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Keywords:

  • cervical cancer;
  • complications;
  • human papillomavirus;
  • pediatric cancer;
  • survivorship;
  • vaccination

Abstract

  1. Top of page
  2. Abstract
  3. Women Surviving Childhood Cancer Are at Increased Risk for HPV-Related Complications
  4. Immunosuppression
  5. Behavioral, Cognitive-Behavioral, and Demographic Risk Factors
  6. Rates and Predictors of HPV Vaccination
  7. Familial decision making in the cancer survivorship context
  8. Future Directions
  9. Conclusions
  10. Conflict of Interest Disclosures
  11. References

Effective vaccination is now available to prevent human papillomavirus (HPV), the most common sexually transmitted infection and the cause of cervical cancer, which is the second most common cancer among women worldwide. HPV vaccine uptake is particularly important for females surviving cancer, some of whom are at high risk for HPV complications because of the direct and indirect effects of cancer treatment. Thus, version 3.0 of the Children's Oncology Group's Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancer recommends HPV vaccination for all eligible females surviving childhood cancer. Because this vaccine was only approved by the US Food and Drug Administration in 2006, little is known regarding the complexity of vaccination uptake among those surviving cancer. The purpose of this article was to describe the HPV vaccine and its usefulness in the survivorship population, provide a rationale for describing cancer survivors as being at increased risk for HPV complications, identify factors associated with HPV vaccination, and discuss the utilization of these predictors in designing strategies to promote adherence to HPV vaccination recommendations within the survivorship context. Cancer 2009. © 2009 American Cancer Society.

Genital human papillomavirus (HPV) is the most common sexually transmitted infection,1, 2 and epidemiologic studies indicate that approximately 80% of sexually active women contract HPV during their lifetime.3-5 Among young women, the prevalence of HPV has been estimated to be as high as 40% among sexually active females ages 14 to 19 years and 49% among those ages 20 to 24 years.6 The United States Youth Risk Behavior Surveillance of 2007, a national school-based survey of health-risk behaviors among high school students, reports 48% of all students and 46% of female students have engaged in sexual intercourse.7 Women who begin having sex at younger ages and those with more sexual partners are at highest risk for HPV exposure. HPV infection rates are highest in younger women and rise sharply soon after the median age of first sexual activity, which is reported to be 16.9 years for females.8

Of the >100 identified types of HPV, approximately 40 affect the genital tract.9 Oncogenic HPV strains have been etiologically linked to cervical, vaginal, vulvar, penile, anal, and oral cancers. Cervical cancer (which is caused by HPV) is the second most common cancer among women worldwide and is the leading cause of cancer-related deaths among women in developing countries.10 In 2004, 11,892 women in the United States were diagnosed with cervical cancer, which resulted in 3850 disease-specific deaths. Because cervical cancer is commonly asymptomatic until it is has progressed beyond the point at which effective treatment is possible, primary prevention is the best approach for reducing the expression of this and other HPV-related malignancies. Regular screening using the Papanicolaou (Pap) test has been the most successful tactic for identifying cervical intraepithelial neoplasia, which is a precursor to cervical cancer.

Approximately 55 million Pap tests are performed each year in the United States, and of these, 3.5 million (6%) yield abnormal results that require medical follow-up.11 HPV infections are primarily asymptomatic, and infected women typically have normal Pap test results, as infections usually clear without abnormality.11 However, all HPV strains have the potential to produce precancerous cells in the cervix that can be identified by Pap screening.

Genital HPV is transmitted by skin or mucosal contact, almost exclusively through sexual contact. Most commonly, the virus is transmitted through vaginal or anal intercourse. Oral and digital infection with genital HPV strains also occurs; however, the risk of transmission by digital-genital or oral-genital contact appears minimal.12 Although most HPV infections clear spontaneously, persistent infection with a high-risk human papillomavirus type is necessary to cause cervical cancer.13 In particular, HPV types 16 and 18 are responsible for the majority of worldwide invasive cervical cancers.14 Progression from HPV infection to precancerous abnormal cell growth to cervical cancer is a slow process that may take decades to complete. Thus, although HPV occurs most often in sexually active adolescents and women ages 15 to 24 years, cervical cancer most often occurs in women aged >40 years, with the median age at diagnosis for all cervical cancer patients being 47 to 48 years.15, 16

Recent efforts to reduce cervical cancer have led to the development of vaccines to protect against HPV, which are currently available and have been demonstrated to be safe and clinically effective.17-19 In June of 2006, the US Food and Drug Administration (FDA)20 approved Gardasil (Merck & Co., Darmstadt, Germany), a quadrivalent vaccine protecting recipients from HPV types 6, 11, 16, and 18, which account for 70% of cervical cancers and 90% of genital warts cases.21 Cervarix (GlaxoSmithKline, London, UK), a bivalent vaccine that is currently available in Australia, the Philippines, and the European Union, protects against HPV types 16 and 18 and has recently been approved for use in the US by the FDA. In clinical trials, these vaccines (when administered as directed) demonstrated 98% efficacy in protecting females against the specified HPV types, thus eliminating the risk of grade 2 of 3 cervical intraepithelial neoplasia, adenocarcinoma in situ, and other HPV-type specific complications.19, 20, 22-24 Furthermore, these vaccines appear to be relatively safe. Specific to Gardasil, injection-site adverse experiences were reported to be generally mild to moderate in intensity for pain, swelling, and erythema. Systemic adverse events were reported to be mild to moderate with 1.5% of vaccine and 1.1% of placebo recipients experiencing fever ≥38.9°C, with no differences emerging across vaccine and placebo groups.4 Vaccine-related serious adverse events occurred in <0.1% of all study participants, and included events such as bronchospasm, gastroenteritis, headache/hypertension, vaginal hemorrhage, and injection site pain/movement impairment. There were no deaths reported in these trials secondary to the HPV vaccine or delivery procedures.24 Contraindications for vaccination include pregnancy and hypersensitivity to active substances/excipients in the vaccine.

