Cost effective approach to prevent Cervical cancer in developing countries –A Reveiw

Cervical cancer can be treated effectively if diagnosed early.Although there are lot of screening methods like colposcopy, Pap Smear etc, but because of th…

The magnitude of cancer in the world is increasing day by day. Cancer in all forms is causing about 12% deaths throughout the world. In the developed world it ranks third in the cause of death; it accounts for 9.5% of all deaths. It strikes people of all ages, socio-economic status, ethnic background, personal habits, occupation and personal or family history of cancer and pre-cancerous conditions1. Cervical cancer is the seventh most common cancer, and in women it comprises 12% of all cancers. Globally, cancer cervix is the second most common cancer in women following breast cancer. Annual incidence of cervical cancer in world is 16 per million/year2.

In Asia highest average annual ASR and MR is found in South central Asia with average ASR and MR of 26.2 per million/year and 15 per million/year respectively. Lowest ASR and MR is found in Western Asia (5.8 per million/year and 2.9 per million/year respectively). Cambodia and India has highest ASR and MR of cervical cancer in whole Asia (38.7 and 21.6 and 30.7 and17.8 per million/year respectively) 3.

In India Cervical cancer is the most common malignancy affecting female population. An estimated 132 thousand new cases, or more than one-fourth of the worldwide total, are reported annually4. The estimated number of women diagnosed with cancer each year is 3,000,000 of women. Among them approximately one third have cervical cancer. According to the data compiled by Indian council of Medical Research (2005) from the cancer registries cervical cancer ranks first among cancers in women5 .

Health care providers in developing countries regularly see women with advanced, incurable cervical cancer. At this late stage, there is little they can do to save women’s lives. Even drugs designed to ease cancer pain often are unavailable. Cervical cancer can be readily prevented, even in women at high risk for the disease, through screening and treatment using relatively simple technologies. When precancerous changes in cervical tissue are found and the abnormal tissue successfully treated, a woman will not develop cancer.

Early detection of cases can be done through screening. Screening women for precancerous changes and treating the abnormal tissue protect women from developing cervical cancer. The aim of screening is to detect and treat those people identified as having early signs of the disease, usually by means of an inexpensive, accurate, and reliable test that can be applied widely.

Cytology is the accepted method for screening of early stages of carcinoma of the uterine cervix all over the world. One of the reason for lack of effective screening is that the favored screening technique of Pap smear requires technical capabilities, system for transportation, follow up and training that is beyond the capability of health care infrastructure in most of the developing countries. It is a major reason for the sharply higher cervical cancer rates in developing countries. Pap smear programs are complex and costly to run and have failed to reach a significant proportion of women in countries where health systems and infrastructure are poor 6.

Health care practitioners in low-resource settings often report a lack of infrastructure providing such facilities, a situation that makes cytology programs ineffective. This preventable disease kills an estimated 274,000 women every year, affecting the poorest and most vulnerable4.

Cheaper cervical cancer screening methods are evaluated for implementation at Primary Care level in low resource settings like India. Few alternatives to cervical cytology are:-

1. Visual inspection with acetic acid (VIA)

2.Visual inspection with lugols Iodine

Even though cytology screening may be feasible in middle-income countries. There are technical, human resource and financial constraints in implementing such programmes in low-income countries. In view of this, Sankaranarayanan, G and Cullin investigated alternative methods based on visual examination of the cervix for the control of cervical cancer in low-resource settings7,8,9.

 

Visual inspection with acetic acid (VIA) is a more promising visual screening approach. It is also known as direct visual inspection (DVI) or aided visual inspection or cervicoscopy. VIA first described by Ottaviano and La Torre in 1981.It involves naked eye examination of the 3-5% acetic-acid swabbed uterine cervix without any magnification with illumination provided by a bright light source to identify acetowhite lesions. A positive test is the detection of well-defined, dull acetowhite lesions on the cervix. The objective of VIA is to detect acetowhite lesions leading to the early diagnosis of high-grade cervical intraepithelial neoplasia and early preclinical, asymptomatic invasive cancer.

Aims and objective of this paper are to

Review effectiveness and  implementation of VIA

Evaluate VIA as cheap ,feasible and quick tool for cervical cancer screening tool.

PATHO- PHYSIOLOGY OF VIA

Application of 5% acetic acid is believed to cause a reversible coagulation, or precipitation of the cellular proteins. Its mucolytic property facilitates penetration into the cell wall, where cell protein coagulation occurs. The blood vessels become sharply delineated and individual cells swell up. This causes tissues to become opaque especially those which are metaplastic or dysplastic. The abnormal cells appear as white patches known as acetowhite patches.

The normal squamous epithelium appears pink and the columnar epithelium red, due to the reflection of light from the underlying stroma, which is rich in blood vessels. If the epithelium contains a lot of cellular proteins as in case of  cervical cancer, acetic acid coagulates these proteins, which may obliterate the colour of the stroma. The resulting acetowhitening is seen distinctly as compared with the normal pinkish colour of the surrounding normal squamous epithelium of the cervix, an effect that is commonly visible to the naked eye. Areas of increased nuclear activity and DNA content exhibit the most dramatic white colour change [IARC, 2005; WHO, 2005].

MATERAIL AND METHODS

An extensive review of articals related to visual inspection with acetic acid was done.Pubmed ,medscape sites were used and research articles from 1982 to 2006 were analysed and presented in paper.

