Review Article
Are We Missing an Opportunity for Cancer Prevention? Human Papillomavirus Vaccination for Survivors of Pediatric and Young Adult Cancers Sarah M. Temkin, MD1; and Nita L. Seibel, MD2
Survivors of pediatric and young adult cancers remain at risk for subsequent diseases, including those related to human papillomavirus (HPV) infection. Prevention of HPV acquisition through vaccination has become possible over the last decade. HPV vaccines have been shown to be safe and effective, yet rates of vaccination among childhood cancer survivors have remained low. Multiple factors, including stronger advocacy for this intervention from providers, could potentially increase vaccination and lead to lower HPV disease burdens for childhood cancer survivors. Health care providers for survivors of pediatric and adolescent cancers should prioritize C 2015 American Cancer Society. counseling for HPV vaccination at follow-up visits. Cancer 2015;121:3395-402. V KEYWORDS: childhood cancer, human papillomavirus (HPV) disease, human papillomavirus (HPV) vaccination, prevention, survivorship.
INTRODUCTION Sequelae of cancer and its treatment expose survivors of pediatric and young adult (PAYA) cancers to an increased risk of subsequent malignancies.1 One would expect a cure for one type of cancer to motivate patients to do everything possible to prevent a subsequent malignancy. However, current human papillomavirus (HPV) immunization practices for childhood and adolescent cancer survivors do not support this notion. The Advisory Committee on Immunization Practices recommends routine HPV vaccination for adolescent girls aged 11 to 12 years and catch-up vaccinations for women up to the age of 26 years. It is recommended that the vaccine be administered before sexual debut because of the mechanism of HPV transmission. Although there are limited studies looking at HPV vaccination practices in pediatric and adolescent survivors of childhood cancer, identifying factors that encourage HPV vaccination and increasing awareness of the importance of vaccination in this group of patients represent an opportunity to change these patterns with long-term results. This article provides an update on HPV vaccination focused on the importance to survivors of childhood and adolescent cancers and the crucial role of the physician in recommending the vaccine. HPV DISEASE AND ITS SEQUELAE HPV is a ubiquitous double-stranded DNA virus with an affinity for specific types of epithelial cells. More than 100 HPV types have been identified, and they are categorized according to their carcinogenic potential. Fewer than 40 of these subtypes infect the anogenital region, and only approximately 15 are considered high-risk or oncogenic.2 Low-risk types (eg, types 6 and 11) can cause benign or low-grade cellular changes, warts, and recurrent respiratory papillomatosis.3 Infection with a high-risk HPV type is necessary for the development of epithelial cervical carcinomas (squamous and adenocarcinomas), and HPV can be identified in virtually all tumors. HPV-16 and HPV-18 are the 2 most frequently encountered high-risk types and account for approximately 70% of cervical cancer cases. In addition, 90% of anal cancers, more than 60% of certain oropharyngeal cancers, and approximately 40% of vaginal, vulvar, and penile cancers are initiated by an oncogenic HPV infection.4 The 2 primary oncoproteins of high-risk HPV types are E6 and E7. These proteins inactivate tumor-suppressor proteins (protein 53 and retinoblastoma protein respectively) inducing proliferation and eventually immortalization and malignant transformation of persistently infected cells.2,3
Corresponding author: Sarah M. Temkin, MD, Community Oncology and Prevention Trials Research Group, Division of Cancer Prevention, National Cancer Institute, 9609 Medical Center Drive, Room 5E448-MSC 9785, Bethesda, MD 20892-9785; [email protected] 1 Community Oncology and Prevention Trials Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland; 2Clinical Investigations Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland.
DOI: 10.1002/cncr.29515, Received: April 22, 2015; Revised: May 13, 2015; Accepted: May 18, 2015, Published online June 25, 2015 in Wiley Online Library (wileyonlinelibrary.com)
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HPV exposure is common through sexual contact. The prevalence of cervical HPV infection peaks following sexual initiation; in the United States, approximately half of the estimated 14 million new HPV infections occurring every year occur among persons less than 24 years old.5 The population-based prevalence after the age of 30 years, however, is low.6 Although infection with high-risk HPV is necessary for the development of cervical cancer, the majority of infections cause no symptoms and are transient; they resolve spontaneously within 2 years of infection. After infection of the cervix, high-risk HPV induces cellular-level changes in the cervix that appear as cervical cell histologic abnormalities. A small number of these lesions will progress to high-grade cervical cell abnormalities, which are precursors to cancer.7 A variety of risk factors increase the chances of persistent and progressive HPV disease; these include immunosuppression (eg, human immunodeficiency virus) and smoking.2,8,9 Significant morbidity around HPV infection and cervical cancer screening exists for girls and young women. After an abnormal Papanicolaou test, the diagnosis of high-grade cervical abnormalities requires colposcopy (microscopic evaluation of the cervix), which, although safe and generally well tolerated, can be uncomfortable and anxiety-provoking in many patients. Excisional biopsies via a loop electrocautery excisional procedure or cold knife are used to treat high-grade premalignant lesions of the cervix (Fig. 1). Complications of these procedures are rare but include bleeding. Although data are mixed, it seems that premalignant cervical cellular changes and/or excisional cervical biopsies are associated with a population-based increase in preterm delivery.10,11 Worldwide, cervical cancer is the third most commonly diagnosed cancer and the fourth leading cause of cancer death among women; it accounted for 9% (529,800) of total new cancer cases and 8% (275,100) of total cancer deaths among females in 2008. More than 85% of these cases and deaths occurred in developing countries.12 In the United States and other high-income countries, the disease has declined in incidence over the last 50 years, with 12,900 cervical cancer cases expected to be diagnosed in 2015.13 This is primarily due to screening programs with Papanicolaou testing, which allows the identification and treatment of pre-invasive disease before the development of cancer.14 HPV VACCINES The first vaccine for HPV infection and its sequelae became available in 2006 in the United States for the indication of cervical cancer prevention. The major structural 3396
Figure 1. Cervix after loop electrocautery excision procedure. Courtesy of Mike Hughey, MD. Military Obstetrics & Gynecology, Brookside Associates LLC, 2008.
