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African Journal of Reproductive Health
Women's Health and Action Research Centre
ISSN: 1118-4841
Vol. 7, Num. 2, 2003, pp. 7-12
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African Journal of Reproductive Health, Vol. 7, No. 2, Aug, 2003 pp. 7-12
Commentary
Prevention of Cervical Cancer in Africa: A Daunting
Task?
Gijs Walraven
Correspondence: Dr Gijs Walraven, Farafenni Field Station, Medical Research
Council Laboratories, P. O. Box 273, Banjul, The Gambia. E-mail:
gijs_walraven@hotmail.com
Code Number: rh03017
ABSTRACT
Africa has a high estimated incidence of cervical cancer, thus requiring
the development of an effective prevention strategy. Cytology-based screening
is beyond the capacity of many African countries, hence the need for alternatives.
Visual inspection of the cervix after application of 3-5% acetic acid (VIA) is a promising screening
test, with similar sensitivity to that of cytology but lower specificity. The
same accounts for other VIA methods using magnification devices, visual inspection
after the application of Lugol's iodine, or human papilloma virus (HPV) DNA
testing, all proposed alternatives to cervical cancer prevention screening
tests. Vaccination against HPV is the most promising strategy for the prevention
of cervical cancer, but a wider variety of HPV types than currently being investigated
must be considered for the development of the multivalent vaccine preparations
required in Africa. Other considerations in developing an effective prevention
programme include full public sector investment and achieving acceptability
of a vaccine against a sexually transmitted infection targeted for
adolescents. Unfortunately, however, if HPV vaccines are developed the initial
impact of prophylactic vaccines will be delayed for many years. Alternative
strategies should, therefore, be promoted in parallel. There are several approac hes
to cervical cancer prevention and their evaluation should be comprehensive
and coordinated to achieve short and long-term public health benefits in different
programme settings. (Afr J Reprod Health 2003;
7[2]: 7-12)
RÉSUMÉ
Prévention du cancer du col en Afrique: une tâche intimidante? Il
y a une haute incidence estimée du cancer du col, exigeant ainsi l'élaboration
d'une stratégie de prévention efficace. Le dépistage à base cytologique est
au-dessus de la capacité de bien de pays africains, ce qui justifie la nécessité des
alternatifs. L'inspection visuelle du col suite à l'application de 3-5% d'acide
acétique (IVA) demeure un test de dépistage prometteur dont la sensitivité est
identique à celle de la cytologie, mais qui a une spécificité plus faible. Voilà ce
qui justifie les autres méthodes IVA qui se servent des mécanismes de grossissement
de l'inspection visuelle suite à l'application de la solution de Lugol ou du
virus de papillome humain (VPH), du test d'ADN, tous les alternatifs aux tests
de dépistage pour la prévention du cancer du col qui ont été proposés. La
vaccination contre le VPH est la stratégie la plus prometteuse pour la prévention
du cancer du col, mais il faut étudier une plus grande variété de types VPH
pour mieux développer la production polyvalente des vaccins dont a besoin en
Afrique. D'autres considérations à l'égard de l'élaboration d'un programme
efficace de la prévention comprennent un investissement dans le secteur public
et le succès au niveau de l'acceptabilité d'un vaccin contre une infection
sexuellement transmissible qui vise les adolescents. Malheureusement, pourtant,
si les vaccins VPH sont élaborés, l'impact initial des vaccins prophylactiques
sera retardé pour beaucoup d'ànnées. Il faudrait donc promouvoir d'autres
stratégies en parallèle. Il y a plusieurs approches à la prévention du cancer
du col et il faut que leur évaluation soit compréhensive et coordonnée pour
réaliser à court et à long terme des bénéfices de la santé publique dans des
cadres des divers programmes. (Rev Afr Santé Reprod 2003; 7[2]: 7-12)
KEY WORDS: Cervical
cancer, prevention, screening, cytology, visual inspection, HPV, DNA detection,
health awareness, vaccines
INTRODUCTION
Cancer of the cervix is the most common cancer among women in
the developing countries. It accounts for more than 80% of all cases worldwide.1 Africa
as a region has one of the highest incidence rates in the world, and five of
the seven countries with the highest rates are in eastern or southern Africa.2 The
number of deaths from cervical cancer worldwide is estimated at 230,000 per
year.3 Many of those who die are relatively young women, as the
peak incidence occurs among women in their forties. Mortality is highest in
countries that are least equipped to deal with the problem. Many patients in
Africa come for examination when the tumour is far advanced and inoperable,
radiation is rarely available, and even palliative care is often of poor quality.
