Recurrent Respiratory Papillomas to Cancer


An Otolaryngologist's Perspective

Fuente: The University of Texas Medical Branch, Galveston, TX.
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ASCCP San Francisco

March 15, 2012

Hyatt Embarcadero

Craig Derkay, MD, FACS, FAAP

Professor and Vice-Chairman,

Dept. OTO-HNS and Pediatrics,

Eastern Virginia Medical School,

Norfolk, VA


Consultant and Project Study Design Advisory Board Member to Merck & Co, Inc (disbanded 2011)

  • To obtain a better understanding of the clinical entity known as recurrent respiratory papillomatosis including its causes, treatment and the potential for prevention.
  • To consider the implication for prevention of oral cavity head and neck cancer of wide-spread use of the HPV vaccine.

Recurrent Respiratory Papillomatosis
  • Also know as laryngeal papilloma, caused by HPV subtypes 6 and 11 which are also responsible for causing anogenital condyloma
  • Most common benign neoplasm of larynx among children
  • 2nd most frequent cause of chronic childhood hoarseness
  • Typically diagnosed between 1-4 yrs of age with delay in diagnosis from time of symptoms onset of 1 year
  • 1,000 new pediatric cases / year in US
  • Prevalence estimated at about 2-4 / 100,000
  • 15,000 surgical procedures, $100 million costs
  • Transmission believed to be through exposure to human papillomavirus when traversing the birth canal of an infected mother
  • Risk of contracting the disease about 1/250-400 if mother has an active condylomata at birth
  • Approximately 1 / 100 RRP patients delivered by Caesarean section while national rates are 15 – 25%
  • ACOG does NOT recommend elective C-section
  • Other modes of transmission in children may be iatrogenic (via surgery); exposure in amniotic fluid; child abuse
  • Typical presentation is progressive hoarseness, slowly progressive stridor, occasionally acute respiratory distress or sudden death
  • Most commonly occurs at areas of squamo-ciliary junctions (true vocal cords, anterior commissure, limen vestibule, carina)
  • Lag of about 1 year between initial onset of symptoms and definitive diagnosis (mis-diagnosed as "asthma" and "croup")
  • Prognosis is very variable: some children require only a few lifetime procedures while others may need more than a hundred
  • National registry from Academic medical centers found an average of 19 surgeries/child
  • Risk factors for more aggressive disease (defined as need for more than 4 surgeries/ year or extension of the disease outside the larynx) are:
    • Diagnosis under age 3
    • Infection by sub-type HPV11
  • About 10-15% of children will develop disease in trachea and 1-2% in lungs
  • Mortality from RRP (1-2%) due to either airway obstruction, malignant degeneration (SCCA), chronic lung disease or anesthesia disaster
  • No definite immunologic deficit / immune compromise (only slightly higher incidence in HIV+)
  • Appears that patients have a lack of immune response to their HPV sub-type but not generalized immune deficiency
  • Efforts under way to identify the genes responsible for susceptibility (two good candidate genes)
  • Extra-esophageal reflux also may play a role
  • Disease tends to get better in late childhood but may be exacerbated during pregnancy
  • Adult onset disease thought to be either due to re-activation of pediatric disease or as a result of STD
  • Adult disease is much less aggressive clinically (fewer yearly surgeries) but still may progress to chronic lung disease and SCCA (is it biologically different or is the adult larynx just larger than a child's and able to accommodate a larger volume of disease?)
  • Adult disease worsened by exposure to tobacco, radiation therapy, reflux
  • Some adults can tolerate office-surgical procedures for removal

Head and neck cancer
  • Refers to a group of biologically similar cancers that start in the upper aerodigestive tract including the lip, oral cavity, nasal cavity, sinuses, pharynx and larynx
  • 90% of head and neck cancers are SCCA originating from the mucosal lining and often spreading to the lymph nodes of the neck
  • Associated traditionally with tobacco and alcohol consumption and exposure to chemicals in the workplace
  • Now recognized to also be associated with HPV infection
  • Estimate of 35,720 new cases in 2009 (3% of adult malignancies, 5th leading cause by incidence and 6th leading cause of cancer deaths). Slight decline in overall H&N cancers but sharp rise in oropharyngeal
  • Worldwide incidence estimated at 640,000 per year and 211,000 deaths per year with 12,000 deaths/yr in US
  • More than twice as common in males vs. females (and males more than twice as likely to die)
  • Disproportionately affect Blacks with younger age of incidence, increased mortality and more advanced disease at presentation
  • H&N cancer increases with age with most patients 50-70