protein L1 is able to self-assemble into pentamers and subsequently into so-called virus-like particles. Available vaccines are made up of these virus-like particles, which are prepared with recombinant DNA technology.15,16 Currently, there are 3 HPV vaccines available in the United States, and they vary slightly in protection, cost, and target population (see Table 1). The quadrivalent vaccine (HPV-4) was the first vaccine available in the United States and prevents infection by 4 strains (HPV-6, HPV11, HPV-16, and HPV-18). HPV-4 is approved for use in males and females who are 9 to 26 years old.16,17 A bivalent vaccine (HPV-2) that protects against HPV strains 16 and 18 became available in the United States in 2009. This vaccine is recommended for administration to females who are 10 to 25 years old.15,17,18 In December 2014, a nonavalent vaccine (HPV-9) that protects against 9 strains of HPV was approved, and it will phase out the HPV-4 vaccine over time. HPV-9 includes protection against the 4 strains approved in the previous HPV-4 vaccine as well as 5 additional high-risk types: 31, 33, 45, 52, and 58. The 5 additional strains included in HPV-9 cause approximately 20% of cervical cancers.18 The Federal Advisory Committee on Immunization Practices currently recommends that routine HPV vaccination be initiated at the age of 11 or 12 years, although the vaccination series can be started as early as the age of 9 years. Vaccination is additionally recommended for females aged 13 to 26 years and for males aged 13 to 21 years who have not been vaccinated previously or who have not completed the 3-dose series.18 The Federal Advisory Committee on Immunization Practices first recommended the vaccine for females in 2006 and added the recommendation for males in 2011.17 These vaccines are currently administered in 3 doses over 6 months. Cancer
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TABLE 1. Characteristics of Quadrivalent (HPV-4), Nonavalent (HPV-9), and Bivalent (HPV-2) Vaccines HPV-4 Types of HPV covered
6, 11, 16, 18
HPV-9 6, 11, 16, 18, 31, 33, 45, 52, 58
Manufacturing
Saccharomyces cerevisiae (baker’s yeast) expressing L1
Saccharomyces cerevisiae (baker’s yeast) expressing L1
Adjuvant
AAHS (500 mg), AS04 (500 mg)
AAHS (225 mg), AS04 (500 mg)
Preservatives
None Sodium chloride, L-histidine, polysorbate 80, sodium borate, and water for injection Refrigerate at 28C-88C (358F-468F). Do not freeze. Intramuscular
None Sodium chloride, L-histidine, polysorbate 80, sodium borate, and water for injection Refrigerate at 28C-88C (358F-468F). Do not freeze. Intramuscular
Storage Administration
HPV-2 16, 18 Trichoplusia ni insect cell line infected with L1 encoding recombinant baculovirus Aluminum hydroxide, 3-O-desacyl-40 -monophosphoryl lipid A (50 mg) None Sodium chloride, sodium dihydrogen phosphate dihydrate, and water for injection Refrigerate at 28C-88C (358C-468F). Do not freeze. Intramuscular
Abbreviations: AAHS, amorphous aluminum hydroxyphosphate sulfate; HPV, human papillomavirus. AS04, “Adjuvant System 04” is a combination of adjuvants used in vaccine product. It consists of aluminum phosphate and monophosphoryl lipid A (MPL).
Although there is evidence showing that 2 doses may be sufficient to provide protection, there are no plans to change the dosing recommendations in the United States.19,20 The efficacy of HPV vaccination is greatest when the vaccine is given to HPV-naive women. Because of the high correlation between HPV infection and the onset of sexual contact, the ideal time to give the vaccine is before the initiation of sexual activity. Among 14-year-olds in the United States, 12.5% of females and 13.1% of males reported ever having sex. A large proportion of those adolescents who were 14 to 19 years old reported at least 3 lifetime partners (45.2% of females and 55.0% of males). Among those who were 14 to 19 years old, 39.4% of females and 48.6% of males had at least 2 partners in the past year.21 In addition, the vaccine elicits a higher immune response from adolescents (11-12 years old) versus older teens.22 HPV vaccination is contraindicated in patients with a history of hypersensitivity to any of the vaccine’s components. The vaccine is also not recommended for use during pregnancy, although pregnancy testing is not required before vaccination, and no interventions are needed if vaccination inadvertently occurs during pregnancy.18 All available HPV vaccines have demonstrated efficacy in the prevention of vaccine type–related cervical precancers.4,23-25 The quadrivalent vaccine has been shown to also prevent vaginal, vulvar, and anal pre-invasive disease.26 Although no data are available on the efficacy for the prevention of HPV-associated cancers or lesions of the oropharynx, the vaccines likely protect against these diseases as well. The quadrivalent vaccine also protects against HPV-6 and HPV-11, and clinical trials show that the vaccine prevents vaccine type–related genital warts.27 Cancer
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Current research suggests that vaccine protection is longlasting: more than 8 years of follow-up data indicate that the vaccines are still effective, and there is no evidence of waning protection, although it is still unknown if recipients will need a booster. VACCINE SAFETY In the United States, postlicensure vaccine safety monitoring and evaluation have reinforced vaccine safety. From June 2006 through March 2014, approximately 67 million doses of HPV-4 were distributed in the United States. During this time, the Vaccine Adverse Event Reporting System (VAERS) received a total of 25,176 adverse event reports after HPV vaccination in the United States; 92.4% of the HPV-4 reports were classified as nonserious. The most common symptoms reported among males were similar to those among females and included injection site reactions, dizziness, syncope, nausea, and headache. Overall, reporting of adverse events to VAERS in 2014 was consistent with prelicensure clinical trial data and consistent with the 2009 published summary of the first 2.5 years of postlicensure reporting to VAERS.28,29 VACCINE UPTAKE IN THE UNITED STATES Actual vaccination rates in the United States are far below the potential rates if every eligible adolescent and young adult were to be vaccinated (Fig. 2).29 At 57%, coverage for the first dose of HPV vaccination among US girls who are 13 to 17 years old lags behind coverage for other vaccines recommended for similarly aged children (Fig. 3).30 Numerous barriers to HPV vaccine uptake have been identified among adolescents and young adults. Individual barriers include cost, safety, and the perception that 3397