On the basis of these favorable findings, routine HPV vaccination is currently recommended by the Advisory Committee on Immunization Practices for adolescent girls ages 11 to 12 years, but the injection series can be started for those as young as 9 years of age, because Gardasil has been approved by the FDA for females between ages 9 and 26 years.19 It is recommended that girls receive the series of injections before the onset of sexual activity because of the mechanism of HPV transmission.20 HPV vaccination is not licensed in the United States for males of any age, although the European Union, Mexico, Australia, New Zealand, Indonesia, Costa Rica, and Korea have approved Gardasil for use in males,25, 26 and a recent Merck-funded phase 3 trial found that Gardasil was effective in preventing 90% of HPV-related external genital lesions among adolescent and young adult males.27 These findings suggest that in the United States, HPV vaccine recommendations may eventually include males, because they are HPV carriers, are vulnerable to HPV-related cancers, and may respond favorably to the HPV vaccine.24

The public health benefits of HPV immunization are considerable. The American Cancer Society estimates a possible reduction of cervical cancer risk by >70% during the next decade with the implementation of the HPV vaccine.24 Such a decline in cervical cancer rates will depend on the number of carcinogenic HPV types eventually targeted by the vaccines, durability of protection by vaccination, degree of vaccination coverage among at-risk populations, and whether the medical community and the public continue to follow recommended screening guidelines.24 Therefore, promotion of HPV vaccine uptake is critical, particularly among those populations at increased risk for HPV-related complications.

Women Surviving Childhood Cancer Are at Increased Risk for HPV-Related Complications

  1. Top of page
  2. Abstract
  3. Women Surviving Childhood Cancer Are at Increased Risk for HPV-Related Complications
  4. Immunosuppression
  5. Behavioral, Cognitive-Behavioral, and Demographic Risk Factors
  6. Rates and Predictors of HPV Vaccination
  7. Familial decision making in the cancer survivorship context
  8. Future Directions
  9. Conclusions
  10. Conflict of Interest Disclosures
  11. References

Although it is well known that survivors of childhood cancer are at increased risk for second malignancies, an increased incidence of cervical carcinoma and other HPV-related cancers has not been uniformly observed across diagnostic groups in this population. This finding begs the question as to whether women surviving childhood cancer are at increased risk for HPV-related complications such as cervical cancer. Because the median age for the expression of cervical cancer is 47 to 48 years,16 and only 2.8% of the female survivors in the Childhood Cancer Survivor Study cohort (which systematically monitors for second malignancies) are older than 51 years, the relative risk of cervical and other HPV-related complications among women surviving childhood cancer risk is not definitively known. As treatment for childhood cancer continues to improve, and the life expectancy of childhood cancer survivors continues to rise, it is likely that the expression of cervical carcinoma and other HPV-related cancers will increase in this population. Nevertheless, for those females receiving specific types of cancer therapy in childhood, evidence for HPV-related vulnerability is already mounting, indicating the increased need for HPV vaccination in these high-risk groups.

Immunosuppression

  1. Top of page
  2. Abstract
  3. Women Surviving Childhood Cancer Are at Increased Risk for HPV-Related Complications
  4. Immunosuppression
  5. Behavioral, Cognitive-Behavioral, and Demographic Risk Factors
  6. Rates and Predictors of HPV Vaccination
  7. Familial decision making in the cancer survivorship context
  8. Future Directions
  9. Conclusions
  10. Conflict of Interest Disclosures
  11. References

It has been well established that women who have undergone renal, liver, or lung transplantation are at increased risk for HPV-related genital and oral disease, including cancer,28-33 and persistent HPV infection resulting from impaired immune clearance has been implicated as the mechanism responsible for these sequelae. Women with human immunodeficiency virus (HIV) are also at increased risk for HPV-associated malignancies, are more frequently diagnosed with advanced and difficult to treat cervical cancers, and are more likely to experience recurrence after treatment.34-39 As impaired immune function appears to be responsible for the increased rates of cervical and oral dysplasia experienced by these groups, we will target our review on female childhood cancer patients with persistent immune compromise (particularly those treated with hematopoietic stem cell transplantation or pelvic irradiation and those diagnosed with Hodgkin lymphoma). The implications of HPV vaccination in these groups will also be discussed.

Hematopoietic stem cell transplantation

Children and adolescents undergoing hematopoietic stem cell transplantation (HSCT) experience extreme immunosuppression as a result of pretransplant conditioning. This conditioning (which includes high-dose chemotherapy, with or without total body irradiation) is necessary to achieve tumor control and, in allogeneic graft recipients, sustained hematopoietic engraftment. Although most patients will have complete immune reconstitution by 2 years after transplant, the severity or duration of immunodeficiency depends on several factors, including the type of stem cells and their pretransplant manipulation, graft-versus-host disease (GVHD), and the age of the transplant recipient. Chronic GVHD, for example, slows immune system reconstitution due to GVHD-associated T-cell dysfunction in addition to the immunosuppressive drugs required for GVHD control. Typically, patients who receive T-cell–replete autologous or allogeneic grafts will develop normal CD3+ cells 3 months after transplant.40 Yet during this period, CD4 positivity (+) is decreased, whereas higher proportions of CD8+ cells exist. This inverted CD4+/CD8+ ratio may continue for >1 year. The longer that immune recovery is delayed, the likelihood of infectious complications from bacteria, fungi, and viruses (such as HPV) increases.40