HPV and Head and Neck Cancer
  • Highest distribution of HPV-positive H&N cancer in the tonsils (67%) followed by hypopharynx (25%), oral cavity (18%) and larynx (7%)
  • Increasing incidence of oropharyngeal cancers (2.1% increase in women and 3.9% among men) despite huge reduction in smoking in US (22% decrease in past 40 yrs)
  • Increasing incidence of H&N cancers in younger age cohort of non-smoker, non-drinkers (HPV+)
  • Among whites HPV-associated, 5.1/1,00k men and 1.3/100k women
  • Among blacks, 6.8/100k men and 1.5/100k women
  • Several studies indicate that oral HPV is sexually acquired
  • D'Souza in case-controlled study showed that a high (>25) number of lifetime vaginal sex partners and >5 lifetime oral sex partners was associated with an increased risk of H&N cancer (OR 3.1 and 3.4 respectively)
  • HPV16 is the dominant sub-type found in 84% of HPV+ tonsillar carcinomas
  • HPV+ status also associated with favourable prognosis compared to HPV- (82& vs 55% response to chemotherapy and chemo-radiation therapy)
  • 33% improved survival after 4 years, lower risk of progression and lower death from any cause
  • HPV+ tumors may be a completely distinct epidemiological, biological and clinical subset of tumors
  • Implications for treatment (may be more amenable to anti-EGFR therapies) and prevention with HPV vaccine
  • Most recent study from T. Sinai suggests that HPV+ tumors have 85-90% 5 year survival vs 25-40% in HPV-
  • Further positive implication for adding vaccination of boys to that of girls
  • In Sweden, Oropharyngeal SCCA linked to 6 or more lifetime sexual partners and 4 or more lifetime oral sexual partners and, for men, earlier age of first sexual intercourse
  • Increasing prevalence of HPV in biopsies specimens of oropharyngeal cancers in US (89% vs 40% last decade) and in Sweden (70% increase in 30 years)
  • Researchers suggest that change in sexual practices over past 40 years may be responsible for these increases

  • 75-80% of men and women may become infected at some point in their lifetime
  • 6 million new cases of genital HPV in the US each year with 74% occurring in 15-24 year olds
  • Many people who have HPV do not know it because the virus often has no signs or symptoms and is passed to partners without knowing it
  • Currently no way to predict who will or won't clear the virus

HPV Infection
  • Divided into three clinical categories: ano-genital, non-genital cutaneous and non-genital mucosal
  • HPV sub-types may cause disease in more than one clinical category
  • More than 1/3 of American women are infected with HPV with 7.5 million 14-24 year olds currently infected and ¼ of women < 60 infected at any given time (CDC, 2007)
  • Up to 90% undetectable clinically at 2 years
  • Highest prevalence in 20-24 year olds
  • > 50% acquire HPV within 4 years of first sexual intercourse
  • Types 6 and 11 commonly found in condyloma and RRP, types 16 and 18 commonly found in cervical cancer

HPV Basics
  • Small non-enveloped ds DNA viruses (8 kb)
  • Exist in an episomal state upon infection of basal epithelium of cutaneous and mucosal surfaces
  • Persistent infections are characterized by integration of the viral genome, which increases expression of oncogenes E6 and E7 due to interruption of E2

Human Papillomaviruses
  • Small (about 8 kb) non-enveloped ds DNA viruses
  • "Wart virus"
  • In 1980s found in cervical cancer
  • More than 100 closely related types
  • Typing is based on nucleic acid sequence, < 90% identity, different type
  • Assigned sequential number based on order of discovery, no relation to phlogeny

Famous and long history
Common warts
  • Hands, feet, face
  • HPV 1, 2, 4, 27, 29
  • Nothing to do with ENT

Cervical cancer
  • Cervical cancer in prostitutes not nuns
  • HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59
    • Nobel prize 2008
    • Harald zur Hausen

Reasons for HPV Sub-typing
  • Prognosis for individual patients at time of diagnosis
    • Plan more frequent surgical interventions
    • Aggressive airway surveillance
    • CT scans of chest at intervals
  • Risk of malignancy (HPV 16, 18, 11?)
    • Clearly, in the pediatric airway, HPV 11 is high risk

