Key Points

• The incidence rate of subsequent malignant neoplasms due to human papillomavirus (SMNHPVs) was nearly 3 times higher among childhood cancer survivors than the general population with a 33-year cumulative incidence of approximately 0.3%.
• Female survivors did not have an increased risk of cervical or vulvar cancers, but oropharyngeal and anorectal cancers were more common among both male and female survivors than the general population.
• Increasing human papillomavirus (HPV) vaccination coverage among childhood cancer survivors is critical to reducing their risk of HPV-related subsequent cancers.

“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.

Study Details

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.

Study Results

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).

Study Interpretation

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.”

中文翻译：

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儿童癌症幸存者面临更大的人乳头瘤病毒后续恶性肿瘤风险

关键点

• 儿童癌症幸存者随后因人乳头瘤病毒 (SMNHPVs) 引发的恶性肿瘤的发病率几乎是普通人群的 3 倍，33 年累积发病率约为 0.3%。
• 女性幸存者患宫颈癌或外阴癌的风险并没有增加，但口咽癌和肛门直肠癌在男性和女性幸存者中比一般人群更常见。
• 增加儿童癌症幸存者的人乳头瘤病毒 (HPV) 疫苗接种覆盖率对于降低他们患 HPV 相关后续癌症的风险至关重要。

“我们知道儿童癌症幸存者的 HPV 疫苗接种率并不理想。......提高这些疫苗接种率对于降低这些[由人乳头瘤病毒引起的后续恶性肿瘤的发病率]至关重要。” -Tara O. Henderson，医学博士，公共卫生硕士

发表在《癌症》杂志(doi:10.1002/cncr.33922) 上的一项新研究发现，儿童癌症幸存者随后患上与 HPV 感染相关的恶性肿瘤的风险更高，并且患有这些癌症的幸存者过早死亡的风险增加。

尽管大多数 HPV 感染不会导致癌症，但几种致癌类型的 HPV（最常见的是 HPV-16 和 HPV-18）可导致宫颈癌、阴道癌、外阴癌、肛门癌、阴茎癌和口咽癌。由于新出现的证据表明儿童癌症幸存者面临更高的 SMNHPV 风险，来自几个主要儿童癌症中心的一组研究人员调查了影响他们患 SMNHPV 风险的因素。

学习详情

研究人员使用了儿童癌症幸存者研究 (CCSS) 队列的数据，该队列包括来自北美 31 个医疗中心的 24,363 名患者。要被纳入 CCSS，患者必须在 1970 年 1 月 1 日至 1999 年 12 月 31 日期间在 21 岁之前被诊断出患有以下疾病之一后至少存活 5 年：骨癌、中枢神经系统恶性肿瘤、霍奇金淋巴瘤、肾癌、白血病、神经母细胞瘤、非霍奇金淋巴瘤或软组织肉瘤。

从过去的研究中得知，大约 91% 的宫颈癌、75% 的阴道癌、69% 的外阴癌、91% 的肛门癌和 70% 的口咽癌的发病机制涉及 HPV 感染。基于这些数字，研究人员“假设大多数宫颈癌、阴道癌、外阴癌、肛门癌和口咽癌与 HPV 相关”，尽管 CCSS 中没有记录个别癌症的 HPV 状态信息。他们还在他们的文章中指出，这些数字主要基于在成年人中诊断出的癌症，并且可能低估了 HPV 感染在 CCSS 病例中的作用，因为一般而言，每种恶性肿瘤的 HPV 相关形式发生的年龄明显小于非 HPV 相关形式。

研究人员通过使用美国国家癌症研究所监测、流行病学和最终结果项目的年龄匹配、性别匹配和日历年匹配率计算了每种 SMNHPV 的标准化发病率 (SIR)。他们使用多变量模型来确定性别、种族、初次诊断、初次诊断时的年龄、吸烟史、放疗史（按身体部位和剂量）和化疗史（烷化剂、铂类药物和蒽环类药物单独考虑）与发展每种 SMNHPV 显着相关。

研究结果

数据中有 46 名幸存者发生了 1 种或更多 SMNHPV。他们的肿瘤位于口咽 (n = 44)、肛门直肠 (n = 6)、子宫颈 (n = 2) 和外阴 (n = 2)。