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Figure 2. The figure above shows actual and potentially achievable vaccination coverage with 1 dose of human papillomavirus (HPV) vaccine if missed vaccination opportunities had been eliminated among girls by age 13 years, by birth cohort (1994– 2000), in the United States during 2007–2013 combined. The percentage of unvaccinated girls at age 13 years with at least one missed opportunity for HPV vaccination ranged from 9.3% (95% confidence interval [CI] 5 8.1%–10.8%) for the 1994 cohort to 83.7% (CI 5 77.8%–88.2%) for the 2000 cohort. Reprinted with permission from the Centers for Disease Control and Prevention.29
Figure 3. Estimated vaccination coverage with selected vaccines and doses among adolescents aged 13 to 17 years by survey year: National Immunization Survey–Teen, United States, 2006-2012. Reprinted with permission from the Centers for Disease Control and Prevention.30
vaccination is unnecessary if the individuals are not sexually active. Parental knowledge, attitudes, and beliefs about the vaccine influence uptake, with parents declining 3398
vaccination for their children because they believe that the vaccine is not needed if their children are not sexually active and that the receipt of the vaccine might increase Cancer
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promiscuity.14 Health care provider recommendation is the most important predictor of vaccine acceptance.4,14,31,32 Multiple strategies will need to be developed and evaluated to improve HPV vaccine coverage among adolescents and young adults, and they should focus on patient, parental, and provider attitudes. HPV DISEASE IN PAYA CANCER SURVIVORS The direct and indirect effects of cancer treatment place female PAYAs surviving childhood cancer at increased risk for HPV persistence and complications. It has been proposed that a portion of subsequent malignancies among PAYA cancer survivors may be related to HPV infections.33 Survivors with a history of hematopoietic stem cell transplants, treatment with pelvic irradiation, and other cancer treatments resulting in sustained immunosuppression are at the greatest increased risk for HPV persistence and complications. Genital HPV has been described as a significant late complication in a cohort of allogenic stem cell transplant patients, with one-third of long term survivors displaying HPV-related disease. The patients at particular risk were those with associated chronic graft-versus-host disease requiring prolonged systemic immunosuppressive therapy.34 PAYA cancer survivors have unique behavioral risks related to HPV infections. Survivors of childhood cancers may have a later sexual debut and decreased sexual function in comparison with unaffected adolescents, but the majority of childhood cancer survivors report sexual activity (93%).35 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 and thus increase their HPV exposure risk.36 The majority (81%) of female survivors do report adherence to the US Preventive Services Task Force cervical cancer screening recommendations regarding Papanicolaou testing.1 However, compared with their siblings, women surviving childhood cancer are less likely to have undergone Papanicolaou testing within the previous 3 years.37 Little is known about the incidence of HPVassociated malignancies in PAYA cancer survivors versus the general population. The relation with HPV has been associated with subsequent malignancies in adult cancer survivors but has not been fully explored.38 Using Surveillance, Epidemiology, and End Results data from 1973 to 2010, investigators reported that female PAYA cancer survivors had a 40% relative excess of HPV-associated malignancies overall in comparison with females in the general US population. Male PAYA cancer survivors had a 150% Cancer
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relative excess of HPV-associated malignancies overall. Investigators have also reported that the median age of diagnosis of invasive cervical cancer is 7 years younger for PAYA cancer survivors versus females in the general US population. The median duration between the primary cancer diagnosis and invasive cervical cancer is 11 years for PAYA survivors.33 This relative excess of HPVassociated malignancies among PAYA cancer survivors cannot be fully attributed to previous therapy. Further studies are needed in this area, particularly to look at the latency period of 10 to 20 years from high-grade cervical intraepithelial neoplasia 3 to the development of invasive disease in the general population and the rapid onset of invasive disease in PAYA cancer survivors.39 As treatments for childhood cancer continue to improve and life expectancy in this cohort continues to rise, it is likely that HPVrelated cancers will increase in this population.40 VACCINE IMMUNOGENICITY DURING TREATMENT PAYA cancer survivors may worry about receiving vaccines during or immediately after treatment, particularly if they are immunosuppressed. Observations of high frequencies of HPV-related disease in human immunodeficiency virus–infected and transplant patients support an important role for immunologic competence in controlling HPV infection.9 HPV vaccination is recommended for other immunocompromised persons who have not been vaccinated previously or have not completed the 3dose series.18 The immunogenicity of the vaccine has been shown to be lower among patients after solid organ transplantation, and decreased immune function is presumably the cause.41 Most pediatric cancer patients do recover normal immune function within 6 months of treatment completion.42 Furthermore, current recommendations support nonliving vaccine administration on schedule, even during chemotherapy, as long as the patient is not severely neutropenic.22,43 Ongoing research will determine the need for boosters in patients who receive vaccinations while they are immunocompromised. VACCINE UPTAKE AMONGST PAYA CANCER SURVIVORS Data on the HPV vaccination patterns and factors influencing vaccination among survivors of pediatric and adolescent cancers are scarce. Only 2 studies have addressed the question of HPV vaccine uptake in childhood cancer survivors. A survey of parents of female cancer survivors (n 5 66) 5 or more years after their diagnosis and 2 or more years after therapy (age range, 11-18 years) at Texas 3399
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Figure 4. Recommendations for HPV vaccination in a PAYA cancer population. HPV indicates human papillomavirus; PAYA, pediatric and young adult.