HPV Sub-typing
  • The Digene® HPV Test*, using Hybrid Capture® 2 (hc2) technology, is the only FDA-approved DNA test and collectively detects the 13 clinically-relevant high-risk HPV types.
  • The Digene HPV Test is a signal-amplified, nucleic acid test that provides standardized, objective results upon which healthcare providers may rely to accurately assess patient risk for cervical intraepithelial neoplasia (CIN) and cancer.
  • The Digene HPV Test is the only FDA-approved test for:
    • Primary screening, in conjunction with a Pap, of women age 30 years and older; and
    • Triage of women of any age with ASC-US Pap results
  • High-risk type: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68
  • Low-risk type: 6, 11, 42, 43, 44

Linear Array Kit
Roche Diagnostics
  • PCR-based linear array HPC product
    • Amplification of target DNA by PCR and Hybridization techniques
  • The linear array identifies 37 HPV genotypes, including all high- and low-risk genotypes
  • Provides specific subtype (genotype) information
    • Digene® HPV Test just groups results into high- and low-risk
    • Considers HPV 11 'low risk'
  • Currently available as research tool only
  • Insurance reimbursement issues
  • Plan is to make commercially available in the future (2012)
    • Will remain RUO only
  • Real Time Assay
    • Detects 16, 18 using light cycler 480 instrument

"These growths will not yield to any form of treatment which has been attempted, however radical, until their period of active growth has passed".
Clark, 1908
Surgical Therapy for RRP
  • Goal: remove as much disease as possible to provide a safe airway and optimal voice while minimizing injury to aerodigestive tract

"Cold Steel"
  • Beneficial for initial debulking / biopsy
  • May be advantageous for high risk areas
    • Anterior commissure
    • Interarytenoid
  • Bleeding may be troublesome
  • Phono-microsurgical techniques: Rosen, Zeitels

CO2 Laser Excision
  • Potential benefits of access, precision, hemostasis
  • CO2 laser considered "gold standard" for laryngeal disease
      Microspot size improves accuracy
  • Light carrier adaptable lasers provide advantages in distal airway
  • Hazards: fire, burns, time-consuming for bulky disease, laser safety

Microdebrider vs CO2 Laser removal of RRP: A prospective analysis
Pasquale, Wiatrak et al, Laryngoscope: 2003; 113:139-143
  • Total procedure time: laser loner
  • Post op Pain assessment: no diff.
  • Cost of procedure: Laser more $
  • Voice quality: shaver better

Other studies:

Myer et al, Laryngoscope: 1999; 109

El Bitar: Archives Oto. 2002; 128

Patel: Annals Oto. 2003; 112

Campisi: OTOHNS 2009; 141, 522-6

  • Presently my preferred method
  • Powerized (500-900 rpm)
  • Minitiaturized shavers in 2 lengths
  • Minimal collateral laryngeal mucosal trauma
  • Less thermal trauma
  • Fast
  • Reduced risk to OR personnel
  • Less expensive to use
  • Minor bleeding issues
  • Can be used with telescope or micro-scope with or without ETT

Use of 532nm pulsed KTP laser and adjuvant intra-lesional Bevacizumab for aggressive RRP in children
  • Arch OTOHNS 2010; 136; 561-565
  • Initial experience at MEE with use of Avastin + pulse dye laser in children with severe RRP
  • 3 children requiring at least 4 surgeries / yr
  • Avastin injected intra-lesionally as 1 ml containing 1.25mg/ml after microdebrider resection and KTP laser treatment of sessile disease and sensitive areas such as anterior and posterior commissure
  • Avastin is monoclonal antibody that binds to and neutralizes VEGF preventing them from binding with receptors
  • Initial results hold some promise
  • 3/3 children experienced lengthening of surgical intervals
  • 2/3 children had substantial decrease in derkay/Coltrea scores (21 to 6 and 13 to 0)
  • 2/3 children had improvement in pediatric voice-related QOL measures
  • Caution: small series, Avastin expensive, potential for significant side effects (seen when given IV but not appreciated when given intra-lesionally in the eye

Flexible CO2 Laser Fiber Omniguide®
  • Flexible CO2 fiber allows access to previously inaccessible or poorly accessible areas
    • Trachea, tongue base, hypopharynx
  • Difficult angles
  • Change focus and intensity manually without adjusting micromanipulator
  • 1.88mm fiber
  • Selection of angled handpieces
  • Hollow core of fiber allows passage of laser beam and nitrogen flow for cooling
  • Can use through ventilating bronchoscope or handheld

