ISSUES IN PREVENTION
| CERVICAL CANCER PREVENTION IN THE ERA OF PROPHYLACTIC VACCINES —Bobbie
Gostout, MD, Associate Professor of Obstetrics and Gynecology, Mayo Clinic College of Medicine, Rochester,
MN
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| Epidemiology of cervical cancer: remains significant cause of morbidity and mortality worldwide;
≈10,000 new cases and ≈4,000 deaths annually in United States; dramatic decreases in incidence and mortality
from squamous cell cervical cancer in North America because of Papanicolaou (Pap) testing and
treatment; reduction in deaths from cervical adenocarcinoma not as significant (Pap test not as reliable in
detecting adenocarcinoma); no significant improvement in survival from cervical cancer in 30 yr; 50% of
cervical cancer seen in women 35 to 55 yr of age
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| Human papillomavirus (HPV): etiologic agent for cervical cancer in 99.7% of cases; responsible for
squamous cell and adenocarcinoma histologies; also implicated in oropharyngeal, anal, vaginal, vulvar,
penile, and nonmelanoma skin cancer (different strain from genital and oral cancers); structure—
nonenveloped, double-stranded DNA virus; genes responsible for cancer transformation packaged in
protein capsid; types—>200 HPV types identified; ≈40 anogenital types; 70% of cervical cancer cases
associated with HPV types 16 (HPV-16) and 18 (HPV-18); ≈38 types associated with cancer; note—
most women with HPV infection do not develop invasive carcinoma; exposure and infection—≈50% of
women exposed to 1 HPV type at 3 yr of sexual activity; HPV infection common in sexually active
women of all ages and at all stages; ≈7% to 10% of women who consider themselves monogamous exposed
to HPV; prevention and vaccination—HPV vaccine works by blocking HPV infection; recommended
all women 9 to 26 yr of age be vaccinated; only lifelong abstinence protects from HPV
infection; cervical cancer screening remains important preventive component in vaccinated and unvaccinated
women
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| Vaccines: capsid proteins assemble into virus-like particles (VLPs); VLPs resemble native HPV particles;
VLPs elicit HPV-neutralizing antibodies; bivalent vaccine trial (2004)—showed 94% efficacy in preventing
HPV-16 infection, 100% efficacy in preventing persistent HPV-18 infection, and 93% efficacy in preventing
atypical squamous cells of undetermined significance, low-grade squamous intraepithelial
lesions, or high-grade squamous intraepithelial lesions related to HPV types 16 and 18; quadrivalent vaccine
trial (2005)—showed ≈90% efficacy against infection and 100% protection against clinical disease;
adverse events with quadrivalent HPV vaccine—pain at injection site (80%), flu-like headache (60%), and
fevers >100°F (12%); most side effects mild or moderate; 0.2% discontinued because of side effects;
fever— acetaminophen (Tylenol) or ibuprofen (Advil) recommended after vaccination (does not interfere
with vaccine efficacy); tendency for slight increase in fever with each successive vaccination (if patient
has fever with first vaccination, instruct to take Tylenol before next vaccination); more trial data—no
type-specific cases of cervical intraepithelial neoplasia (CIN) II or III or adenomacarcinoma in situ observed
in vaccine group of >1000 women; vaccine effective against only 2 oncogenic types that cause abnormal
Pap test (continued possibility of abnormal Pap test does not mean vaccine failed); 100%
protective against CIN I and 99% protective against external genital lesions; vaccine not shown effective
for existing cervical, vaginal, or vulvar lesions; even patient with abnormal Pap test should receive vaccine
(to protect from HPV strains not yet acquired)
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| Approach to vaccination: low incidence of sexual activity in girls <13 yr of age; dramatic increase in
early- and mid-adolescent years; early vaccination necessary for primary prevention of cervical cancer;
best antibody response at 9 to 13 yr of age; treat as routine vaccination; discuss at age-appropriate level;
antibody levels remain high 5 yr after vaccination
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| HPV recombinant vaccine, quadrivalent (Gardasil): Centers for Disease Control and Prevention (CDC)
recommends vaccine for girls 11 to 12 yr of age (indicated age range 9 to 26 yr); speaker recommends
for girls as young as 9 yr of age; reported cost $500 to $700 for series of 3 injections; updates on insurance
carriers covering vaccine available from Merck; pregnancy—category B; where appropriate, counsel
patient to use contraception during 6-mo vaccine series, but assure patient of low risk for adverse
event in pregnancy; report pregnancies exposed to Gardasil to Merck registry; lactating women can receive
vaccination; additional considerations—>50% of parents want child vaccinated (acceptance of vaccine
increases with patient education); vaccination not approved for males; ongoing clinical trial shows
safety profile and antibody levels in men equal to women; speaker believes reasonable to offer vaccine to
men at high risk for infection with HPV; vaccine shown cost effective; bivalent vaccine submitted for
approval at end of 2006 (may offer cross protection from HPV types 31 and 45, as well as 16 and 18)
