Journal Update November 2003

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Journal UpdateNovember 2003

• Soma Wali, M.D.
• Michael Rotblatt, M.D.
• Olive View-UCLA SFV Program

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Topics

• Frequency of PAP screens 1 vs. 3 yrs
• Malaria prophylaxis in travelers
• Pharmaceutical Update

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Case 1

• A 42 year old female with no PMH visits your
  clinic requesting an annual pap smear
• She is married, with annual Paps since age 18
  last Pap one year ago (all Paps normal)
• She has a PMD, who told her she doesnt need
  another annual Pap based on new recommendations
• Patient is concerned and wants to know why she
  shouldnt continue getting annual Pap smears

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Background

• Cervical cancer incidence/prevalence data (for
  1997)
• 14,500 new cases
• 4,800 deaths
• Women 65 years
• 25 of cases
• 40-50 of women dying from cervical cancer

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Background...

• Risks associated with increased rate of Ca
• Multiple sexual partners
• Sexual activity at a young age
• Hx of STDs
• Exposure to certain types of HPV
• Signs and sxs of cervical Ca
• Abnormal or post-coital vaginal bleeding
• Hematuria, rectal bleeding
• Pelvic pain, leg pain, back pain
• Dyspareunia

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Background...

• Screening recommendations prior to 2003
• Start Pap smears at age 18
• Women of all ages to be screened annually
• Pap smears can be stopped after age 70
• The age cut off was controversial

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Types of Screening Tests

• Traditional Pap smears
• Newer liquid based system
• More sensitive, but not as widely available
• Plastic extended tip spatula
• The spatula is rapidly washed in a vial with an
  alcohol based preservative to avoid drying, then
  the sample is processed
• HPV testing
• For ASC-US
• Combination of Pap and HPV

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Bethesda Classification of Cervical Cytology

• Squamous cell
• Atypical squamous cell (ASC)
• Of undetermined significance (ASC-US)
• Can not exclude HSIL (ASC-H)
• Low grade squamous intraepithelial lesion (LSIL)
• cellular changes consistent with HPV, mild
  dysplasia (CIN1)
• High grade squamous intraepithelial lesion (HSIL)
• moderate/severe dysplasia, CIN 2, CIN 3, CIS
• Squamous cell carcinoma

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Bethesda Classification...

• Glandular Cell
• Atypical
• Endocervical, endometrial, glandular cells
• Endocervical adenocarcinoma in situ (AIS)
• Adenocarcinoma
• Endocervical, endometrial, extrauterine

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Sawaya et al. Risk of Cervical Cancer Associated
with Extending the Interval Between Cervical
Cancer ScreeningNEJM Oct. 16, 3003349

• Study Question
• What is the risk of cervical cancer associated
  with less frequent than annual screening?
• Estimate rate of
• Cancer w/in 3 yrs after one or more negative paps
• Additional Paps and coloposcopic exams required
  to avert one case of cancer

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Methods

• Data from CDCs National Breast and Cervical
  Cancer Early Detection Program
• Cervical cancer screening to low-income women
  throughout the U.S. (1991-2000)
• 1,174,727 Paps in 938,576 women
• All women
• The largest percentage of women 45-64 yrs
• 50 non-white

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Data Exclusion

• 0.9 (11,276 out of 1,174,727) of tests which
  were reported unsatisfactory
• 1,446 results which were pending
• 7,062 tests that were unclassified
• 157 women with missing data

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Screening Categories

• Women were grouped into four categories
• Women with only one Pap
• Women with initial negative Pap followed by a
  second Pap
• Two negative Paps followed by a third Pap
• Three negative Paps followed by fourth Pap

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Model and Estimates

• Investigators estimated the average risk of
  cancer in a hypothetical cohort of 100,000 women
  who were screened three years after the last
  negative Pap
• Hypothesis
• few cases of cancer would be found in women with
  three or more previous negative Paps
• To avoid underestimating risks, they assumed that
  all grade 2 lesions will progress to invasive
  cancer

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Results

• Highest prevalence of cervical dysplasia
• women
• women with no previous Pap tests
• Among all age groups
• As of previous negative Paps increased -- Ca
  prevalence decreased
• True whether the Pap was done annually or every 3
  years

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Results...

• Among women who had 3 consecutive neg. tests,
  high grade dysplasia was very uncommon
• 0.028 had grade 2 0.022 had grade 3 and none
  had invasive Ca
• In a cohort of 100,000 women with 3 negative
  Paps, if screening done three years after a
  negative Pap, the average estimated number of
  extra Ca cases
• 30-44 yrs old - 3 extra cases/100,000
• 45-59 yrs old - 1 extra case/100,000
• 60-64 yrs old - 0 extra cases

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Results...