Two FDA approved vaccines

Cervarix: Human Papillomavirus Bivalent (Types 16 and 18) vaccine, Recombinant

Gardasil: Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine Two Commercialized HPV L1 VLP Vaccines

Quadrivalent: HPV 16, HPV 18 . 70% of Cervical Cancer

ASO4 Adjuvant (Aluminum + MPL) Made in insect cells

Quadrivalent: HPV 16, HPV 18, 70% of Cervical Cancer

HPV6, HPV11, 90% of Genital Warts

Aluminum Adjuvant

Made in yeast

Three intramuscular injections given over 6 months

Regulatory status of HPV VLP vaccines
  • Quadrivalent approved by FDA in 2006 for females 9-26, 2009 for males 9-26
  • Quadrivalent approved 2009 by FDA for females
  • Main target group in US for either vaccines: 11-12 y.o. girls, prior to becoming sexually active
  • Catch-up vaccination for 13-26 y-o- girls/women
  • Included for girls in Federal Vaccines for Children (VFC) program (provides vaccine for girls < 19 y.o. from poor families)

HPV4 routine vaccination for boys
  • 10/25/20111 the Advisory Committee on Immunization Practices (ACIP) for the CDC recommend ROUTINE (as opposed to prior recommendation of PERMISSIVE9 vaccination of boys 9-21
  • Indication is for prevention of genital warts, penile and anal carcinoma
  • Also recommends vaccination of 22-26 year olds who are immune-compromised
  • Also recommend vaccination of men who have sex with men who are 22-26 who did not receive any or all doses when they are younger

Gardasil (quadrivalent HPV recombinant vaccine)
  • In women Gardasil prevented:
    • 100% of HPV16- and 18-related cervical pre-cancers and non-invasive cervical cancer (CIN 2/3): 0/8487 in vaccine vs 53/8460 in placebo
    • 95% of low-grade cervical dysplasia and pre-cancers caused by HPV 6, 11, 16 or 18: 4/7858 in vaccine vs 83/7861 in placebo
    • 99% of genital warts caused by HPV 6 or 11: 1/7897 in vaccine vs 91/7899 in placebo
  • In boys and men prevented:
    • 90% genital warts caused by HPV 6 or 11: 3/1397 in vaccine vs 31/1408 in placebo

Long term follow-up of recipients
  • NORDIC study: average follow-up is 6 years but some subjects at 9 years
  • No new cases involving relevant sub-types (100% protective)
  • Appears to also offer high level of cross-protection
  • Immunologic persistence (high levels of antibodies) at 1 year after 3rd dose at 100% and at 6 years at 99-100% (implication for not needing a booster)

Effect of HPV 16/18 L1 vaccine among young women with pre-existing infection
Hildesheim, A et al, JAMA 2007; 298; 7; 743-753
Editorial: Markowitz LE, p805
  • Randomized trial in Costa Rica of 2189 women with positive HPV DNA on cervical biopsy given HPV 16/18 L1 VLP vaccine (GSK)
  • No evidence of increased viral clearance at 6 or 12 months between the groups (48% vs 49% at 12 mos and 33% vs 31% at 6 mos)
  • Conclude that vaccination in women should not be used to treat prevalent infections
  • Does cervix = larynx? Dog data suggests some benefit for treating canine papilloma with L1 VLP vaccine

HPV 6 and 11 Serology Status of Patients with RRP (SyRRuP)
  • Do people with RRP make antibodies to HPV 6 or 11 and if so what is the strength of the response?
  • 72 subjects
    • Children and adults
    • Not excluded if they have had HPV vaccine
    • Results presented at international HPV 2011
    • Both adults and children with RRP had high rates of sero-negativity
    • Vaccine resulted in serologic response in RRP children
    • Potential to identify patients who might benefit therapeutically from receiving the quadrivalent HPV vaccine

Need to give the vaccine before they get exposed!
  • Median rate of serologic positive subjects at baseline for the randomized studies (>20,000 subjects) was 1.7% at age 12
  • Median rate of serologic positive subjects who entered at age 15 was 15.9%

Current vaccination coverage
  • Between 2007 and 2009, coverage among girls (receiving at least one shot) increased from 25% to 44% and complete series coverage increased from 18% to 27%
  • Overall, among 13-17 year old girls, 41% have received at least one dose and 53% completed the series (still below the target levels)
  • tDap and meningococcal adolescent vaccination also increased (11-12% to 56-54% respectively)
  • Still need staregies to increase parental knowledge and provider recommendations