Children’s Hospital revealed that 32% of cancer survivors, including 36% of those who were 13 to 17 years old, had received at least 1 dose of HPV vaccine. Parents/guardians of survivors who had discussed HPV vaccination with a health care provider were more likely to have their children vaccinated.44 A similar but larger study was performed at St. Jude Children’s Research Hospital, and it showed that 32.6% (75 of 230) of cancer survivors initiated and 17.9% completed the 3-dose vaccine series, whereas 34.3% (24 of 70) of healthy controls initiated and 20.0% completed the HPV vaccine series.45 Multivariate logistic regression analyses found vaccine initiation to be associated with older daughter age and physician recommendation of vaccination, whereas mothers who perceived greater barriers to having their daughters receive the HPV vaccine (eg, financial or religious conflicts and concerns about the vaccine promoting sexual activity) were less likely to have initiated vaccination. Among those who initiated vaccination, risk factors for noncompletion included being nonwhite, increased perceived severity of HPV, and increased perceived barriers to vaccination. 3400
Although these studies represent small samples, these numbers mirror vaccine uptake in the general population. In this vulnerable population, it is concerning that the prevalence of HPV vaccination is not higher. Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers (version 4.0) from the Children’s Oncology Group is the template for screening late effects of cancer treatment, and it recommends HPV vaccination for all eligible females surviving childhood cancer.46 Lack of physician endorsement of HPV vaccination is one of the most commonly cited reasons that parents do not consent to this vaccine. In the study performed at St. Jude’s Children’s Research Hospital, investigators noted a trend: a minority of survivor families received a physician recommendation for vaccination, whereas a majority of controls reported receiving one.12 This highlights the importance of ensuring that survivors of pediatric and adolescent cancers are being told about the importance of the vaccine at the time of follow-up by their health care providers (pediatric oncologists, medical oncologists, primary care physicians, Cancer
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and internists). This conversation should be a routine aspect of the follow-up visit, and discussions should be continued during subsequent visits for those who have not initiated or completed the HPV vaccine series (Fig. 4). HPV vaccination provides an opportunity for pediatric cancer survivors to prevent the morbidity related to HPV disease and subsequent HPV-related malignancies. Providing information to patients and providers regarding the benefits of this vaccine should be prioritized among those who care for pediatric cancer survivors. FUNDING SUPPORT No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES The authors made no disclosure.
REFERENCES 1. Nathan PC, Ness KK, Mahoney MC, et al. Screening and surveillance for second malignant neoplasms in adult survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. Ann Intern Med. 2010;153:442-451. 2. Munoz N, Castellsague X, de Gonzalez AB, Gissmann L. Chapter 1: HPV in the etiology of human cancer. Vaccine. 2006;24(suppl 3): S1-S10. 3. Munger K, Baldwin A, Edwards KM, et al. Mechanisms of human papillomavirus–induced oncogenesis. J Virol. 2004;78:11451-11460. 4. Jemal A, Simard EP, Dorell C, et al. Annual report to the nation on the status of cancer, 1975-2009, featuring the burden and trends in human papillomavirus (HPV)–associated cancers and HPV vaccination coverage levels. J Natl Cancer Inst. 2013;105:175-201. 5. Satterwhite CL, Torrone E, Meites E, et al. Sexually transmitted infections among US women and men: prevalence and incidence estimates, 2008. Sex Transm Dis. 2013;40:187-193. 6. Wheeler CM, Hunt WC, Cuzick J, et al. A population-based study of human papillomavirus genotype prevalence in the United States: baseline measures prior to mass human papillomavirus vaccination. Int J Cancer. 2013;132:198-207. 7. Wheeler CM. The natural history of cervical human papillomavirus infections and cervical cancer: gaps in knowledge and future horizons. Obstet Gynecol Clin North Am. 2013;40:165-176. 8. Castellsague X, Munoz N. Chapter 3: cofactors in human papillomavirus carcinogenesis—role of parity, oral contraceptives, and tobacco smoking. J Natl Cancer Inst Monogr. 2003;2003:20-28. 9. Denny LA, Franceschi S, de Sanjose S, Heard I, Moscicki AB, Palefsky J. Human papillomavirus, human immunodeficiency virus and immunosuppression. Vaccine. 2012;30(suppl 5):F168-F174. 10. Conner SN, Frey HA, Cahill AG, Macones GA, Colditz GA, Tuuli MG. Loop electrosurgical excision procedure and risk of preterm birth: a systematic review and meta-analysis. Obstet Gynecol. 2014; 123:752-761. 11. Kyrgiou M, Koliopoulos G, Martin-Hirsch P, Arbyn M, Prendiville W, Paraskevaidis E. Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and meta-analysis. Lancet. 2006;367:489-498. 12. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69-90. 13. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5-29. 14. Pierce Campbell CM, Menezes LJ, Paskett ED, Giuliano AR. Prevention of invasive cervical cancer in the United States: past, present, and future. Cancer Epidemiol Biomarkers Prev. 2012;21: 1402-1408.