• To avert one case of cancer in 100,000 women, the
  of additional Paps and colposcopies needed
• Age group of Paps of Colpos
• 30-44 69,665
  3,861
• 45-59 209,324
  11,502
• 60-64 313,519
  17,353

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Authors Conclusion

• Women 30-64 yrs of age with three or more
  previous negative Pap tests who are screened once
  every 3 yrs, rather than annually, have an excess
  risk of cancer of about 3 in 100,000 (varies with
  age)
• 30-44 yrs old - 3 extra cases/100,000
• 45-59 yrs old - 1 extra case/100,000
• 60-64 yrs old - 0 extra cases

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Study Limitations

• Data were collected for the purpose of program
  administration and evaluation, not as a
  prospective research study
• We dont have other information about risk
  factors on these women
• No verification of cytology
• It was assumed that all women would adhere to
  screening, follow up and tx
• The risk of cancer might be underestimated in
  women who dont adhere to follow up

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Our Bottom Line

• We agree with the authors on their estimates
• Annual Pap screens may not be necessary after 3
  negative tests
• esp. in women 30 yrs old
• However, as this study was not a prospective RCT,
  other studies are needed to substantiate results

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Perspective

• New cervical Ca screening recommendations were
  published in 2003 due to several factors
• Technological changes
• Liquid based cytology test
• Better understanding of the development of
  cervical cancer
• Dysplasia takes several yrs to develop after
  infection with HPV
• Additional clinical studies

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Another study...

• 2.4 million members of an HMO
• Risk of cervical Ca
• After 1 negative Pap 3/100,000 women
• After 2 negative Paps 2.5/100,000 women
• After 3 negative Paps 1.4/100,000 women

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New Screening Recommendations

• American Cancer Society, 2003
• Start 3 yrs after the onset of sexual activity,
  but no later than age 21
• Screening interval depends upon choice of test,
  previous test results and presence of risk
  factors
• Pap smears annually
• Liquid based cytology tests every 2 years
• These intervals can be increased to every 2-3
  years if tests are normal in women 30 yrs old
• HIV/immunocompromised Test twice in the first
  year after dx, and then annually
• Can stop screening at age 70

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New Screening Recommendations...

• American College of OB, 2003
• Start screening at onset of sexual activity
• Annual screening for women
• Every 2-3 yrs in women with at least two normal
  tests
• Pap or liquid based cytology
• Can stop at age 70

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Related Screening Issues

• Other authoritative recommendations for stopping
  screening
• USPSTF
• Women who had a total hysterectomy
• 65 yrs with previous negative tests
• American Geriatric Society
• 70 yrs
• An annual pelvic exam is still recommended in all
  women
• Annual sexual hx should be obtained and if new
  partner or risks are identified, consider repeat
  Pap

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Perspective

• Despite the new guidelines indicating that the
  screening interval can be increased...
• (Some) physicians and patients have been
  reluctant to change due to
• Patients concern about cancer
• Physicians concern about medicolegal issues
• Success and simplicity of annual screening

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Practical concerns about screening less
frequently (q 2-3 yrs)

• More patients may be lost to follow up
• More difficult to keep track of tests done every
  few years
• We dont want to risk losing the impressive gains
  of the past 60 yrs
• Continued annual screening with the use of more
  sensitive tests reduces risk

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Benefits of screening less frequently

• Cost, harm and discomfort associated with
  over-screening is avoided
• Annual screening requires substantial resources
  and results in many unneeded Paps and
  colposcopies
• The number of missed dysplasias and preventable
  cancers appears extremely small

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Case

• 42 yr old woman with negative annual Pap smears
  wants to know what she should do
• Study findings do provide reassurance that
  extending the screening intervals to every three
  years after 3 or more negative tests is a safe
  and reasonable option (esp. 30 yrs old)

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Case 2

• A 32 yo M presents to your office with fevers and
  chills, 6 months after returning from a one month
  trip to Ethiopia
• He was fastidiously compliant with the CDC
  recommended malaria prophylaxis medications
• Does this patient need a work-up for malaria?

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Background

• Febrile illness in returning traveler
• Malaria
• Typhoid
• Dengue (
• 4 species of malaria
• P. falciparum -- severe disease
• P. vivax -- latent infection
• P. ovale -- latent infection
• P. malariae -- 3 dy RBC life-cycle, nephrotic
  synd

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Background...

• 30 million travelers/yr visit malaria areas
• 30,000 cases/yr in travelers from industrialized
  countries
• 600 cases/yr in U.S. travelers
• Roughly 1200 result in fatalities
• Transmission (endemic region x 1 month)
• Oceana/Sub-Saharan Africa 140
• India/SE Asia 1250 - 11000
• South/Central America 12,500 - 110,000

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Malaria

• 2 main stages of infection
• Liver stage multiply in hepatocytes
• All species 1-2 week
• vivax, ovale may persist x months-years
• Blood stage hepatocytes rupture, releasing
  parasites into bloodstream ? invade RBCs ?
  clinical illness
• Clinical sxs 2-4 weeks after mosquito bite
• Latent infection (vivax, ovale) ? months-years

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Chemoprophylaxis

• Drugs that act on the blood stage
• Chloroquine
• Mefloquine -- neuro-psychiatric
• Doxycycline -- sun sensitivity
• Drugs that act on the liver stage
• Malarone (atovaquone/proguanil)
• Primaquine -- hemolysis if G6PD deficient

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Chemoprophylaxis (www.cdc.gov/travel)