Although cervical cancer is preventable with early diagnosis and treatment,
in many developing countries it has been difficult to establish and maintain
effective screening programmes.4 Initiation and maintenance of cytology-based
screening programmes involving sexually active women every 1-5 years have probably resulted in a large decline
in cervical cancer incidence and mortality over the last 40-50 years in many industrialised countries.5 However,
implementing such programme in areas with inadequate health service coverage
and low appreciation of preventative medicine means first overcoming issues
such as access to the population, acceptability and availability of the screening
examinations, quality of the specimen collection and evaluation, follow-up
and treatment, the considerable cost and resource implications, and demands
of competing health needs.
NATURAL HISTORY
Cervical cancer generally develops slowly over a period of 10-15 years. It is preceded by detectable and treatable
precursor conditions in which certain cells in the cervix develop abnormal
characteristics but are not yet cancerous. Broadly known as cervical dysplasia,
these pre-cancerous abnormalities are classified according to severity. One
classification system refers to the abnormal conditions as cervical intraepithelial
neoplasia (CIN), while under a newer system (the Bethesda system), they are
known as squamous intraepithelial lesions (SIL). Low grade SIL includes early
cellular abnormalities and mild dysplasia (comparable to CIN I). Low grade
SIL regresses spontaneously in about 60% of women within two to three years
and generally does not require treatment. High grade SIL (comparable to CIN
II or III) is more likely to progress to cancer if untreated; 30-70% progresses to invasive cancer within 10 years
and, therefore, generally requires treatment. These factors are important to
consider in planning a screening and treatment programme, particularly where
resources are limited.
HUMAN PAPILLOMA VIRUS AND OTHER RISK FACTORS
A causal link between human papilloma virus (HPV), a sexually
transmitted infection (STI), and the development of cervical cancer has been
established. It is estimated that over 99% of cancers worldwide contain HPV
DNA.6 Commonly accepted risk factors for HPV and, hence, for cervical
cancer include a history of other STIs, early onset of sexual activity, more
than one sexual partner and/or a partner with more than one sexual partner.
Other possible cervical cancer risk factors include early childbearing, high
parity, tobacco use, use of oral contraceptives, genital schistosomiasis and
nutritional factors such as low intake of vitamins A, C, E, carotenoids and
folate.7,8 Some of the other cervical cancer risk factors identified
are closely interrelated, making it difficult not only to assess the relative
importance of these factors but also to know whether they have an independent
effect. Both genital HPV and HIV are STIs and may interact, but the nature
of such interaction has not been determined. Most studies show an association
of HIV with HPV and SIL, but published data from Africa do not (yet) support
an increased risk of cervical cancer in women with HIV. However, prospective
studies show an association between HIV and persistent HPV, leading to possible
subsequent development of cervical dysplasia.9
CERVICAL CYTOLOGY SCREENING
Cervical cytology is considered to be a very specific test for
high-grade precancerous lesions or cancer. Even if the quality of collection
and smearing of cells, fixation and staining of smears, and reporting by well-trained
technicians and cytopathologists is good, its sensitivity of around 60% is
still relatively moderate.5,10 A high screening frequency is then
needed to detect a missed high grade lesion during the subsequent rounds, and
a screening frequency of once every one to five years has considerable cost
and resource implications. Women found to have low grade lesions typically
are asked to return for a follow-up smear every six months so that progression
or regression of the abnormality can be monitored. Women who have a high grade
lesion are then evaluated using a colposcope and biopsy to confirm diagnosis
before treatment is initiated. Colposcopy services in low resource settings
are often insufficient to meet the demand. Furthermore, colposcopes may not
always function properly, they are expensive and not easy to repair or replace.
Follow-up is often problematic due, for example, to transportation difficulties
of specimen; long delays between screening, diagnosis and treatment; inability
to contact women with abnormal cytology results; and difficulty in convincing
women of the need for further evaluation and treatment.