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15. Keam SJ, Harper DM. Human papillomavirus types 16 and 18 vaccine (recombinant, AS04 adjuvanted adsorbed) [CervarixTM]. Drugs. 2008;68:359-372. 16. Siddiqui MA, Perry C. Human papillomavirus quadrivalent (types 6, R ). Drugs. 2006;66:126311, 16, 18) recombinant vaccine (GardasilV 1271. 17. Markowitz LE, Dunne EF, Saraiya M, et al. Human papillomavirus vaccination recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2014;63:1-30. 18. Petrosky E, Bocchini JA, Hariri S, et al. Use of 9-valent human papillomavirus (HPV) vaccine: updated HPV vaccination recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2015;64:300-304. 19. Dobson SM, McNeil S, Dionne M, et al. Immunogenicity of 2 doses of HPV vaccine in younger adolescents vs 3 doses in young women: a randomized clinical trial. JAMA. 2013;309:1793-1802. 20. Kreimer AR, Rodriguez AC, Hildesheim A, et al. Proof-ofprinciple evaluation of the efficacy of fewer than three doses of a bivalent HPV16/18 vaccine. J Natl Cancer Inst. 2011;103:14441451. 21. Liu G, Hariri S, Bradley H, Gottlieb SL, Leichliter JS, Markowitz LE. Trends and patterns of sexual behaviors among adolescents and adults aged 14 to 59 years, United States. Sex Transm Dis. 2015;42: 20-26. 22. Crawford NW, Bines JE, Royle J, Buttery JP. Optimizing immunization in pediatric special risk groups. Expert Rev Vaccines. 2011;10:175-186. 23. Joura EA, Giuliano AR, Iversen OE, et al. A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. N Engl J Med. 2015;372:711-723. 24. Group TFIS. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med. 2007;356:19151927. 25. Paavonen J, Naud P, Salmeron J, et al. Efficacy of human papillomavirus (HPV)216/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet. 2009;374:301-314. 26. Joura EA, Leodolter S, Hernandez-Avila M, et al. Efficacy of a quadrivalent prophylactic human papillomavirus (types 6, 11, 16, and 18) L1 virus-like-particle vaccine against high-grade vulval and vaginal lesions: a combined analysis of three randomised clinical trials. Lancet. 2007;369:1693-1702. 27. FUTURE I/II Study Group, Dillner J, Kjaer SK, et al. Four year efficacy of prophylactic human papillomavirus quadrivalent vaccine against low grade cervical, vulvar, and vaginal intraepithelial neoplasia and anogenital warts: randomised controlled trial. BMJ. 2010;341:c3493. 28. Slade BA, Leidel L, Vellozzi C, et al. Postlicensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine. JAMA. 2009;302:750-757. 29. Stokley S, Jeyarajah J, Yankey D, et al. Human papillomavirus vaccination coverage among adolescents, 2007-2013, and postlicensure vaccine safety monitoring, 2006-2014—United States. MMWR Morb Mortal Wkly Rep. 2014;63:620-624. 30. Centers for Disease Control and Prevention (CDC). National and state vaccination coverage among adolescents aged 13-17 years— United States, 2012. MMWR Morb Mortal Wkly Rep. 2013;62:685693. 31. Dorell C, Yankey D, Strasser S. Parent-reported reasons for nonreceipt of recommended adolescent vaccinations, National Immunization Survey: teen, 2009. Clin Pediatr. 2011;50:1116-1124. 32. Rosenthal SL, Weiss TW, Zimet GD, Ma L, Good MB, Vichnin MD. Predictors of HPV vaccine uptake among women aged 19-26: importance of a physician’s recommendation. Vaccine. 2011;29:890895. 33. Ojha RP, Tota JE, Offutt-Powell TN, et al. Human papillomavirus– associated subsequent malignancies among long-term survivors of pediatric and young adult cancers. PLoS One. 2013;8:e70349. 34. Savani BN, Stratton P, Shenoy A, Kozanas E, Goodman S, Barrett AJ. Increased risk of cervical dysplasia in long-term survivors of allogeneic
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stem cell transplantation—implications for screening and HPV vaccination. Biol Blood Marrow Transplant. 2008;14:1072-1075. Ford JS, Kawashima T, Whitton J, et al. Psychosexual functioning among adult female survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Clin Oncol. 2014;32:3126-3136. Zebrack BJ, Casillas J, Nohr L, Adams H, Zeltzer LK. Fertility issues for young adult survivors of childhood cancer. Psychooncology. 2004;13:689-699. Yeazel MW, Oeffinger KC, Gurney JG, et al. The cancer screening practices of adult survivors of childhood cancer. Cancer. 2004;100: 631-640. Huang SF, Li HF, Liao CT, et al. Association of HPV infections with second primary tumors in early-staged oral cavity cancer. Oral Dis. 2012;18:809-815. Gravitt PE. The known unknowns of HPV natural history. J Clin Invest. 2011;121:4593-4599. Klosky JL, Gamble HL, Spunt SL, Randolph-Frye M, Green DM, Hudson MM. Human papillomavirus (HPV) vaccination in survivors of childhood cancer. Cancer. 2009;115:5627-5636.
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41. Kumar D, Unger ER, Panicker G, Medvedev P, Wilson L, Humar A. Immunogenicity of quadrivalent human papillomavirus vaccine in organ transplant recipients. Am J Transplant. 2013;13:2411-2417. 42. Zignol M, Peracchi M, Tridello G, et al. Assessment of humoral immunity to poliomyelitis, tetanus, hepatitis B, measles, rubella, and mumps in children after chemotherapy. Cancer. 2004;101:635-641. 43. Cesaro S, Giacchino M, Fioredda F, et al. Guidelines on vaccinations in paediatric haematology and oncology patients. Biomed Res Int. 2014;2014:707691. 44. Hoffman L, Okcu MF, Dreyer ZE, Suzawa H, Bryant R, Middleman AB. Human papillomavirus vaccination in female pediatric cancer survivors. J Pediatr Adolesc Gynecol. 2012;25:305-307. 45. Klosky JL, Russell KM, Canavera KE, et al. Risk factors for noninitiation of the human papillomavirus vaccine among adolescent survivors of childhood cancer. Cancer Prev Res (Phila). 2013;6:11011110. 46. Children’s Oncology Group. Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers, Version 4.0. Monrovia, CA: Children’s Oncology Group; 2013.
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Are We Missing an Opportunity for Cancer Prevention? Human Papillomavirus Vaccination for Survivors of Pediatric and Young Adult Cancers Sarah M. Temkin, MD1; and Nita L. Seibel, MD2
Survivors of pediatric and young adult cancers remain at risk for subsequent diseases, including those related to human papillomavirus (HPV) infection. Prevention of HPV acquisition through vaccination has become possible over the last decade. HPV vaccines have been shown to be safe and effective, yet rates of vaccination among childhood cancer survivors have remained low. Multiple factors, including stronger advocacy for this intervention from providers, could potentially increase vaccination and lead to lower HPV disease burdens for childhood cancer survivors. Health care providers for survivors of pediatric and adolescent cancers should prioritize C 2015 American Cancer Society. counseling for HPV vaccination at follow-up visits. Cancer 2015;121:3395-402. V KEYWORDS: childhood cancer, human papillomavirus (HPV) disease, human papillomavirus (HPV) vaccination, prevention, survivorship.