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| PREVENTION OF RECURRENT URINARY TRACT INFECTION —James R. Johnson, MD, Professor,
Department of Medicine, Division of Infectious Diseases and International Medicine, University of
Minnesota Medical School, and Director, Infectious Diseases Fellowship Program, Infectious Diseases
Section, Minneapolis Veterans Affairs Medical Center
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| Epidemiology: most urinary tract infections (UTIs) occur in patients with past history
|
 | Risk factors: premenopausal women—behavioral factors (eg, sexual activity, antimicrobial use), family
history, and early onset of UTIs; postmenopausal women—UTIs before menopause predictive of infections
after menopause, incontinence, and biologic predisposition (nonsecretor status); complicating
factors—long-term indwelling catheters, urolithiasis, voiding disorders, and anatomic abnormalities
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| Ascending UTI: most common pathogenesis pathway; organisms causing UTI (mostly Escherichia coli)
arise from gut flora; organisms colonize vagina and urethra and enter bladder, causing cystitis or pyelonephritis;
fecal-perineal–urethral hypothesis—in most women with acute UTI, causative organism present in
vaginal and fecal flora, usually as predominant strain; other strains, if present, less virulent than organism
causing symptomatic infection; vaginal colonization of extraintestinal pathogenic E coli (ExPEC) risk factor
for UTI; vaginal and fecal flora important reservoir; spermicide use, antibiotic use, and lack of estrogen
decrease vaginal lactobacilli and increase vaginal pH (creating overgrowth of E coli, which allows for entry
through urethra into urinary tract); diaphragm-spermicide exposure—associated with markedly increased
vaginal colonization with E coli; causes depletion of lactobacilli (due to microbicidal action of nonoxynol-
9 [N-9]); also leads to increased vaginal pH and overgrowth of other organisms not normal to vaginal flora;
data show use of spermicide in combination with sex appear to promote entry and persistence of E coli into
urinary tract and vagina; vaginal E coli and hydrogen-peroxide–producing lactobacilli—absence of strains of
lactobacilli that produce hydrogen peroxide may predispose to E coli colonization and UTI; lack of
estrogen—causes depletion of lactobacilli; lactobacilli commonly replaced by E coli in postmenopausal
women; trial showed risk for symptomatic UTI decreased nearly 10-fold in women randomized to topical
vaginal estriol vs placebo
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| Endogenous issues: nonsecretor of blood group antigens—marker for increased risk for recurrent UTI in
premenopausal and postmenopausal women; increased likelihood of colonization of vaginal E coli and
increased receptivity of vaginal epithelial cells to attachment by E coli; microbes bind to host’s cell surface
through adhesins that recognize specific receptors; receptor analogue therapy—provides false receptor
to block adhesins; cranberry, blueberry and lingonberry juice contain inhibitors of 2 adhesins of
uropathogenic E coli; urine of people who consume cranberry juice shows antiadherence activity; trials
looking at cranberry juice inconclusive; antiadhesin vaccine being researched; interplay between host
defenses, E coli, and bladder
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| Catheter-related UTI: in acute care setting, risk for bacteruria increases 3% to 10% each day catheter indwelling
(in direct proportion to duration of catheterization); almost always asymptomatic; organisms
introduced into urinary tract around catheter, at urethra-catheter interface, through lumen of catheter
from break in connecting system, or through backwash from collecting bag; patient catheterized long
term usually has bacteriuria or funguria (E coli, Pseudomonas, enterococci, group B streptococci, staphylococci
and coagulase-negative staphylococci make up normal flora of patient catheterized long term);
treat if patient symptomatic
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| In-household transmission of E coli: E coli clones, including ExPEC, can be extensively shared among
human and animal household members in absence of sexual contact and in patterns suggesting host-to-
host transmission
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| Summary: note—UTI in connection with food supply being investigated; management—avoidance of
spermicides or discontinuance of antibiotics recommended; data involving UTI and cranberry juice incomplete;
topical estrogen recommended for postmenopausal women; therapeutic options—continuous
(daily or 3 times weekly) low-dose prophylaxis, intermittent patient-initiated therapy, and post-coital
prophylaxis for women with sex-related infection; fewer indications for urologic evaluation and intervention;
avoid long-term indwelling catheterization
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Educational Objectives
| The goal of this program is to educate the listener about the vaccine developed to prevent cervical cancer
(and other diseases) and issues in preventing recurrent urinary tract infection (UTI). After hearing and assimilating
this program, the clinician will be better able to:
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| 1. Discuss the importance of the cervical cancer vaccine and how it works.