Data on demand and acceptability of cervical cytology screening programmes
are rare. A South African anthropological study found that the common perception
is that a cervical smear is primarily diagnostic and not preventative. The
general perception that cancer of the "womb"
is inevitably fatal also made this a powerful disincentive to be screened for
many women.11 Few women in a study
in Kenya were aware that early diagnosis and treatment of pre-cancerous lesions
greatly improve the probability of a successful cure and prevention of cancer.12 Often,
limited information is provided to women and as a result they may have wrong
perceptions. In addition, there might be cultural barriers including fear of
pelvic examinations, and there is the issue of general accessibility and quality
of health care services including routine gynaecological care. It is common
to find clinics that are without trained personnel and laboratories. They may
also not have fresh water, electricity, slides, spatulas and many of the other
basics that are necessary for cytology-based screening programmes.13
Cytology Alternatives
Several recent studies have demonstrated that direct visual inspection
of the cervix with acetic acid 3B5% (VIA)
is a reliable, reasonably sensitive and cost-effective alternative to cytology
screening.10,14,15 VIA using magnification devices and visual inspection
after the application of Lugol's iodine are being investigated.16 It
requires a lower level of infrastructure and provides immediate results and
possibility to treat immediately. However, the relatively low specificity,
possibly related to high prevalence of STIs, is a problem with danger of over-treatment.17 Another
unknown factor is how well VIA performs when genital schistosomiasis is prevalent.
Standardised initial training and continuing education programmes including
supervision and mechanisms for quality control will need to be developed if
wide scale VIA screening is to be introduced. There is also no study yet showing
that a VIA screening programme reduces cervical cancer incidence and mortality.
HPV DNA testing of health worker obtained cervical samples has sensitivity
for detection of high grade lesions or cervical cancer that is equivalent or
superior to that of cytology. A recent South African survey indicated that
HPV testing of self-administered vaginal swabs was as sensitive as cytology
screening for detecting high grade cervical disease in women aged 35 years
and above.18 HPV detection in urine specimens is another promising
method removing the obstacle on the need for a gynaecological examination.19
HPV DNA testing is also not (yet) cheap. Theoretically, the polymerase chain
reaction (PCR) needed is not a difficult technique and generates large amounts
of target DNA by using known oligonucleotide primers and heat stable DNA polymerase. It
is a very sensitive technique, which is also its drawback. Contamination of
specimens in the laboratory can be a major problem, hence the need to use positive
and negative controls. The sensitivity of PCR throws up another problem: minute
quantities of viral DNA can be detected. Is a positive result for high-risk
HPV based on a tiny amount of DNA as clinically significant as a positive result
from a larger amount of DNA remains an unanswered question.
As with VIA, HPV testing also has the disadvantage of relatively low specificity
compared to cytology.17 Studies are needed to evaluate carefully
the medical and programmatic side effect of over-treating significant numbers
of women without cervical disease and the efficacy of outpatient modalities
when performed by mid level health care workers in the absence of colposcopic
guidance in a low resource setting. Moreover, to determine the comparative
cost-effectiveness of the different screening tests and approaches in reducing
mortality from cervical cancer in low resource settings, formal cost-effective
modelling using country-specific costs needs to be performed.10
What should not be forgotten is that health education and promotion, as well
as behavioural change programmes directed at HIV and other STIs might equally
prevent cervical cancer, although the evidence is inconclusive.20, 21
Treatment
For cervical cancer screening to result in reduced morbidity
and mortality, effective treatment and/or follow-up must also be available.
In many resource poor settings, the only treatments available at present are
cold knife cone biopsy and hysterectomy. Use of these methods certainly results
in severe over-treatment of many women. They are associated with significant
complications and side effects and require significant infrastructural support
for anaesthesia, equipment and in-patient care, and they are costly. Of interest
for use in low resource settings (due to their effectiveness, low incidence
of side effects, low cost, lack of requirement for general anaesthesia and
relatively technical simplicity) are loop electrosurgical excision procedure
(LEEP) and cryotherapy. Cryotherapy destroys ab normal cells by using
a low temperature probe (- 600 to -900C) to
freeze the transformation zone. Liquid nitrogen or carbon dioxide are the most
commonly used refrigerants because they produce sufficiently low temperatures
and are readily available and inexpensive, particularly carbon dioxide. Cryotherapy
causes virtually no bleeding and little or no pain. A recent study from rural
Thailand showed that a single visit approach with VIA and immediate
cryotherapy appears safe, acceptable and feasible.22 The most common
side effect of cryotherapy is profuse watery discharge for 2-3 weeks, and women are at risk for infection until
the epithelium is completely healed. Another disadvantage of cryotherapy is
that a specimen is not obtained for histological evaluation. The disadvantages
of LEEP or excision of the epithelium with cauterisation are the requirements
for electricity, the higher costs along with the technical expertise required
compared to cryotherapy, and the risk of bleeding complications. Studies are
needed to establish the efficacy of cryotherapy and LEEP when performed without
colposcopy.