INTRODUCTION Sequelae of cancer and its treatment expose survivors of pediatric and young adult (PAYA) cancers to an increased risk of subsequent malignancies.1 One would expect a cure for one type of cancer to motivate patients to do everything possible to prevent a subsequent malignancy. However, current human papillomavirus (HPV) immunization practices for childhood and adolescent cancer survivors do not support this notion. The Advisory Committee on Immunization Practices recommends routine HPV vaccination for adolescent girls aged 11 to 12 years and catch-up vaccinations for women up to the age of 26 years. It is recommended that the vaccine be administered before sexual debut because of the mechanism of HPV transmission. Although there are limited studies looking at HPV vaccination practices in pediatric and adolescent survivors of childhood cancer, identifying factors that encourage HPV vaccination and increasing awareness of the importance of vaccination in this group of patients represent an opportunity to change these patterns with long-term results. This article provides an update on HPV vaccination focused on the importance to survivors of childhood and adolescent cancers and the crucial role of the physician in recommending the vaccine. HPV DISEASE AND ITS SEQUELAE HPV is a ubiquitous double-stranded DNA virus with an affinity for specific types of epithelial cells. More than 100 HPV types have been identified, and they are categorized according to their carcinogenic potential. Fewer than 40 of these subtypes infect the anogenital region, and only approximately 15 are considered high-risk or oncogenic.2 Low-risk types (eg, types 6 and 11) can cause benign or low-grade cellular changes, warts, and recurrent respiratory papillomatosis.3 Infection with a high-risk HPV type is necessary for the development of epithelial cervical carcinomas (squamous and adenocarcinomas), and HPV can be identified in virtually all tumors. HPV-16 and HPV-18 are the 2 most frequently encountered high-risk types and account for approximately 70% of cervical cancer cases. In addition, 90% of anal cancers, more than 60% of certain oropharyngeal cancers, and approximately 40% of vaginal, vulvar, and penile cancers are initiated by an oncogenic HPV infection.4 The 2 primary oncoproteins of high-risk HPV types are E6 and E7. These proteins inactivate tumor-suppressor proteins (protein 53 and retinoblastoma protein respectively) inducing proliferation and eventually immortalization and malignant transformation of persistently infected cells.2,3
Corresponding author: Sarah M. Temkin, MD, Community Oncology and Prevention Trials Research Group, Division of Cancer Prevention, National Cancer Institute, 9609 Medical Center Drive, Room 5E448-MSC 9785, Bethesda, MD 20892-9785; [email protected] 1 Community Oncology and Prevention Trials Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland; 2Clinical Investigations Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland.
DOI: 10.1002/cncr.29515, Received: April 22, 2015; Revised: May 13, 2015; Accepted: May 18, 2015, Published online June 25, 2015 in Wiley Online Library (wileyonlinelibrary.com)
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HPV exposure is common through sexual contact. The prevalence of cervical HPV infection peaks following sexual initiation; in the United States, approximately half of the estimated 14 million new HPV infections occurring every year occur among persons less than 24 years old.5 The population-based prevalence after the age of 30 years, however, is low.6 Although infection with high-risk HPV is necessary for the development of cervical cancer, the majority of infections cause no symptoms and are transient; they resolve spontaneously within 2 years of infection. After infection of the cervix, high-risk HPV induces cellular-level changes in the cervix that appear as cervical cell histologic abnormalities. A small number of these lesions will progress to high-grade cervical cell abnormalities, which are precursors to cancer.7 A variety of risk factors increase the chances of persistent and progressive HPV disease; these include immunosuppression (eg, human immunodeficiency virus) and smoking.2,8,9 Significant morbidity around HPV infection and cervical cancer screening exists for girls and young women. After an abnormal Papanicolaou test, the diagnosis of high-grade cervical abnormalities requires colposcopy (microscopic evaluation of the cervix), which, although safe and generally well tolerated, can be uncomfortable and anxiety-provoking in many patients. Excisional biopsies via a loop electrocautery excisional procedure or cold knife are used to treat high-grade premalignant lesions of the cervix (Fig. 1). Complications of these procedures are rare but include bleeding. Although data are mixed, it seems that premalignant cervical cellular changes and/or excisional cervical biopsies are associated with a population-based increase in preterm delivery.10,11 Worldwide, cervical cancer is the third most commonly diagnosed cancer and the fourth leading cause of cancer death among women; it accounted for 9% (529,800) of total new cancer cases and 8% (275,100) of total cancer deaths among females in 2008. More than 85% of these cases and deaths occurred in developing countries.12 In the United States and other high-income countries, the disease has declined in incidence over the last 50 years, with 12,900 cervical cancer cases expected to be diagnosed in 2015.13 This is primarily due to screening programs with Papanicolaou testing, which allows the identification and treatment of pre-invasive disease before the development of cancer.14 HPV VACCINES The first vaccine for HPV infection and its sequelae became available in 2006 in the United States for the indication of cervical cancer prevention. The major structural 3396
Figure 1. Cervix after loop electrocautery excision procedure. Courtesy of Mike Hughey, MD. Military Obstetrics & Gynecology, Brookside Associates LLC, 2008.
protein L1 is able to self-assemble into pentamers and subsequently into so-called virus-like particles. Available vaccines are made up of these virus-like particles, which are prepared with recombinant DNA technology.15,16 Currently, there are 3 HPV vaccines available in the United States, and they vary slightly in protection, cost, and target population (see Table 1). The quadrivalent vaccine (HPV-4) was the first vaccine available in the United States and prevents infection by 4 strains (HPV-6, HPV11, HPV-16, and HPV-18). HPV-4 is approved for use in males and females who are 9 to 26 years old.16,17 A bivalent vaccine (HPV-2) that protects against HPV strains 16 and 18 became available in the United States in 2009. This vaccine is recommended for administration to females who are 10 to 25 years old.15,17,18 In December 2014, a nonavalent vaccine (HPV-9) that protects against 9 strains of HPV was approved, and it will phase out the HPV-4 vaccine over time. HPV-9 includes protection against the 4 strains approved in the previous HPV-4 vaccine as well as 5 additional high-risk types: 31, 33, 45, 52, and 58. The 5 additional strains included in HPV-9 cause approximately 20% of cervical cancers.18 The Federal Advisory Committee on Immunization Practices currently recommends that routine HPV vaccination be initiated at the age of 11 or 12 years, although the vaccination series can be started as early as the age of 9 years. Vaccination is additionally recommended for females aged 13 to 26 years and for males aged 13 to 21 years who have not been vaccinated previously or who have not completed the 3-dose series.18 The Federal Advisory Committee on Immunization Practices first recommended the vaccine for females in 2006 and added the recommendation for males in 2011.17 These vaccines are currently administered in 3 doses over 6 months. Cancer
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TABLE 1. Characteristics of Quadrivalent (HPV-4), Nonavalent (HPV-9), and Bivalent (HPV-2) Vaccines HPV-4 Types of HPV covered
6, 11, 16, 18
HPV-9 6, 11, 16, 18, 31, 33, 45, 52, 58
Manufacturing
Saccharomyces cerevisiae (baker’s yeast) expressing L1
Saccharomyces cerevisiae (baker’s yeast) expressing L1
Adjuvant
AAHS (500 mg), AS04 (500 mg)
AAHS (225 mg), AS04 (500 mg)
Preservatives
None Sodium chloride, L-histidine, polysorbate 80, sodium borate, and water for injection Refrigerate at 28C-88C (358F-468F). Do not freeze. Intramuscular
None Sodium chloride, L-histidine, polysorbate 80, sodium borate, and water for injection Refrigerate at 28C-88C (358F-468F). Do not freeze. Intramuscular
Storage Administration
HPV-2 16, 18 Trichoplusia ni insect cell line infected with L1 encoding recombinant baculovirus Aluminum hydroxide, 3-O-desacyl-40 -monophosphoryl lipid A (50 mg) None Sodium chloride, sodium dihydrogen phosphate dihydrate, and water for injection Refrigerate at 28C-88C (358C-468F). Do not freeze. Intramuscular
Abbreviations: AAHS, amorphous aluminum hydroxyphosphate sulfate; HPV, human papillomavirus. AS04, “Adjuvant System 04” is a combination of adjuvants used in vaccine product. It consists of aluminum phosphate and monophosphoryl lipid A (MPL).