Women who undergo bone marrow transplant as part of cancer treatment are at significantly increased risk for cervical dysplasia and second cancers, including cervical cancers. When Socie et al41 examined second malignancies among 3182 children who received allogeneic bone marrow transplant as part of treatment for acute lymphoblastic leukemia, the estimated cumulative risk for a new solid cancer was 11% by 15 years after transplant, which represented a 34-fold increased risk compared with expected population-based rates. Those who received transplants at earlier ages and those who received higher doses of total body irradiation as part of transplant conditioning were more likely to develop solid tumors after transplant. Female survivors of bone marrow transplantation are also at significantly increased risk for cervical dysplasia, a precancerous marker of cervical cancer. Whereas the proportion of abnormal Pap smears is typically 3% to 6% among healthy women, those 3 years after bone marrow transplantation had a disproportionate rate of abnormal Pap smears that ranged from 14% to 54% and from 4% to 33% for allogeneic and autologous transplant recipients, respectively.42 At 7 years after allogeneic transplant, 43% of females had abnormal Pap cytology smear findings, with 20% experiencing HPV-related high-grade (and 14% experiencing low-grade) squamous intraepithelial lesions. Those women experiencing chronic GVHD post-transplant that required prolonged systematic immunosuppressive therapy for >3 years were at the highest risk for dysplasia and more aggressive abnormalities of the cervix. Specific to cervical cancer, Bhatia et al43 conducted a retrospective study examining the occurrence of new solid cancers among 2129 patients who received bone marrow transplantation between 1976 and 1998. Similar to the findings reported by Socie et al,41 the cumulative probability for developing a solid cancer was nearly 15% at 15 years after bone marrow transplant. Transplant recipients had a 13-fold increased risk for the development of cervical cancer compared with expected population-based rates. Pretreatment conditioning factors were not found to be associated with the expression of new cervical cancers, and the authors concluded that immunodeficiency in combination with HPV exposure best explained the elevated rates of cervical dysplasia and cancer in this population.

Hodgkin lymphoma

Hodgkin lymphoma is characterized by malignant transformation of lymphocytes. Generalized immune deficiency/suppression is a classic disease feature of Hodgkin lymphoma and is associated with persistent deficits in cellular immunity relating to enhanced sensitivity to suppressor monocytes and T-suppressor cells and abnormal interleukin-2 production.44, 45 This immune deficiency is worsened by cancer treatments (such as chemotherapy, radiotherapy, or splenectomy), and often persists long after treatment. Clinically, the immune deficiency associated with Hodgkin lymphoma results in increased susceptibility and persistence of bacterial, fungal, and viral infections such as HPV. Therefore, vaccinations and prompt treatment of infections are particularly important in this population.

It is not yet clear whether patients develop Hodgkin lymphoma because of these deficits in cellular immunity or as a result of the disease, and specific to HPV-related complications, there appears to be evidence for both etiologies. A premorbid history of genital warts or herpes zoster has, for example, been associated with the later development of Hodgkin lymphoma,46 whereas HPV-related epidermodysplasia verruciformis and cervical cancers have also been reported in patients after treatment for Hodgkin lymphoma.47, 48 In what to our knowledge is the largest study of HPV infection among women with Hodgkin lymphoma performed to date, the medical charts of 666 patients consecutively treated at The University of Texas M. D. Anderson Cancer Center between 1963 and 1982 were retrospectively reviewed. Records that included the results of Pap testing, cervical biopsy, colposcopy, or related examinations were included in the study.49 Among the 85 participants who met the study entry criteria, 46% had HPV infection and related neoplasia of the cervix or anogenital region. Specifically, 38% had unicentric or multicentric condylomatous lesions either with (n = 14) or without (n = 19) intraepithelial neoplastic lesions, and 7% (n = 6) had experienced invasive carcinoma of the cervix and/or vulva. Furthermore, being HPV positive was associated with a 2.88 excess risk for having high-grade Hodgkin lymphoma (stage III or IV) and with being more likely to receive combined radiation and chemotherapy treatment. These findings suggest that women with Hodgkin lymphoma have increased vulnerability to HPV-related complications, and that this susceptibility is because of the compromised immune functioning associated with Hodgkin lymphoma.

Pelvic irradiation

Initiation of the immune response to genital HPV infection is largely orchestrated by epithelial cells within the lower genital tract. Genital tract epithelial cells play a key role in immunity to HPV by means of pathogen recognition, expression of antimicrobial mediators, and production of cytokines and chemokines that direct the immune response.50 Female cancer patients treated with therapies toxic to mucosal surfaces, such as anthracyclines and radiotherapy, may be more prone to HPV infection simply on the basis of impaired genital tract epithelial cell function. Similarly, survivors with chronic GVHD that involves the genital tract mucosa may have impaired epithelial cell function. When considering the potential for an underlying genetic predisposition to malignancy in patients treated for childhood cancer, who may then acquire impaired epithelial cell function after radiotherapy, one can argue that it is important for females undergoing pelvic irradiation as part of childhood cancer treatment to undergo HPV vaccination to prevent HPV-related complications.

Similar to those treated for Hodgkin lymphoma or with HSCT, women who have received pelvic irradiation are significantly more likely to experience HPV-related cervical and vaginal dysplasia and carcinomas of the genital tract. When examining lesions of postirradiation dysplasia among 17 women previously treated with pelvic irradiation because of malignancies of the uterine cervix, vagina, and endometrium, 1 or more types of HPV DNA was identified in 8 (47%) of the lesions, and condyloma acuminatum was found in 5 of 11 (46%) cases.51 Similarly, 43 of 88 (49%) of women developed colposcopy-verified vaginal dysplastic lesions after pelvic irradiation, with high-risk HPV being identified in 42 (98%) of the lesions.52 Approximately one– third of women who experienced gynecologic cancers after irradiation for cervical, endometrial, vulvar, or colon cancer had HPV-related tumors 10 to 37 years after radiotherapy exposure.

