ARTICLE IN PRESS

GYNECOLOGICAL ONCOLOGY

Screen-and-treat methods were safe and efficacious in

screening for cervical cancer in low-resource settings
Denny L, Kuhn L, De Souza M, Pollack AE, Dupree W, Wright TC. Screen-and-treat approaches for cervical cancer prevention in lowresource settings: A randomized controlled trial. JAMA 2005; 294: 2173^ 81.

OBJECTIVE To determine the ecacy and safety of

screen-and-treat approaches for cervical cancer
screening compared to a delayed evaluation (control)
group in a low resource setting.
DESIGN A randomized clinical trial, with allocation in
a 1:1:1 ratio using a computer-generated randomization
schedule. Schedules were provided in sealed envelopes to
the clinics. In order to have 80% power to detect a
reduction of more than 50% in the prevalence of highgrade cervical intraepithelial neoplasia and cancer (CIN
2+) at 6 months in the treatment groups compared to the
control group, 1664 women were needed in each group.
SETTING Three ambulatory womens health clinics
in South Africa.
SUBJECTS In total, 6555 non-pregnant women
between the ages of 35 and 65 years who had never been
screened for cervical cancer. Following their enrolment
visit, women with suspicious lesion or women who were
ineligible for cryotherapy were excluded.
INTERVENTION At the time of enrolment,
women completed a pregnancy test (if pre-menopausal), anonymous HIV serotesting, tests for Neisseria
gonorrhoeae, Chlamydia trachomatis and a DNA test
for human papillomavirus (HPV). A visual inspection
with acetic acid (VIA) was carried out by an appropriately trained nurse. The cervix was washed with 5%
acetic acid and inspected for aceto-whitening and
abnormalities and a 35 mm photograph was taken. A
VIA+ result was dened as the presence of any acetowhite lesions.Two to six days after their enrolment visit
women returned to the clinic and were randomized to
the HPV DNA,VIA or delayed evaluation group. In the
HPV DNA group all women with HPV+ test results
received cryotherapy and in the VIA group women
with VIA+ tests received cryotherapy. Nitrous oxide
and a cryosurgical unit were used to complete two

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Evidence-based Obstetrics and Gynecology (2006) 8,116 ^117

doi:10.1016/j.ebobgyn.2006.06.003

3-minute freezes. Women in all 3 groups returned 4

weeks after randomization to complete a questionnaire.
At 6 months, endocervical curettage and a colposcopy
was carried out by a physician blinded to group
allocation. Some women underwent a further
colposcopy at 12 months.
MAIN OUTCOME MEASURES Ecacy of screenand-treat approaches determined by the presence of biopsy
conrmed cervical cancer and precursor lesions in the
treatment groups as compared to the delayed evaluation
group. Safety analyses also looked at cryotherapy
complications.
MAIN RESULTS In total, 467 women (22%) in the
HPV DNA group and 482 women (22%) in the VIA
group underwent cryotherapy.The presence of CIN 2+ at
6 and 12 months was signicantly less in the screen-andtreat groups than in the control group (Table 1). At 6
months HPV DNA and VIA groups were associated with
a 77% and a 37% reduction, respectively, in the prevalence
of CIN 2+ compared to the control group. Minor complications, including vaginal discharge and bleeding, were
common but only one serious adverse event occurred.
From a number-needed-to-benet perspective, it can be
concluded that for every 25 women enrolled in the HPV
DNA group 1 case of CIN 2+ was averted, and for every
40 women in theVIA group 1case of CIN 2+ was averted.
CONCLUSION Both HPV DNA and VIA screenand-treat methods were ecacious and safe when
compared to the delayed evaluation group.
Overall study quality (out of 10)
Topic importance
Methodological quality
Practical relevance

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1361-259X/$ - see front matter

ARTICLE IN PRESS
Table 1
Occurrence of CIN 2+ at 6 and 12 months, by intervention group

Time since randomization

HPV DNA %
(95%CI)

VIA % (95% CI)

DE % (95%CI)

6 months
12 months

0.8 (0.4^1.2)
1.42 (0.88^1.97)

2.23 (1.57^2.89)
2.91 (2.12^3.69)

3.55 (2.71^4.39)
5.41 (4.32^6.5)

DE=delayed evaluation.
 Calculated as a weighted average f the stratum-specic Kaplan-Meier estimates of the cumulative. proportions with CIN 2+ by 12 months per 100 women.