Although there is evidence showing that 2 doses may be sufficient to provide protection, there are no plans to change the dosing recommendations in the United States.19,20 The efficacy of HPV vaccination is greatest when the vaccine is given to HPV-naive women. Because of the high correlation between HPV infection and the onset of sexual contact, the ideal time to give the vaccine is before the initiation of sexual activity. Among 14-year-olds in the United States, 12.5% of females and 13.1% of males reported ever having sex. A large proportion of those adolescents who were 14 to 19 years old reported at least 3 lifetime partners (45.2% of females and 55.0% of males). Among those who were 14 to 19 years old, 39.4% of females and 48.6% of males had at least 2 partners in the past year.21 In addition, the vaccine elicits a higher immune response from adolescents (11-12 years old) versus older teens.22 HPV vaccination is contraindicated in patients with a history of hypersensitivity to any of the vaccine’s components. The vaccine is also not recommended for use during pregnancy, although pregnancy testing is not required before vaccination, and no interventions are needed if vaccination inadvertently occurs during pregnancy.18 All available HPV vaccines have demonstrated efficacy in the prevention of vaccine type–related cervical precancers.4,23-25 The quadrivalent vaccine has been shown to also prevent vaginal, vulvar, and anal pre-invasive disease.26 Although no data are available on the efficacy for the prevention of HPV-associated cancers or lesions of the oropharynx, the vaccines likely protect against these diseases as well. The quadrivalent vaccine also protects against HPV-6 and HPV-11, and clinical trials show that the vaccine prevents vaccine type–related genital warts.27 Cancer
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Current research suggests that vaccine protection is longlasting: more than 8 years of follow-up data indicate that the vaccines are still effective, and there is no evidence of waning protection, although it is still unknown if recipients will need a booster. VACCINE SAFETY In the United States, postlicensure vaccine safety monitoring and evaluation have reinforced vaccine safety. From June 2006 through March 2014, approximately 67 million doses of HPV-4 were distributed in the United States. During this time, the Vaccine Adverse Event Reporting System (VAERS) received a total of 25,176 adverse event reports after HPV vaccination in the United States; 92.4% of the HPV-4 reports were classified as nonserious. The most common symptoms reported among males were similar to those among females and included injection site reactions, dizziness, syncope, nausea, and headache. Overall, reporting of adverse events to VAERS in 2014 was consistent with prelicensure clinical trial data and consistent with the 2009 published summary of the first 2.5 years of postlicensure reporting to VAERS.28,29 VACCINE UPTAKE IN THE UNITED STATES Actual vaccination rates in the United States are far below the potential rates if every eligible adolescent and young adult were to be vaccinated (Fig. 2).29 At 57%, coverage for the first dose of HPV vaccination among US girls who are 13 to 17 years old lags behind coverage for other vaccines recommended for similarly aged children (Fig. 3).30 Numerous barriers to HPV vaccine uptake have been identified among adolescents and young adults. Individual barriers include cost, safety, and the perception that 3397
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Figure 2. The figure above shows actual and potentially achievable vaccination coverage with 1 dose of human papillomavirus (HPV) vaccine if missed vaccination opportunities had been eliminated among girls by age 13 years, by birth cohort (1994– 2000), in the United States during 2007–2013 combined. The percentage of unvaccinated girls at age 13 years with at least one missed opportunity for HPV vaccination ranged from 9.3% (95% confidence interval [CI] 5 8.1%–10.8%) for the 1994 cohort to 83.7% (CI 5 77.8%–88.2%) for the 2000 cohort. Reprinted with permission from the Centers for Disease Control and Prevention.29
Figure 3. Estimated vaccination coverage with selected vaccines and doses among adolescents aged 13 to 17 years by survey year: National Immunization Survey–Teen, United States, 2006-2012. Reprinted with permission from the Centers for Disease Control and Prevention.30
vaccination is unnecessary if the individuals are not sexually active. Parental knowledge, attitudes, and beliefs about the vaccine influence uptake, with parents declining 3398
vaccination for their children because they believe that the vaccine is not needed if their children are not sexually active and that the receipt of the vaccine might increase Cancer
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promiscuity.14 Health care provider recommendation is the most important predictor of vaccine acceptance.4,14,31,32 Multiple strategies will need to be developed and evaluated to improve HPV vaccine coverage among adolescents and young adults, and they should focus on patient, parental, and provider attitudes. HPV DISEASE IN PAYA CANCER SURVIVORS The direct and indirect effects of cancer treatment place female PAYAs surviving childhood cancer at increased risk for HPV persistence and complications. It has been proposed that a portion of subsequent malignancies among PAYA cancer survivors may be related to HPV infections.33 Survivors with a history of hematopoietic stem cell transplants, treatment with pelvic irradiation, and other cancer treatments resulting in sustained immunosuppression are at the greatest increased risk for HPV persistence and complications. Genital HPV has been described as a significant late complication in a cohort of allogenic stem cell transplant patients, with one-third of long term survivors displaying HPV-related disease. The patients at particular risk were those with associated chronic graft-versus-host disease requiring prolonged systemic immunosuppressive therapy.34 PAYA cancer survivors have unique behavioral risks related to HPV infections. Survivors of childhood cancers may have a later sexual debut and decreased sexual function in comparison with unaffected adolescents, but the majority of childhood cancer survivors report sexual activity (93%).35 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 and thus increase their HPV exposure risk.36 The majority (81%) of female survivors do report adherence to the US Preventive Services Task Force cervical cancer screening recommendations regarding Papanicolaou testing.1 However, compared with their siblings, women surviving childhood cancer are less likely to have undergone Papanicolaou testing within the previous 3 years.37 Little is known about the incidence of HPVassociated malignancies in PAYA cancer survivors versus the general population. The relation with HPV has been associated with subsequent malignancies in adult cancer survivors but has not been fully explored.38 Using Surveillance, Epidemiology, and End Results data from 1973 to 2010, investigators reported that female PAYA cancer survivors had a 40% relative excess of HPV-associated malignancies overall in comparison with females in the general US population. Male PAYA cancer survivors had a 150% Cancer