Among women treated with pelvic irradiation, the etiology of post-treatment cervical dysplasia and cancers has been attributed to recurrence of original malignancy, mutation of cervicovaginal mucosa cells because of radiation exposure, natural HPV dysplastic processes, or a combination of these mechanisms driven by treatment-induced immunosuppression.51 Although it is difficult to isolate 1 process primarily responsible for these dysplastic and neoplastic outcomes, the higher–than–expected HPV infection rates, multiple types of HPV DNA identified in cervical lesions developing after radiotherapy, and similarities between naturally occurring cervical dysplasia and cancers reinforce the notion that HPV (in combination with immunosuppression) is primarily responsible for these post-treatment events.51-53 Although the HPV vaccine to our knowledge has yet to be tested among women who received pelvic irradiation as part of their cancer treatment, murine models examining the effect of pelvic radiotherapy and cisplatin on HPV vaccine responsiveness found that previous cancer treatment does not prevent the induction of an effective immune response by a peptide vaccine. This finding suggests that HPV vaccine efficacy should not be compromised among girls who receive pelvic radiation before vaccine administration. Although the impact of chemotherapy-related immunosuppression on antibody response to the HPV vaccine has not been evaluated, these preclinical data also suggest that HPV vaccination may be effective even in women who have had previous chemotherapy. Further studies are needed to confirm the efficacy of the HPV vaccine in this group.

Behavioral, Cognitive-Behavioral, and Demographic Risk Factors

  1. Top of page
  2. Abstract
  3. Women Surviving Childhood Cancer Are at Increased Risk for HPV-Related Complications
  4. Immunosuppression
  5. Behavioral, Cognitive-Behavioral, and Demographic Risk Factors
  6. Rates and Predictors of HPV Vaccination
  7. Familial decision making in the cancer survivorship context
  8. Future Directions
  9. Conclusions
  10. Conflict of Interest Disclosures
  11. References

Behavioral risk factors

Despite their increased risk for cervical dysplasia and cancers, female survivors of childhood cancer are not engaging in cervical cancer screening at rates recommended by the American Cancer Society. After adjusting for age, ethnicity, education, income, and health insurance, women surviving childhood cancer were found to be significantly less likely than their healthy siblings to have undergone a Pap smear within the previous 3 years,54 with Hispanic survivors being the least likely to have undergone this screening.55 Survivors of childhood cancer without insurance and those aged >30 years are already less likely to report secured medical care, and this risk increases as the survivor ages and time since diagnosis increases.56 It has also been suggested that survivors who perceive themselves to be infertile as a result of cancer therapy may engage in riskier sexual behaviors, which in turn increases HPV exposure risk.57

Cognitive-behavioral risk factors

Up to 40% of survivors of childhood cancer have neurocognitive deficits, with inattention and hyperactivity being among the most commonly reported late effects of treatment.58, 59 Within the general population, evidence exists linking inattention and/or hyperactivity to increased risky sexual behavior. For example, Flory et al60 found that young adults who were diagnosed with attention deficit hyperactivity disorder as children were more likely to engage in behaviors such as earlier initiation of sexual activity and intercourse, increased number of sexual partners, increased casual sexual encounters, and increased partner pregnancies (among men) as compared with unaffected community peers. Similarly, those experiencing hyperactivity in childhood are more likely to become parents and to have been treated for a sexually transmitted disease.61 Because survivors of childhood cancer are more likely to experience inattention and/or hyperactivity, they are consequently at risk for increased engagement in risky sexual behaviors and contracting sexually transmitted infections such as HPV.

Demographic risk factors

In US population-based studies, the occurrence of cervical cancer has been associated with lower education, lower household income, and Hispanic ethnicity.62 Socioeconomic differences in male and female sexual behavior, along with access to cervical cancer screening, have been suggested to potentially explain these findings.63 Among childhood cancer survivors, women who are college educated, medically insured, and older are more likely to have undergone Pap testing within the previous 3 years as compared with survivors who are less educated, without insurance, and younger.54 Because survivors of childhood cancer are more likely to report unemployment, lower educational attainment, and lower annual incomes compared with their siblings,64 they are at increased risk for cervical cancer and suboptimal cervical cancer screening as a socioeconomic consequence of their childhood cancer treatment.

Rates and Predictors of HPV Vaccination

  1. Top of page
  2. Abstract
  3. Women Surviving Childhood Cancer Are at Increased Risk for HPV-Related Complications
  4. Immunosuppression
  5. Behavioral, Cognitive-Behavioral, and Demographic Risk Factors
  6. Rates and Predictors of HPV Vaccination
  7. Familial decision making in the cancer survivorship context
  8. Future Directions
  9. Conclusions
  10. Conflict of Interest Disclosures
  11. References

To the best of our knowledge, there are no studies published to date regarding rates of vaccination in the childhood cancer survivor population; thus, findings must be extrapolated from the healthy population. Although adolescents in the general population report high levels of acceptance regarding HPV vaccination, the actual rates of vaccination initiation and completion are reportedly low, ranging from 5% to 25%.65-67 Although differences in reported vaccination rates may be attributed to time since the vaccine's FDA approval, in addition to variability in regard to sampling methods, sexual history, and age of female participants, the reported HPV vaccination rates are significantly lower than the 90% target established by the Healthy People 2010 initiative.