Vaccines
Given the long record of viral vaccines as a cost-effective
approach to preventing life-threatening infections, an effective vaccine directed
against the major oncogenic HPV types could have tremendous impact on the global
cervical cancer burden, particularly if made available to developing countries.
In many developing countries, it has been difficult to establish and maintain
effective screening programmes. On the other hand, these countries have, in
many instances, developed comprehensive vaccination programmes, which, with
appropriate adjustments, could prove to be instrumental in cervical cancer
prevention .
There is growing consensus that a safe, effective and accessible prophylactic
and possibly curative HPV vaccine will offer the best solution to significantly
reduce cervical cancer mortality especially in resource poor countries. There
is consensus that virus-like particles (VLP) are the immunogens of choice for
prophylactic vaccines.23 Recombinant viral L1 capsid protein from
HPV, which contains no viral DNA and is therefore non-infectious and safe,
forms virus-like particles. VLPs stimulate the production of antibodies that
bind and neutralise the infectious virus, and studies in animal models indicate
that protection induced by prophylactic immunisation is efficacious, long-lasting
and type-specific. Human trials with L1 VLPs have shown safety, excellent tolerability
and high immunogenicity. A recent randomised controlled trial of a HPV type
16 VLP vaccine reduced the incidence of both HPV-16 infection and HPV-16 related
CIN.24 However, vaccine candidates currently under evaluation are
mainly targeting HPV types 16 and 18, which account for the majority of cancer
cases in industrialised countries. Limited epidemiological data available
suggest that a much wider variety of HPV types are involved in the pathogenesis
of cervical neoplasia in developing countries.25-28 All these HPV
types must be considered for the development of multivalent vaccine preparations
capable of inducing an immune response to a variety of HPV vaccines. As this
is unlikely to be very profitable, public sector commitment and spending are
needed. The fact that HPV infection is a sexually transmitted infection may
pose an obstacle to the acceptance of a prophylactic HPV vaccine. Positioning
an STI vaccine raises sensitive social issues especially when it will be targeted
at adolescents to ensure protection before the onset of sexual activity. Meanwhile,
effective HPV vaccines are not yet available, and if they are developed the
initial impact of prophylactic HPV vaccines will be delayed for ten
or twenty years, while the existing infections continue to progress to cancer .
CONCLUSION
Prevention of cervical cancer in Africa seems daunting, even
overwhelming, but the scale of the problem means we cannot ignore it. Instead,
a practical and pragmatic strategy is required.
There are several approaches to cervical cancer prevention, and only their
comprehensive and coordinated evaluation will deliver short and long-term public
health benefits in different programme settings. Cytology-based screening programmes
for cervical cancer have not been a success; they are difficult
to initiate and perhaps even more difficult to maintain. The choice of a screening
test in countries that plan to initiate new programmes should be based on the
comparative performance characteristics of the test, costs, technical requirements,
the laboratory and local health infrastructure, and awareness and perceptions
within the community. In very resource poor countries, of which there are many
in Africa, this might lead to a minimum package of a one-visit strategy of
VIA with immediate cryotherapy treatment once in a lifetime, e.g., in the high
risk age group of women between 35 and 50 years. This strategy ign ores
the low specificity of VIA and accepts over-treatment. However, advocates
of this approach will point out that cytological and colposcopic services are
unlikely to become available in many resource poor settings in the foreseeable
future. They also believe that invasive cervical cancer represents a serious
health problem for women, which needs to be dealt with immediately. The development
and testing of the efficacy and effectiveness of vaccines directed against
the major oncogenic HPV types for cervical cancer in Africa has high priority.
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