• Chloroquine-sensitive areas of P. falciparum
• Chloroquine weekly -- 4 wks after
• Chloroquine-resistant areas
• Mefloquine weekly -- 4 wks after
• Doxycycline daily -- 4 wks after
• Malarone (atovaquone/proguanil) daily -- 7 dys
  after
• Primaquine daily -- 7 dys after (for special
  circumstances, call CDC)
• Prolonged exposure to P. vivax/ovale areas
• Add primaquine x 2 wks after departure
• prolonged exposure vague (Missionairies/Peace
  Corps)

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Schwartz, et al. Delayed onset of malaria
implications for chemoprophylaxis in travelers.
NEJM Oct. 16, 20033491510

• Most antimalarial agents used by travelers act
  on the parasites blood stage, not the liver
  stage, and may not prevent late-onset illness
  from P. vivax, ovale
• Measure prevention of late-onset disease with
  recommended prophylaxis regimens
• U.S. and Israeli investigators examined malaria
  surveillance data

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Methods

• Malaria reportable disease in Israel US
• Investigators analyzed all surveillance data of
  malaria cases in civilian travelers
• Israel 1994-1999 (5 years)
• U.S. 1992-1998 (6 years)
• Cases defined as parasitemia confirmed by blood
  smears
• Israel all patients interviewed by
  nurse-epidemiologists

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Results

• Israel 307 cases ? 300 usable
• 2 months
• Early Onset Late Onset
• total Eff Pro total Eff Pro
• P. falcip 135 135 14 0 0
• P. viv/ov 161 28 3 133
  108
• 81 of late-onset illness had taken effective
  prophylaxis

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Results

• U.S. 5185 cases ? 2822 usable
• Early Onset Late Onset
• total Eff Pro total
  Eff Pro
• P. falcip 1290 1231 167
  59 20
• P. viv/ov 1408 531 157
  877 555
• 62 of late-onset illness had taken effective
  prophylaxis
• Late onset range (2 mo 4.7 yrs) mean (6 mo)

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Authors Conclusion

• In 1/3 of malaria-infected travelers,
  late-onset (P. vivax/ovale) illness developed
  despite effective tx
• Most of these illnesses are not prevented by the
  commonly used prophylaxis agents
• Recommendation Agents that act on the liver
  phase are needed for more effective prevention of
  malaria in travelers

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Study Limitations

• Epidemiologic study
• U.S. cases not interviewed (compliance?)

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Our Bottom Line

• Late-onset (P. vivax/ovale) infection can readily
  develop despite usual prophylaxis (chloroquine or
  mefloquine) in many travelers
• Travelers
• By taking CDC recommended drugs you might think
  youre well protected from malaria, but
• Clinicians
• Consider recommending primaquine for high risk P.
  vivax/ovale areas, even for non-prolonged
  visits (check for G6PD deficiency first!)
• Consider P. vivax/ovale malaria in the DDx for
  late febrile illnesses in travelers

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Perspective

• Investigators suggest using liver-agents as
  primary prophylaxis, instead of blood-agents
• Primaquine evaluated as primary prophylaxis
• 3 studies in malaria-endemic countries
• 85-90 protective for P. vivax and P. falciparum
• 1 study in travelers (2 week rafting trip to
  Ethiopia)
• Mefloquine 13 of 25 persons infected (52)
• Primaquine 6 of 106 persons infected (6), and
  no cases of late-onset illness with 16 month f/u
• Atovaquone/proguanil prophylaxis
• Effective to prevent P. faciparum infections
• Data for P. vivax/ovale more limited

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Case

• 32 yo M with F/C, 6 months after returning from
  Ethiopia and very compliant with appropriate
  prophylaxis per CDC
• Should he be worked up for malaria?
• Yes!very likely he has P. vivax/ovale

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Pharmaceutical Update

• November 2003

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New Drug Interaction

• Gemfibrozil inhibits CYP450, significantly
  increasing levels of
• Rosiglitazone, (pioglitazone?)
• Repaglinide

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New Drugs

• Carbinoxamine maleate (PalgicR)
• New prescription antihistamine
• 4 mg daily
• DBCT -- mild sedation in 11, resolved in 2-3
  days of use
• SeasonaleR
• New OCP
• 3 month supply, with last 7 days placebo
• 1 menstrual period every 3 months

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Memantine HCl (NamendaR)

• New drug for moderate-severe Alzheimers
• All other agents approved for mild-moderate AD
• Available in Germany since 1982
• NMDA receptor antagonist (like amantadine)
• 5 mg QD -- 10 mg BID
• SE dizzyness, HA, constipation, confusion
• Moderate effects in improving performance in
  studies with moderate-severe AD

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Flu Vaccine T-F Questions

• 2003-2004 flu vaccine
• Contains the same viral strains as last years
  vaccine
• Patients who received last years vaccine dont
  need to be vaccinated this year
• Last years vaccine can be used this year
• Intranasal flu vaccine (FluMistR)
• Approved for adults 50 yrs old
• Can be administered to pregnant women
• Can be administered to patients with mild URI and
  fever

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To download this lecture

• www.uclaSFVP.org/lectures.htm