Acceptability

Despite relatively low rates of HPV vaccination, between 66% and 74% of adolescent/young adult females report intention to receive HPV vaccination in the future.66, 68 Although encouraging, the majority of females in this age range are already positive for HPV, underscoring the importance of vaccination before infection. As with adolescents, parents are also accepting of HPV vaccination for their daughters. Specifically, 55% to 100% of parents are willing to vaccinate adolescents, and brief educational interventions have been found to increase acceptability among parents who were initially opposed or undecided regarding HPV vaccine utilization.69-71

Physician recommendation

Adolescents surviving childhood cancer are often monitored by medical teams specializing in cancer survivorship, and it is well known that medical providers have considerable influence on their patients” immunization decisions.72, 73 Although 90% of pediatricians endorse HPV immunization, many report parental barriers to HPV vaccination administration, including concerns regarding vaccine safety, reluctance to immunize their child for a sexually transmitted infection and to have discussions regarding sexuality and HPV transmission, belief that their child already receives too many vaccines, denial that their child may be at risk for HPV, and concerns that vaccination would lead to riskier adolescent behaviors.74, 75 Of the 10% of physicians who report being unlikely to recommend HPV vaccination, factors such as being male, discomfort discussing sexuality issues with patients, and not routinely prescribing oral contraceptives are associated with being unlikely to recommend the vaccine.76 Physician factors associated with intent to recommend the HPV vaccine included personal and professional characteristics (eg, age, race, practice location, HPV knowledge), office procedures (eg, vaccinating children during sports physicals, ill visits, reminder calls), and vaccine cost and reimbursement.75 Finally, pediatricians' intent to recommend the HPV vaccine may be influenced by the endorsement of trusted sources (eg, American Cancer Society, Center for Disease Control and Prevention, American Academy of Pediatrics, Advisory Committee for Immunization Practices).74 The recent inclusion of HPV vaccination in the new version of the Children's Oncology Group's Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancer may promote successful vaccine delivery in this patient population.

Familial decision making in the cancer survivorship context

  1. Top of page
  2. Abstract
  3. Women Surviving Childhood Cancer Are at Increased Risk for HPV-Related Complications
  4. Immunosuppression
  5. Behavioral, Cognitive-Behavioral, and Demographic Risk Factors
  6. Rates and Predictors of HPV Vaccination
  7. Familial decision making in the cancer survivorship context
  8. Future Directions
  9. Conclusions
  10. Conflict of Interest Disclosures
  11. References

Despite physician influence, immunization against HPV is ultimately a familial decision-making process. As the recommended age for vaccination is relatively young, child attitudes concerning HPV vaccination are typically consistent with those of their parents, who often determine whether to vaccinate their daughters.73 Familial predictors of HPV vaccination approval include family history of cancer, older age of daughter, and familial communication regarding cervical cancer and other HPV-related topics, in addition to increased perceived vulnerability to and severity of HPV-related complication.68, 77, 78 On the basis of this cluster of predicative factors, HPV vaccine implementation in the context of cancer survivorship visits appears plausible in that all of these families will have a history of cancer, which is frequently accompanied by an increased sense of health vulnerability among both cancer survivors and their parents.79 Physician recommendation of HPV vaccine within the oncology setting may maximize the likelihood of HPV vaccination, in that this vaccine provides primary prevention of cervical and other HPV-related cancers.

Future Directions

  1. Top of page
  2. Abstract
  3. Women Surviving Childhood Cancer Are at Increased Risk for HPV-Related Complications
  4. Immunosuppression
  5. Behavioral, Cognitive-Behavioral, and Demographic Risk Factors
  6. Rates and Predictors of HPV Vaccination
  7. Familial decision making in the cancer survivorship context
  8. Future Directions
  9. Conclusions
  10. Conflict of Interest Disclosures
  11. References

Although the Advisory Committee on Immunization Practices recommends the HPV vaccine for “those immunosuppressed as a result of disease or medications,” the immunogenicity of the HPV vaccine has not yet been established among immunocompromised individuals. Antibody titers for HPV types 6 and 18 have been found to be significantly lower among vaccinated HIV-infected children as compared with healthy controls,80 suggesting that longitudinal trials are necessary in immunocompromised groups to determine long-term efficacy, appropriate dosing, and timing of vaccine administration. For immunocompromised survivors of childhood cancer, longitudinal studies will not only allow for the development of informed recommendations related to both vaccine administration and safer sexual behavior, but will also allow for close monitoring of vaccine-related long-term side effects.

In addition to vaccine safety and efficacy, research is needed to determine whether specific factors, such as perceived vulnerability to second cancers, familial history of cancer, and physician recommendation, are particularly relevant in decision making regarding the HPV vaccine for childhood cancer survivors and their parents. These factors could then be used in interventions designed to increase rates of vaccination in this high-risk group. Examination of barriers to vaccine completion (cost, access to healthcare, physician and parent education) would also be beneficial in reducing potential healthcare disparities specific to the HPV vaccine. The behavioral impact of the vaccine in terms of sexual behavior and cervical cancer screening should also be studied.

Conclusions

  1. Top of page
  2. Abstract
  3. Women Surviving Childhood Cancer Are at Increased Risk for HPV-Related Complications
  4. Immunosuppression
  5. Behavioral, Cognitive-Behavioral, and Demographic Risk Factors
  6. Rates and Predictors of HPV Vaccination
  7. Familial decision making in the cancer survivorship context
  8. Future Directions
  9. Conclusions
  10. Conflict of Interest Disclosures
  11. References

The HPV vaccine is an important public health tool that has specific benefits relating to the primary prevention of cervical and other cancers. The Children's Oncology Group's Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancer (version 3.0), which serves as the gold standard in the screening for late effects that may arise because of treatment of pediatric cancer, has recommended HPV vaccination for all eligible females surviving childhood cancer. Survivors at the highest risk for HPV infection and its related complications include those undergoing HSCT, those with Hodgkin lymphoma, those treated with pelvic irradiation, and those receiving other treatments resulting in sustained immunosuppression. This risk profile is further potentiated by suboptimal cervical cancer screening, cognitive late effects, and declines in socioeconomic status commonly observed in childhood cancer survivors. The endorsement of the HPV vaccine by these guidelines is an important first step in addressing the need for HPV vaccination in childhood cancer survivors, but interventions are needed to translate these recommendations into a successful HPV vaccination strategy.