研究作者发现，所有 SMNHPV 的组合在儿童癌症幸存者中的发生率几乎是普通人群的 3 倍（SIR，2.86；95% CI，2.05-4.00）。当他们单独考虑 SMNHPV 位点时，与普通人群相比，女性幸存者患宫颈癌或外阴癌的风险并未增加。无论性别，幸存者患口咽部 SMNHPV（男性 SIR，4.06；95% CI，2.37-6.97；女性 SIR，8.44；95% CI，4.88-14.61）和肛门直肠 SMNHPV（男性 SIR，13.56）的风险均较高；95% CI，5.09-36.13；女性的 SIR，9.15；95% CI，2.29-36.61）。研究人员强调了他们在儿童癌症的女性幸存者中发现口咽癌高发病率的重要性，因为一般人群中的女性患这种肿瘤类型的频率低于男性。

在多变量分析中，男性比女性更容易患上 SMNHPV，相对标准化发病率 (rSIR) 为 2.23 (95% CI, 1.09-4.54)。与未接受任何放射治疗的幸存者相比，接受超过 3000 cGy 头部、颈部或盆腔放射治疗的幸存者的 SMNHPV 风险更高（rSIR，4.03；95% CI，2.50-6.50）。接受 >400 mg/m ²的铂类化疗（与未使用铂类药物相比）也增加了 SMNHPV 风险（rSIR，4.71；95% CI，1.91-11.59）。被诊断出患有 SMNHPV（与没有随后的恶性肿瘤相比）增加了过早死亡的可能性，风险比为 4.90（95% CI，1.83-13.14）。

学习解释

该研究的主要作者、伊利诺伊州芝加哥市芝加哥大学科默儿童医院儿科教授兼儿童癌症幸存者中心主任、医学博士、公共卫生硕士 Tara O. Henderson 表示，尽管儿童的预后有了显着改善——目前的 5 年生存率超过 85%——由于他们之前的癌症诊断和治疗，不幸的是，幸存者的过早死亡率很高。“在检查大量幸存者时，我们了解到，过早死亡的第二常见原因是新的原发性癌症的发展（原发性癌症的复发是主要原因）。因此，识别有其他新癌症风险的患者并实施早期发现和预防策略以减少这种过早死亡至关重要。”

“重要的是，我们知道儿童癌症幸存者的 HPV 疫苗接种率并不理想，”亨德森博士说。“这些数据告诉我们，提高这些疫苗接种率对于降低这些癌症发病率至关重要。”

在癌症(doi:10.1002/cncr.33920) 的一篇随附社论中，由 Heather M. Brandt 博士（田纳西州孟菲斯市圣裘德儿童研究医院 HPV 癌症预防项目）领导的癌症预防研究小组写道需要紧急关注以解决儿童癌症幸存者中随后发生的与 HPV 相关的癌症。“通过 HPV 疫苗接种和推荐的筛查实践，几乎可以完全预防 HPV 癌症。”

他们注意到儿童癌症幸存者中完整的 HPV 疫苗接种率低得令人不安。与健康人 2030 年目标 80% 的 13 至 15 岁青少年接种 HPV 疫苗相比，2017 年发表的一项研究发现，在 2012 年至 2015 年期间，未患癌症的青少年完成 HPV 疫苗接种率为 40%，只有 24 % 在有癌症病史的人群中。

社论作者建议，未来对儿童癌症幸存者进行 HPV 疫苗接种的研究应该“根据年龄、性别、种族、民族、地理位置和其他社会因素，确定儿童癌症幸存者开始和系列完成的决定因素以及 HPV 疫苗接种的不公平性。健康的决定因素。”

Henderson 博士补充说：“我们知道幸存者的子宫颈抹片检查率与普通人群大致相同，这可能就是我们没有观察到这些幸存者宫颈癌发病率增加的原因。但它确实向临床医生表明，我们应该通过口腔和牙科检查来筛查其他部位（例如口咽部），特别是在这些部位暴露于辐射和暴露于铂化疗的幸存者中。”