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relative excess of HPV-associated malignancies overall. Investigators have also reported that the median age of diagnosis of invasive cervical cancer is 7 years younger for PAYA cancer survivors versus females in the general US population. The median duration between the primary cancer diagnosis and invasive cervical cancer is 11 years for PAYA survivors.33 This relative excess of HPVassociated malignancies among PAYA cancer survivors cannot be fully attributed to previous therapy. Further studies are needed in this area, particularly to look at the latency period of 10 to 20 years from high-grade cervical intraepithelial neoplasia 3 to the development of invasive disease in the general population and the rapid onset of invasive disease in PAYA cancer survivors.39 As treatments for childhood cancer continue to improve and life expectancy in this cohort continues to rise, it is likely that HPVrelated cancers will increase in this population.40 VACCINE IMMUNOGENICITY DURING TREATMENT PAYA cancer survivors may worry about receiving vaccines during or immediately after treatment, particularly if they are immunosuppressed. Observations of high frequencies of HPV-related disease in human immunodeficiency virus–infected and transplant patients support an important role for immunologic competence in controlling HPV infection.9 HPV vaccination is recommended for other immunocompromised persons who have not been vaccinated previously or have not completed the 3dose series.18 The immunogenicity of the vaccine has been shown to be lower among patients after solid organ transplantation, and decreased immune function is presumably the cause.41 Most pediatric cancer patients do recover normal immune function within 6 months of treatment completion.42 Furthermore, current recommendations support nonliving vaccine administration on schedule, even during chemotherapy, as long as the patient is not severely neutropenic.22,43 Ongoing research will determine the need for boosters in patients who receive vaccinations while they are immunocompromised. VACCINE UPTAKE AMONGST PAYA CANCER SURVIVORS Data on the HPV vaccination patterns and factors influencing vaccination among survivors of pediatric and adolescent cancers are scarce. Only 2 studies have addressed the question of HPV vaccine uptake in childhood cancer survivors. A survey of parents of female cancer survivors (n 5 66) 5 or more years after their diagnosis and 2 or more years after therapy (age range, 11-18 years) at Texas 3399
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Figure 4. Recommendations for HPV vaccination in a PAYA cancer population. HPV indicates human papillomavirus; PAYA, pediatric and young adult.
Children’s Hospital revealed that 32% of cancer survivors, including 36% of those who were 13 to 17 years old, had received at least 1 dose of HPV vaccine. Parents/guardians of survivors who had discussed HPV vaccination with a health care provider were more likely to have their children vaccinated.44 A similar but larger study was performed at St. Jude Children’s Research Hospital, and it showed that 32.6% (75 of 230) of cancer survivors initiated and 17.9% completed the 3-dose vaccine series, whereas 34.3% (24 of 70) of healthy controls initiated and 20.0% completed the HPV vaccine series.45 Multivariate logistic regression analyses found vaccine initiation to be associated with older daughter age and physician recommendation of vaccination, whereas mothers who perceived greater barriers to having their daughters receive the HPV vaccine (eg, financial or religious conflicts and concerns about the vaccine promoting sexual activity) were less likely to have initiated vaccination. Among those who initiated vaccination, risk factors for noncompletion included being nonwhite, increased perceived severity of HPV, and increased perceived barriers to vaccination. 3400
Although these studies represent small samples, these numbers mirror vaccine uptake in the general population. In this vulnerable population, it is concerning that the prevalence of HPV vaccination is not higher. Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers (version 4.0) from the Children’s Oncology Group is the template for screening late effects of cancer treatment, and it recommends HPV vaccination for all eligible females surviving childhood cancer.46 Lack of physician endorsement of HPV vaccination is one of the most commonly cited reasons that parents do not consent to this vaccine. In the study performed at St. Jude’s Children’s Research Hospital, investigators noted a trend: a minority of survivor families received a physician recommendation for vaccination, whereas a majority of controls reported receiving one.12 This highlights the importance of ensuring that survivors of pediatric and adolescent cancers are being told about the importance of the vaccine at the time of follow-up by their health care providers (pediatric oncologists, medical oncologists, primary care physicians, Cancer
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and internists). This conversation should be a routine aspect of the follow-up visit, and discussions should be continued during subsequent visits for those who have not initiated or completed the HPV vaccine series (Fig. 4). HPV vaccination provides an opportunity for pediatric cancer survivors to prevent the morbidity related to HPV disease and subsequent HPV-related malignancies. Providing information to patients and providers regarding the benefits of this vaccine should be prioritized among those who care for pediatric cancer survivors. FUNDING SUPPORT No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES The authors made no disclosure.
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