References

  1. Top of page
  2. Abstract
  3. Women Surviving Childhood Cancer Are at Increased Risk for HPV-Related Complications
  4. Immunosuppression
  5. Behavioral, Cognitive-Behavioral, and Demographic Risk Factors
  6. Rates and Predictors of HPV Vaccination
  7. Familial decision making in the cancer survivorship context
  8. Future Directions
  9. Conclusions
  10. Conflict of Interest Disclosures
  11. References
  • 1
    Sauvageau C, Duval B, Gilca V, Lavoie F, Ouakki M. Human papilloma virus vaccine and cervical cancer screening acceptability among adults in Quebec, Canada. BMC Public Health. 2007; 7: 304.
  • 2
    Weinstock H, Berman S, Cates W Jr. Sexually transmitted diseases among American youth: incidence and prevalence estimates, 2000. Perspect Sex Reprod Health. 2004; 36: 6-10.
  • 3
    Mariam A. Cervical cancer vaccines available in 2007. Drug Discov Today. 2005; 10: 949-950.
  • 4
    Markowitz LE, Dunne EF, Saraiya M, Lawson HW, Chesson H, Unger ER. Quadrivalent human papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2007; 56( RR-2): 1-24.
  • 5
    Myers ER, McCrory DC, Nanda K, Bastian L, Matchar DB. Mathematical model for the natural history of human papillomavirus infection and cervical carcinogenesis. Am J Epidemiol. 2000; 151: 1158-1171.
  • 6
    Dunne EF, Unger ER, Sternberg M, et al. Prevalence of HPV infection among females in the United States. JAMA. 2007; 297: 813-819.
  • 7
    Eaton DK, Kann L, Kinchen S, et al. Youth risk behavior surveillance-United States, 2007. MMWR Surveill Summ. 2008; 57: 1-131.
  • 8
    Wulf D. In Their Own Right: Addressing the Sexual and Reproductive Health Needs of American Men. New York, NY: Alan Guttmacher Institute; 2002.
  • 9
    Munoz N, Bosch FX, de Sanjose S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003; 348: 518-527.
  • 10
    American Cancer Society. Cancer Facts & Figures, 2008. Atlanta, GA: American Cancer Society; 2008.
  • 11
    National Cancer Institute. National Cancer Institute Fact Sheet. 5.16th ed. The Pap Test: Questions and Answers. Bethesda, MD: National Cancer Institute; 2007.
  • 12
    Burchell AN, Winer RL, de Sanjose S, Franco EL. Epidemiology and transmission dynamics of genital HPV infection. Vaccine. 2006; 24( suppl 3): S52-S61.
  • 13
    Ault KA. Long-term efficacy of human papillomavirus vaccination. Gynecol Oncol. 2007; 107( 2 suppl 1): S27-S30.
  • 14
    Paavonen J, Lehtinen M. Introducing human papillomavirus vaccines—questions remain. Ann Med. 2008; 40: 162-166.
  • 15
    Ries LAG, Melbert D, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2003. Bethesda, MD: National Cancer Institute; 2006.
  • 16
    Watson M, Saraiya M, Ahmed F, et al. Using population-based cancer registry data to assess the burden of human papillomavirus-associated cancers in the United States: overview of methods. Cancer. 2008; 113( 10 suppl): 2841-2854.
  • 17
    Harper DM, Franco EL, Wheeler CM, et al. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet. 2006; 367: 1247-1255.
  • 18
    Koutsky LA, Harper DM. Current findings from prophylactic HPV vaccine trials. Vaccine. 2006; 24( suppl 3): S114-S121.
  • 19
    Centers for Disease Control. Quadrivalent human papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2007; 56( RR-2): 1-26.
  • 20
    United States Food and Drug Administration. HPV (human papillomavirus) 2006. Available to: http://www.fda.gov/womens/getthefacts/hpv.html. Accessed on June 18, 2008.
  • 21
    Villa LL, Costa RL, Petta CA, et al. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial. Lancet Oncol. 2005; 6: 271-278.
  • 22
    Villa LL. Overview of the clinical development and results of a quadrivalent HPV (types 6, 11, 16, 18) vaccine. Int J Infect Dis. 2007; 11( suppl 2): S17-S25.
  • 23
    Villa LL, Costa RL, Petta CA, et al. High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up. Br J Cancer. 2006; 95: 1459-1466.
  • 24
    Saslow D, Castle PE, Cox JT, et al. American Cancer Society Guideline for human papillomavirus (HPV) vaccine use to prevent cervical cancer and its precursors. CA Cancer J Clin. 2007; 57: 7-28.
  • 25
    Twombly R. U.S. girls to receive HPV vaccine but picture unclear on potential worldwide use, acceptance. J Natl Cancer Inst. 2006; 98: 1030-1032.
  • 26
    Hoffman J. Vaccinating boys for girls' sake? New York Times. February 24, 2008: ST1.
  • 27
    Merck Pharmaceutical Company. Gardasil, Merck's cervical cancer vaccine, demonstrated efficacy in preventing HPV-related disease in males in phase III study. Research & Development News, 2008.
  • 28
    Malouf MA, Hopkins PM, Singleton L, Chhajed PN, Plit ML, Glanville AR. Sexual health issues after lung transplantation: importance of cervical screening. J Heart Lung Transplant. 2004; 23: 894-897.
  • 29
