Heather M. Brandt, PhD (HPV Cancer Prevention Program, St. Jude Children's Research Hospital, Memphis, Tennessee), wrote that urgent attention is needed to address subsequent HPV-related cancers among childhood cancer survivors. “HPV cancers are almost entirely preventable through HPV vaccination and recommended screening practices.” They noted the disturbingly low prevalence of complete HPV vaccination among childhood cancer survivors. In contrast to the Healthy People 2030 goal of 80% of adolescents aged 13 to 15 years being up to date for HPV vaccination, 1 study published in 2017 found that HPV vaccine completion during 2012 to 2015 was 40% among adolescents without cancer and only 24% among those with a history of cancer. The editorial writers recommended that future research on HPV vaccination in childhood cancer survivors should “identify determinants of initiation and series completion as well as inequities in HPV vaccination among childhood cancer survivors based on age, sex, race, ethnicity, geographic location, and other social determinants of health.” Dr. Henderson adds, “We know that survivors get Pap smears at around the same rate as the general population, which may be why we aren't observing increased cervical cancer rates in these survivors. But it does indicate to clinicians that we should be screening for other sites (oropharynx for example) with oral and dental exams, especially in survivors exposed to radiation in these sites and with exposure to platinum chemotherapy.”