HPV Vaccination series initiation and completion; 2008-9
Dorrell, Pediatrics 2011; 128; 830-9
  • National immunization survey data for girls 13-17
  • 40.5% received one or greater doses
  • 53.3% of those completed the series
  • Provider recommendation was the factor most associated with initiation
  • White girls (60.4%) > Black (46.0%) > Hispanic (40.3%)
  • Most common reasons to "not" vaccinate were: lack of knowledge of the vaccine; daughter not sexually active and provider did not recommend

Gardasil statistics
  • 72 million doses administered globally (36 million in US)
  • Available in 122 countries
  • In US: 80% of Medicaid girls and 40% of Medicaid boys are fully covered
  • 9 valent vaccine due to be reviewed by FDA in summer 2012

Can we prevent RRP by Widespread implementation of HPV Vaccine?
  • Vaccinating a woman should drastically lower the risk of JRRP in her children (reducing JRRP is an unintended positive consequence)
  • Coverage of >80% of one gender is likely to induce herd immunity for the HPV types in the vaccine (e.g. HPV6 and HPV11)
    • By decreasing the prevalence of HPV6/11 in the population, herd immunity should lower the risk of JRRP even in children of unvaccinated women
    • Remember back to acute epiglottis era before HiB vaccine

How might HPV Vaccine Coverage be Increased in the US?
  • Gradual acceptance, mandatory vaccination, school-based vaccination, second generation HPV vaccine?
  • Example of other countries:
    • Australia: school-based vaccination 12-18 (Merck Vaccine), about 80% coverage
    • United Kingdom: school-based vaccination (GSK Vaccine) 12-13: start 9/08; in 11 months, about 87% 1 dose, about 85% 2 doses, about 78% 3 doses
    • Netherlands nearly 100% vaccination levels (free and mandatory)

Early effects of the HPV vaccination programme on cervical abnormalities in Victoria, Australia
Brotherton JM, Lancet 2011; 377, 9783; 2085-2092
  • Analyzed trends in cervical abnormalities before and after the introduction of quadrivalent HPV vaccine to Australia in 12-26 year old women
  • Australia was the first country to launch a national HPV vaccine program with a school-based strategy with 72% coverage
  • Reviewed the cervical Cytology Registry between 2003 and 2009 and compared the incidence of high grade cervical abnormalities in 5 age groups 2003-2007 and 2007-2009
  • Found a decrease in girls younger than 18 years by 38%. Decrease was progressive and significantly different to the linear trend in incidence before the introduction of the vaccine
  • No similar temporal declines noted for any other age groups
  • Implication: May be an early sentinel of the potential real-life effect of the vaccine

Public Health Impact: Expectations
  • The vaccines will NOT replace Pap screening or RRP surgeries:
    • They don't protect against all oncogenic HPV types
    • They don't make established infections go away
  • The vaccines will substantially reduce the number of:
    • Abnormal Paps
    • Follow ups; retests, colposcopies, and biopsies
    • Surgeries to remove pre-malignant cervical lesions
  • The vaccines may substantially reduce the number of:
    • New cases of RRP in children

Public Health Impact: Long Term
  • The vaccines may also reduce head/neck cancer rates because HPV 16 and 18 commonly found in Oropharyngeal (tonsil, base of tongue) SCCA as well as cervical cancers, but not significantly for more than several decades
  • Non-smoker, non-drinker younger head and neck patients

Public Health Issues
  • Texas, Virginia and Nevada have passed MANDATORY vaccination prior to entering 6th grade (middle school) with easy opt-out. New Hampshire has free voluntary program. 24 styates considering legislation.
  • AAP and AMA no position on mandates – too early.
  • Opposition from civil libertarians and 2religious right" (concerns regarding encouraging sexual activity)
  • Cost/benefit analysis appears to favor this approach; combine with other late childhood vaccines
  • Addition of vaccination of boys will significantly increase the cost of the program (but will add to herd immunity)

No more epiglottitis and smallpox: will there be no more RRP? Or cancer?
  • Not likely
  • Over 100 different types of HPV and current vaccine only covers 4 of the most common (9-valent coming)
  • If boys are not routinely vaccinated, not likely to achieve herd immunity
  • Existing pediatric and adult RRP patients may not benefit from the vaccine and they will be around for many decades to come
  • Will be >20 years till we see benefits 9in preventing H&N cancer. Unclear what the interactions are between smoking, alcohol and HPV with regards to developing oropharyngeal cancer … only affecting one risk factor.