    Rose B, Wilkins D, Li W, et al. Human papillomavirus in the oral cavity of patients with and without renal transplantation. Transplantation. 2006; 82: 570-573.
  • 30
    Courtney AE, Leonard N, O'Neill CJ, McNamee PT, Maxwell AP. The uptake of cervical cancer screening by renal transplant recipients. Nephrol Dial Transplant. 2009; 24: 647-652.
  • 31
    Vacher-Coponat H, Dussol B, Berland Y. Neoplastic disorders and organ transplantation [in French]. Rev Med Interne. 1999; 20: 992-1003.
  • 32
    Mass K, Quint EH, Punch MR, Merion RM. Gynecological and reproductive function after liver transplantation. Transplantation. 1996; 62: 476-479.
  • 33
    Seshadri L, George SS, Vasudevan B, Krishna S. Cervical intraepithelial neoplasia and human papilloma virus infection in renal transplant recipients. Indian J Cancer. 2001; 38: 92-95.
  • 34
    Hagensee ME, Cameron JE, Leigh JE, Clark RA. Human papillomavirus infection and disease in HIV-infected individuals. Am J Med Sci. 2004; 328: 57-63.
  • 35
    Fruchter RG, Maiman M, Arrastia CD, Matthews R, Gates EJ, Holcomb K. Is HIV infection a risk factor for advanced cervical cancer? J Acquir Immune Defic Syndr Hum Retrovirol. 1998; 18: 241-245.
  • 36
    Palefsky JM, Minkoff H, Kalish LA, et al. Cervicovaginal human papillomavirus infection in human immunodeficiency virus-1 (HIV)-positive and high-risk HIV-negative women. J Natl Cancer Inst. 1999; 91: 226-236.
  • 37
    Di Stefano L, Coppola G, Moro S, Colageo E, Cellini A, Coletti G. Cervical-vaginal disease in HIV immunosuppressed patients: management and present screening programme. Eur J Gynaecol Oncol. 2006; 27: 267-270.
  • 38
    Parham GP, Sahasrabuddhe VV, Mwanahamuntu MH, et al. Prevalence and predictors of squamous intraepithelial lesions of the cervix in HIV-infected women in Lusaka, Zambia. Gynecol Oncol. 2006; 103: 1017-1022.
  • 39
    Sirivongrangson P, Bollen LJ, Chaovavanich A, et al. Screening HIV-infected women for cervical cancer in Thailand: findings from a demonstration project. Sex Transm Dis. 2007; 34: 104-107.
  • 40
    Bunin N, DiDomenico C, Guzikowski V. Hematopoietic stem cell transplantation. In: Schwartz CL, Hobbie WL, Constine LS, Ruccione KS, eds. Survivors of Childhood and Adolescent Cancer. Berlin, Germany: Springer; 2005: 271-282.
  • 41
    Socie G, Curtis RE, Deeg HJ, et al. New malignant diseases after allogeneic marrow transplantation for childhood acute leukemia. J Clin Oncol. 2000; 18: 348-357.
  • 42
    Sasadeusz J, Kelly H, Szer J, Schwarer AP, Mitchell H, Grigg A. Abnormal cervical cytology in bone marrow transplant recipients. Bone Marrow Transplant. 2001; 28: 393-397.
  • 43
    Bhatia S, Louie AD, Bhatia R, et al. Solid cancers after bone marrow transplantation. J Clin Oncol. 2001; 19: 464-471.
  • 44
    Slivnick DJ, Ellis TM, Nawrocki JF, Fisher RI. The impact of Hodgkin's disease on the immune system. Semin Oncol. 1990; 17: 673-682.
  • 45
    Slivnick DJ, Nawrocki JF, Fisher RI. Immunology and cellular biology of Hodgkin's disease. Hematol Oncol Clin North Am. 1989; 3: 205-220.
  • 46
    Serraino D, Franceschi S, Talamini R, et al. Socio-economic indicators, infectious diseases and Hodgkin's disease. Int J Cancer. 1991; 47: 352-357.
  • 47
    Gross G, Ellinger K, Roussaki A, Fuchs PG, Peter HH, Pfister H. Epidermodysplasia verruciformis in a patient with Hodgkin's disease: characterization of a new papillomavirus type and interferon treatment. J Invest Dermatol. 1988; 91: 43-48.
  • 48
    Hennig EM, Nesland JM, Di Lonardo A, Venuti A. Multiple primary cancers and HPV infection: are they related? J Exp Clin Cancer Res. 1999; 18: 53-54.
  • 49
    Katz RL, Veanattukalathil S, Weiss KM. Human papillomavirus infection and neoplasia of the cervix and anogenital region in women with Hodgkin's disease. Acta Cytol. 1987; 31: 845-854.
  • 50
    Quayle AJ. The innate and early immune response to pathogen challenge in the female genital tract and the pivotal role of epithelial cells. J Reprod Immunol. 2002; 57: 61-79.
  • 51
    Fujimura M, Ostrow RS, Okagaki T. Implication of human papillomavirus in postirradiation dysplasia. Cancer. 1991; 68: 2181-2185.
  • 52
    Barzon L, Pizzighella S, Corti L, Mengoli C, Palu G. Vaginal dysplastic lesions in women with hysterectomy and receiving radiotherapy are linked to high-risk human papillomavirus. J Med Virol. 2002; 67: 401-405.
  • 53
    Seidman JD, Kumar D, Cosin JA, Winter WE III, Cargill C, Boice CR. Carcinomas of the female genital tract occurring after pelvic irradiation: a report of 15 cases. Int J Gynecol Pathol. 2006; 25: 293-297.
  • 54
    Yeazel MW, Oeffinger KC, Gurney JG, et al. The cancer screening practices of adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Cancer. 2004; 100: 631-640.
  • 55