Commentary
Direct Visual Inspection (DVI) and immediate treatment with
cryotherapy have been the basis of test and immediate treatment proposals for cervical cancer control in low resource settings. Both have been demonstrated to be eff|cacious, safe1, and
highly cost effective methods that have the potential to rapidly
drop cervical cancer deaths in low resource settings.2 However,
this strategy has not yet been routinely implemented in any
country. It is criticized because many studies suffered from verif|cation bias: the reference -colposcopy guided biopsy- is applied
to all those who screen positive, but to only a low fraction of
those who screen negative. Most research has been conducted
under controlled conditions, with relatively low numbers and
short follow up periods, which raises doubts about its performance in real life situations and its long term effectiveness and
safety. Finally, test and treat is criticized for its higher rate of
over-treatment in comparison with conventional management.
Denny et als paper is among the best-designed studies for
short term evaluation of the test and treat strategy. It had randomized assignment of the intervention, close to100% outcome assessment of women independent of screen result, and used a
blinded and controlled reference. This strategy addresses most
of the research design criticisms. It is one of the few test and
treat studies that evaluate HPV as the primary screening. They
clearly demonstrated that to avoid cervical lesions (CIN2 or
worse at 6 and 12 months), test and treat is superior to conventional cytology based programs (delayed approach) and that HPV
DNA is superior to visual inspection of the uterine cervix with
acetic acid (VIA) (real-world performance of VIA may be even
worse for the high inter-observer variability and higher diff|culty
in quality control1). Denny demonstrated that cryotherapy, if
needed, could be used in the majority of women: 6,637 out of
7,088 (94%) were eligible for cryotherapy.
Unfortunately only short term effectiveness was reported
with complete ascertainment for 6 months, while at 12 months
they re-examined all the positives but only 36.9% of those who
screened negative.
The main benef|t of the test and treat approach is to prevent
loses to follow up. Lack of compliance explains the failure of traditional cervical cancer control programs in low resource settings. The current Papanicolaou based screening programs in
poor areas of Latin America only reach appropriate treatment

of 23% of those who screened positive.3 The risk of over-treatment will be widely compensated by the number of cervical cancers averted.
While women from developed or underdeveloped areas will
benef|t with a test and treat approach, the techniques selected
may be diverse. In low-income countries, HPV DNA testing is
currently inaccessible and DVI (VIA or other) is the most effective screening option; in this setting, cryotherapy is the best
treatment because it is safe, eff|cacious, does not require anesthesia or electricity, and can be applied by non-medical health
personnel in a primary care setting. In high resource settings,
there are many more eff|cacious options for the test and treat
strategy. DVI, HPV DNA testing, or colposcopy are available for
testing, and laser therapy, loop electrosurgical excision procedure (LEEP) or cold knife conization, for immediate treatment.
The excisional options have the advantage over ablative therapy
of providing tissue for pathology.
The evidence is suff|cient to initiate long term effectiveness
trials in real life settings with the techniques that are the most
appropriate for the local reality, considering the womens possibilities and preferences. Screen and treat should decrease womens
anxiety and cervical cancer burden and mortality by increasing
sensitivity, participation and compliance over cytology based
screening programs.
Catterina Ferreccio, MD, MPH
Pontif|cia Universidad Catolica de Chile, Santiago, Chile

Literature cited
1. Reviews of VIA http://www.paho.org/English/AD/DPC/NC/cc-via.htm
and cryotherapy http:www.path.org/f|les/RH_cryo_white_paper.pdf
www.path.
2. Goldie SJ,Gaff|kin L,Goldhaber-Fiebert JD,Gordillo-Tobar A, Levin C,
Mahe C, Wright TC; Alliance for Cervical Cancer Prevention Cost
Working Group. Cost-effectiveness of cervical-cancer screening in
f|ve developing countries. N Engl J Med. 2005 Nov17; 353(20):2158 ^ 68.
3. Gage J, Ferreccio C, Gonzales M, Arroyo R, Huivin M, Robles M. Follow-up care of women with an abnormal cytology in a low-resource
setting Cancer Detection and Prevention 2003; 27(6):466 ^71.

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