Social Issues
  • Support by parents who would like to prevent their daughters from developing cervical cancer
  • HPV primarily passed on by skin to skin contact and therefore condoms not 100% effective while the vaccine is nearly 100% effective if given to sexually naïve children
  • Research suggests that the vaccine will NOT encourage sexual activity: much like using a seat belt doesn't promote reckless driving
  • If a significant resistance to use of the vaccine develops it will not achieve the goal of reducing cervical cancer by >70%

Vaccination ethics
Charo RA; NEJM 2007; 356; 1905-8
Kahn JA, Ambl Peds 2007; 7; 367-373
Tissot AM, J Adol Health 2007; 41; 119-125
  • Settled law in federal and state courts upholding vaccination mandates for children
  • Mandating immunization for school attendance clearly increases immunization rates
  • DPT and meningococcal vaccine also given at age 11-12 so minor inconvenience
  • Exceptions are incorporated into vaccine programs to allow for individual, medical, religious and philosophical objections
  • Can be set up as "opt-in" or "opt-out" (favored)
  • Critics contend that abstinence is a safe alternative to vaccination but abstinence-only sex education approaches do not delay the age of sexual initiation or the number of sexual encounters
  • Critics also fear dis-inhibiting effect and encouragement of sexual activity by talking about this ... sex education and distribution of condoms to counter teenage pregnancy and AIDS have not been shown to increase sexual activity and actually delay initiation
  • Almost all Pediqatricians favor universal rather than targeted vaccination but opinions vary regarding legislative mandates
  • Cost and side effects are really the issues: $850 million/yr and mass vaccination will likely bring out a few rare serious adverse events

Social Issues
  • Opposition from civil libertarians
  • Argument against "mandatory vaccination": why force healthy children to get the vaccine to prevent against future behavior that might result in disease
  • This is the principle of every immunization program 8polio, smallpox): vaccinate the masses to create herd immunity to protect the relatively few who would otherwise become ill and suffer devastating consequences
  • Poll on School-mandate supported by only 44% of US parents
  • Objections raised regarding costs: $360 for full course with possibility of needing booster down the road
  • Treating HPV infections is far more costly: American Journal OBGYN: annual cost of cervical HPV-related disease $2.25-4.6 billion (not to mention the physical and emotional costs of cervical cancer to affected women and their families)

Annual cost of HPV-associated Disease and vaccination of a Birth Cohort

  • Cervical cancer screening*
  • $5,740,000,000
  • Cervical cancer
  • $350,000,000
  • Other anogenital cancers
  • $127,000,000
  • Oropharyngeal cancer
  • $38,000,000
  • Anogenital warts
  • $220,000,000
  • RRP (JRRP $109; ARRP $42)
  • $151,000,000
  • Total
  • >$6.5 billion

Cost of vaccination program estimated at $850,000,000 for girls and $1.7 billion for boys and girls
13 cents spent on vaccination will save $1 in treatment costs
Adverse reactions
Post-licensure safety for Gardasil Marketing HPV Vaccine: Risks and benefits of HPV vaccination
JAMA; 2009; 7 ; 750-7; 781-6; 795-6
  • 16 million doses administered as of 2008
  • 9749 VAERS reports of adverse events
    • 94% classified as non-serious:

Syncope; pain at injection site; headache, nausea, fever
  • 6% classified as serious

20 deaths: no pattern and all causes of death were explained by factors other than the vaccine
Guillain-Barre Syndrome: no increased rate above the population expected rate
Thromboembolic disorders: all occurred in patients with risk factors for blood clots (oral contraceptives and clotting disorders). Merck will conduct post-marketing study.
Based on the CDC and FDA reviews, Gardasil continues to be safe and effective and its benefits outweigh its risks
CDC has not changed its recommendations for use of Gardasil
Safety, tolerability and immunogenicity of Gardasil given concomitantly with menactra and Adacel
Pediatrics 2010; 125; 1142-1151
  • Open label study designed and funded by Merck involving 394 boys and 648 girls
  • Premise: ACIP has recommended that 11-12 year olds receive HPV, tDap and meningococcal vaccines. Is it safe to administer these three vaccines at the same time?
  • Prior studies have shown that Gardasil could be safely given at the same time as Recombivax (hepatitis B vaccine) and with Repevax (diphtheria, pertussis, tetanus and poliomyelitis vaccine)
  • 10-17 year olds were randomized at multiple sites to receive either concomitant (in the opposite limb) or non-concomitant doses of the three vaccines
  • Subjects were then monitored for safety, tolerability and immunogenicity
  • Immune response to HPV, Neisseria meningitides and diphtheria, Tetanus and acellular pertussis was the same in both groups
  • There was no difference in the adverse events in either group with pain/bruising at the site of injection reported in 87% vs 86%. No serious AEs related to the vaccines were reported in either group.
  • Conclude that Gardasil can be safely administered at the same time as other adolescent vaccines.