    Castellino SM, Casillas J, Hudson MM, et al. Minority adult survivors of childhood cancer: a comparison of long-term outcomes, health care utilization, and health-related behaviors from the childhood cancer survivor study. J Clin Oncol. 2005; 23: 6499-6507.
  • 56
    Oeffinger KC, Mertens AC, Hudson MM, et al. Health care of young adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Ann Fam Med. 2004; 2: 61-70.
  • 57
    Zebrack BJ, Casillas J, Nohr L, Adams H, Zeltzer LK. Fertility issues for young adult survivors of childhood cancer. Psychooncology. 2004; 13: 689-699.
  • 58
    Moleski M. Neuropsychological, neuroanatomical, and neurophysiological consequences of CNS chemotherapy for acute lymphoblastic leukemia. Arch Clin Neuropsychol. 2000; 15: 603-630.
  • 59
    Mulhern RK, Fairclough D, Ochs J. A prospective comparison of neuropsychologic performance of children surviving leukemia who received 18-Gy, 24-Gy, or no cranial irradiation. J Clin Oncol. 1991; 9: 1348-1356.
  • 60
    Flory K, Molina BSG, Pelham WE Jr, Gnagy E, Smith B. Childhood ADHD predicts risky sexual behavior in young adulthood. J Clin Child Adolesc Psychol. 2006; 35: 571-577.
  • 61
    Barkley RA, Fischer M, Smallish L, Fletcher K. Young adult outcome of hyperactive children: adaptive functioning in major life activities. J Am Acad Child Adolesc Psychiatry. 2006; 45: 192-202.
  • 62
    Benard VB, Johnson CJ, Thompson TD, et al. Examining the association between socioeconomic status and potential human papillomavirus-associated cancers. Cancer. 2008; 113 ( 10 suppl): 2910-2918.
  • 63
    Parkin DM, Bray F. The burden of HPV-related cancers. Vaccine. 2006; 24( suppl 3): S3/11-S3/25.
  • 64
    Gurney JG, Krull KR, Kadan-Lottick N, et al. Social outcomes in the Childhood Cancer Survivor Study cohort. J Clin Oncol. 2009; 27: 2390-2395.
  • 65
    Kahn JA, Rosenthal SL, Jin Y, et al. Vaccine-type HPV infection and post-licensure attitudes about HPV vaccination in young women. J Adolesc Health. 2008; 42( 2 suppl 1): 28-29.
  • 66
    Kahn JA, Rosenthal SL, Jin Y, Huang B, Namakydoust A, Zimet GD. Rates of human papillomavirus vaccination, attitudes about vaccination, and human papillomavirus prevalence in young women. Obstet Gynecol. 2008; 111: 1103-1110.
  • 67
    Centers for Disease Control. Vaccination coverage among adolescents aged 13-17 years—United States, 2007. MMWR Morb Mortal Wkly Rep. 2008; 57: 1100-1103.
  • 68
    Boehner CW, Howe SR, Bernstein DI, Rosenthal SL. Viral sexually transmitted disease vaccine acceptability among college students. Sex Transm Dis. 2003; 30: 774-778.
  • 69
    Brewer NT, Fazekas KI. Predictors of HPV vaccine acceptability: a theory-informed, systematic review. Prev Med. 2007; 45: 107-114.
  • 70
    Davis K, Dickman ED, Ferris D, Dias JK. Human papillomavirus vaccine acceptability among parents of 10- to 15-year-old adolescents. J Low Genit Tract Dis. 2004; 8: 188-194.
  • 71
    Gerend MA, Lee SC, Shepherd JE. Predictors of human papillomavirus vaccination acceptability among underserved women. Sex Transm Dis. 2007; 34: 468-471.
  • 72
    Ziv A, Boulet JR, Slap GB. Utilization of physician offices by adolescents in the United States. Pediatrics. 1999; 104( 1 pt 1): 35-42.
  • 73
    Zimet GD, Mays RM, Winston Y, Kee R, Dickes J, Su L. Acceptability of human papillomavirus immunization. J Womens Health Gend Based Med. 2000; 9: 47-50.
  • 74
    Kahn JA, Zimet GD, Bernstein DI, et al. Pediatricians” intention to administer human papillomavirus vaccine: the role of practice characteristics, knowledge, and attitudes. J Adolesc Health. 2005; 37: 502-510.
  • 75
    Kahn JA, Rosenthal SL, Tissot AM, Bernstein DI, Wetzel C, Zimet GD. Factors influencing pediatricians” intention to recommend human papillomavirus vaccines. Ambul Pediatr. 2007; 7: 367-373.
  • 76
    Daley MF, Liddon N, Crane LA, et al. A national survey of pediatrician knowledge and attitudes regarding human papillomavirus vaccination. Pediatrics. 2006; 118: 2280-2289.
  • 77
    Marlow LA, Waller J, Wardle J. Parental attitudes to pre-pubertal HPV vaccination. Vaccine. 2007; 25: 1945-1952.
  • 78
    Dempsey AF, Zimet GD, Davis RL, Koutsky L. Factors that are associated with parental acceptance of human papillomavirus vaccines: a randomized intervention study of written information about HPV. Pediatrics. 2006; 117: 1486-1493.
  • 79
    Mulhern RK, Tyc VL, Phipps S, et al. Health-related behaviors of survivors of childhood cancer. Med Pediatr Oncol. 1995; 25: 159-165.
  • 80
    Weinberg A, Song LY, Handelsman E, et al. Safety and immunogenicity of a quadrivalent vaccine to prevent human papilloma virus infection in HIV-infected children: IMPAACT P1047. Paper presented at: 15th Conference on Retroviruses and Opportunistic Infections, February 3-6, 2008, Boston, Massachusetts.