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| 2. State the age range at which it is recommended girls be vaccinated and side effects that may be experienced.
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| 3. Discuss use of the cervical cancer vaccine in pregnancy.
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| 4. List the risk factors for recurrent UTI.
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| 5. Discuss the role of hydrogen-peroxide–producing lactobacilli and Escherichia coli in recurrent UTI.
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Discussed on This Program
Acetaminophen (N-acetyl-P-aminophenol; APAP) [Tylenol Caplets, others]
Human papillomavirus recombinant vaccine, quadrivalent [Gardasil]
Ibuprofen [Advil, others]
Nonoxynol-9
Resources
Patient education brochure available through the Gynecologic Cancer Foundation at: www.thegcf.org
Suggested Reading
Bosch X: Prevention strategies of cervical cancer in the HPV vaccine era. Gynecol Oncol 203(1):21, 2006;
Collins et al: Cervical cancer prevention in the era of prophylactic vaccines: A preview for gynecologic
oncologists. Gynecol Oncol 102(3):552, 2006; Gupta K et al: Inverse association of H202-producing lactobacilli
and vaginal Escherichia coli colonization in women with recurrent urinary tract infections. J Infect
Dis 178(2):446, 1998; Hooton TM et al: Escherichia coli bacteriuria and contraceptive method. JAMA
265(1):64, 1991; Johnson JR et al: Sharing of virulent Escherichia coli clones among household members
of a woman with acute cystitis. Clin Infect Dis 43(10):e101, 2006; Kontiokari T et al: Randomised trial of
cranberry-lingonberry juice and Lactobacillus GG drink for the prevention of urinary tract infections in
women. BMJ 322(7302), 2001; Mao C et al: Efficacy of human papillomavirus-16 vaccine to prevent cervical
intraepithelial neoplasia: a randomized controlled trial. Obstet Gynecol 107(1):18, 2006; Monsonego
J: Cervical cancer prevention: the impact of HPV vaccination. Gynecol Obstet Fertil 34(3):189, 2006; Steinbrook
R: The potential of human papillomavirus vaccines. N Engl J Med 354(11):1109, 2006; Villa LL:
Prophylactic HPV vaccines: reducing the burden of HPV-related diseases. Vaccine 24 Suppl 1:S23, 2006.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any
significant financial relationship with the manufacturer or provider of any commercial product or service
discussed. The following has been disclosed: Dr. Johnson has received research or education grants from
Merck and Bayer, and has acted as a consultant to Rochester Medical.
Dr. Gostout was recorded at OB/GYN Clinical Reviews, sponsored by the Mayo Clinic College of Medicine, and held
on November 2-3, 2006, in Rochester, MN. Dr. Johnson was recorded at Emerging Infections in Clinical Practice
and Public Health, sponsored by the University of Minnesota and the Mayo Clinic College of Medicine, and held on
November 2-3, 2006, in Minneapolis. The Audio-Digest Foundation thanks the speakers and the sponsors for their
cooperation in the production of this program.
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