Vaccination in Boys
Giuliano R, Gynecol Oncol 2007; 107; S24-S26
Colgrove J, NEJM 2006; 355; 2389
Reisenger KS, Ped Inf Dis J 2007; 26; 201-9
  • Vaccine is well-tolerated and induced persistent anti-HPV serologic response in boys
  • Currently registered for use in boys and girls in Australia
  • Concerns raised with resurgence of rubella in the UK after initial decline when only women were vaccinated
  • Infection in males = females but often asymptomatic (leads to high rate of transmission between partners)
  • Genital warts increasing in frequency (250/100K)
  • Herd immunity may be necessary to protect unvaccinated women against cervical cancer

I3 and Merck sponsored study on incidence and prevalence of RRP
  • Focus on juvenile-onset and adults 20-40
  • Chart review utilizing large managed-care and state Medicaid databases covering 2 years for incident and prevalent cases
  • Plan to have data collected in the course of the next year
  • Goal is to be able to measure the effect of Gardasil on incidence and prevalence in the future
  • Dr. Campisi's Canadian study running simultaneously

If not used to treat existing RRP, what other uses are possible: Post-Licensing Suggestions for RRP Vaccine Trials
  • Establish the anti-HPV 6 and anti-HPV 11 antibody levels in cohort of actively treated RRP patients to determine who might benefit from therapeutic administration of vaccine
  • Vaccinate a cohort of children (girls and boys) currently in remission and follow for several years
  • Begin surveillance study of new-onset RRP and compare over time the incidence and prevalence in a community
  • Attempt a therapeutic trial, perhaps in conjunction with artemisinin or another cytotoxic drug

Public Health Impact: Long Term
  • The vaccines may also reduce head/neck cancer rates because HPV 16 and 18 commonly found in Oropharyngeal (tonsil, base of tongue) SCCA as well as cervical cancers, but not significantly for more than several decades

Summary and Conclusions
  • Identification of HPV as the infectious cause of cervical cancer has led to an effective preventive vaccine
  • The vaccine works by inducing neutralizing antibodies against the targeted HPV types
  • The current HPV vaccine can prevent many HPV-induced diseases
    • Almost all RRP
    • About 90% of genital warts
    • About 70% of cervical cancers
    • About 90% of other HPV-associated cancers
  • These reductions will only be achieved if there is widespread implementation of the vaccine
  • Second generation HPV vaccines with activity against a broader range of HPV types will be required to achieve the greatest reduction in HPV-associated cancers. They could also lead to wider implementation of the vaccine.
  • Optimism regarding therapeutic vaccines in the near future

Adjuvant therapies besides surgery to treat RRP
  • Not perfect but it is the best that we have
  • Controversial areas:
    • Dosing (need to give at least 5mg/ml)
    • Interval (seems best to commit to giving at least monthly for 4-6 months)
    • Starting early or late (appears to benefit more those who get it earlier in their disease but many confounding factors in this analysis)
    • Dysplasia / Malignancy risk (higher than with the disease alone? Risk to surgeon with off-label use)

Adjuvant antiviral therapy for RRP
Chadha, Cochrane collaboration 2010; 1
  • Update to an initial review published in 2005 analyzing 143 papers on antiviral therapy for RRP
  • Only one randomized controlled trial identified ( McMurray's cidofovir study)
  • Showed no benefit (though small dose and only 19 subjects)
  • However, complete resolution in 57% and partial response in 35% using Cidovir over 10 year systematic review
  • Conclude: still insufficient evidence to support use of adjuvant antiviral therapy (cidofovir); recommend that future studies use QOL measures and symptom-based outcome measures

Intralesional cidofovir for RRP: A Systematic Review
Chadha NK, J Laryngol Voice 2011, 1, 1, 22-26
  • Medline and Cochrane review of 41 studies
  • Found cidofovir more effective in adults (63% complete remission rate) vs children (37% complete remission rate)
  • No evidence for increased rate of dysplasia or malignancy
  • Recommend that Cidofovir should only RARELY be used in children as it may be less effective and long-term risks are potentially increased

Signs that You're Growing Old
  • You choose your cereal for the fiber, not the toy
  • By the time you've lit the last candle on your birthday cake, the first one has burned out
  • Your grandkids drive cars while you ride a bike
  • You recognize Led Zeppelin songs that have been turned into elevator Muzak
  • You have a party and the neighbors don't even realize it
  • Walmart and target seem to share your fashion sense

  • Study funded by NIH
  • DSMB group established and 5 centers participating
  • Celebrex has been approved for use in children >2 years with rheumatoid arthritis (protocol will allow >4 years) with administration at 200-400 mg/d
  • Double-blind, placebo-control with 6 month drug-free start-up to establish baseline for comparison
  • Pilot data: 3/3 patients have achieved remission in 3, 6 and 9 months with 1 year of follow-up. All 3 had severe disease and one had tracheal involvement!

(peginterferon alfa-2a)
  • Roferon®-A, recombinant
    • Roche no longer manufactures
    • Initial dosing was q-day for 30 days eventually getting to 3 times per week SQ
  • Pegasys® Roche
    • To help interferon last longer in the body, science has turned to a process called "pegylation". Through pegylation, a special strand (commonly called a PEG) is attached to the interferon molecule. Once attached, the PEG helps protect the interferon from being destroyed by your immune system. As a result, interferon that has a PEG can last longer in the body.
  • Dose
    • 180 µg (1.0 mL vial or 0.5 mL prefilled syringe) sub-q once weekly
  • Side effects
    • Flu-like symptoms
    • Extreme fatigue
    • Nausea, dysgesia, loss of appetite
    • Autoimmune problems
    • Teratogenic, risk of miscarriage

  • Wormwood – traditional Chinese medicine for skin diseases and malaria since 200 BC
  • WHO: preferred therapy for treatment of malaria but not as monotherapy
  • Artesunate and Artemether are most popular combination therapies (ACT) but have short half-life and have to be given 4 times/day
  • Used for treatment not prophylaxis
  • Only clinical study in RRP: Bob Bastian, 10 adult patients, closely monitored with video-laryngoscopy, no effect
  • University of Washington: investigating anti-cancer benefits due to effect on angiogenesis and VEGF

DNA HPV Vaccine
  • Plasmid DNA is a new generation biotechnology product
  • DNA plasmid platform generates both a humoral immune response to prevent new infection and a cell-mediated immunity to eliminate established infections
  • Phase I/ii clinical trials (Kenter et al, NEJM 2009) in patients with cervical cancer associated with HPV 16 using a DNA plasmid expressing a mutated non-functional E7 incapable of binding and with no transforming activity promising
  • Peng, Tunkel et al. HPV-11 therapeutic vaccine targeting E6 gene administered to mice. Strong CD8 T cell response against the E6 peptide. Hopeful model for clinical vaccine.

RRP Task Force
  • Multi-disciplinary group that meets twice yearly (September and May) in conjunction with the AAO and COSM
  • No further funding from CDC to continue registry
  • Coordination of research efforts and assistance to investigators to disseminate information and recruit interested centers and patients
  • Formulated statement on Public Health Infection concerns for children with RRP
  • Formulating best-practice statement on Cidofovir safety and use
  • Tackling statement on HPV typing

RRPF and Intl RRP ISA Center
  • Patient support groups offering education, information and discussion
  • Membership surveys
  • Newsletter
  • Literature reviews
  • RRPF:; PO Box 6643, Lawrenceville, NJ 08648-0643
  • Intl RRP ISA:; Po Box 30821, Seattle, WA 98113-0821

Self-assessment questions
  • What are the two most frequent sub-types of HPV responsible for both the development of RRP and genital warts?
    • 1 and 2
    • 6 and 11 *
    • 16 and 18
    • 23 and 35
    • 53 and 67
  • All of the following statements regarding squamous cell carcinoma of the head and neck are true EXCEPT:
    • HPV 16 has been implicated as a common finding in cancers of the tonsil
    • HPV+ oropharyngeal cancers have a worse prognosis than HPV- oropharyngeal cancers **
    • HPV+ oropharyngeal cancers are increasing in frequency
    • HPV+ oropharyngeal cancers are being seen in younger adults who do not smoke and drink
  • HPV vaccination prior to sexual debut may result in a future decrease in oropharyngeal cancers