RESULTS

Lot of studies have been conducted to assess the efficacy of VIA and it has been found that its sensitivity and specificity is comparable with pap smear. Main studies are listed below:-

Ottaviano and La Torre [Ottaviano and La Torre 1982] were first to describe VIA. They published study involving 2,400 women who were examined visually and colposcopically after a cervical wash with acetic acid. Visual inspection with acetic acid (VIA) identified 98.9% of the cases as normal (i.e., in 1,568 of 1,584 women diagnosed as normal by colposcopy) and concluded that “colposcopic magnification is not essential in clinical practice for the identification of the cervix ‘at risk'”10.

Slawson [Slawson et al 1992] found that VIA detected disease in approximately 64% of women who eventually had an abnormal biopsy, a very similar rate to what they found for the Pap smear (68%). In addition, as the investigator became more experienced, positive predictive value improved by almost 30%. Thus they concluded that “VIA is a safe, simple and effective adjunct to the Papanicolaou smear for cervical cancer screening. Various studies were conducted to compare the test characteristics of VIA and cervical cytology.Van Le [Van et al 1993] found that VIA resulted in an additional 15% of CIN cases being identified among cytology-negative women, but 40% of women with positive VIA underwent unnecessary colposcopy (false positives). Cecchini [Cecchini et al 1993] provided evidence on the accuracy of VIA. VIA was more sensitive than cytology, but less specific. Additionally, screening sequentially using VIA was more cost-effective than with cervicography11,12,13.

In  the other study by Megevand [Megevand et al 1996] in South Africa, in 2426 women, VIA detected 65% of high-grade squamous intraepithelial lesions (HSIL) confirmed by the reference standard14.

Londhe [Londhe et al 1996]  studied 372 women who underwent VIA, cytology and colposcopy in a gynecology outpatients clinic. VIA identified 78% of HSIL (and 1 cancer) diagnosed through colposcopy, 3.5 times more than those identified via cytology.Lodhe [Londhe et al 1997] conducted a prospective study to determine the accuracy of VIA for detection of CIN as compared to cytology using 3% acetic acid in 500 sexually active women visiting Gynecology OPD in CMCH,Vellore  also postulated that sensitivity of VIA (72.4%) was higher than pap smear (13.2%)  but was less specific (VIA was 54% as compared to Pap test  96.3%) .The false negative rate of VIA was much less (15%) than pap smear clearly depicting that VIA can miss less positive cases as compared to pap smear15.

In India Sankaranarayan [Sankaranarayan et al 1998] studied 3000 women in Kerala during 1996-1997 and women were recruited from women attending access clinics in outreaches of South Kerala, who had VIA and cytology provided by trained cytotechnicians. The sensitivities between two test i.e. VIA and cervical cytology was calculated and analyzed by Mc Nemar’s test. It was found that the performance of VIA was similar to cervical cytology with a sensitivity ratio of 1.05 in detecting low grade squamous intraepithelial lesions (LSIL) and HSIL. Specificity was less.  In a study conducted by same authors in 1999, in 1351 women in India, VIA detected more (P <0.001) LSIL and HSIL lesion than cytology but VIA was only 68% specific as compared to 90% of cytology. In this study, nurses were trained to provide VIA and all recruits were subjected to both VIA and conventional cytology16.

JHIPEGO [JHIPEGO ,1999] conducted a cross sectional study test in 15 primary clinics in Chitungwiza and greater Harea area comparing VIA and cytology performed by nurses on 10,000 women in primary health clinics was the first study to yield direct estimates of sensitivity and specificity. Univaraite analysis was done on questionnaire. Analysis of sensitivity and specificity and positive predictive was done by standard formula. The first phase of the study suffered from verification bias with only tenth women screened with a negative test result undergoing reference standard, colposcopy with or without biopsy. In second phase of the study 2203 women were referred to colposcopy thus avoiding verification bias. 4% acetic acid was used to perform VIA in the study. The sensitivity of VIA (for HSIL +) was 1.75 times than that of cytology (76.6% versus 44.3% respectively) whereas specificity was 1.4 times lower (64.1% and 90.6%) 17.

 

Denny [Denny et al 2000]studied the comparative performance of VIA, cytology and three other tests including human Papillomavirus (HPV) testing in South Africa in 2944 women, all performed in a primary health care clinic. VIA and HPV testing were similar to cytology in their ability to detect HSIL.VIA, however, yielded more false positives. The same authors in a subsequent study on 2754 women in South Africa compared VIA with and without magnification to cytology and found VIA to be similar to cervical cytology in terms of sensitivity (58.3 Vs 57.4% for cytology)  but less specific (83.5% Vs 96.3% for cervical cytology)18.

In a study conducted between January 1996 and December 1999 in Pakistan, Tayyeb [Tayyeb et al 2000] reported that out of 540 subjects, 356 were negative with both screening techniques. One hundred and fifty-six subjects were positive with VIA (28.9%) while Pap smear was positive in seventy-eight subjects (14.4%). The sensitivity of VIA (93.9%) was much higher than that of Pap smear (46.9%). Corresponding specificities were 30.4% and 69.5%19.

Basu [Basu et al 2003] studied 5881 eligible women who underwent VIA, VIAM, Cytology and Colposcopy. VIA detected 2.2 times CIN I as compared to   cytology (VIA 18.7 tested CIN I and cytology 8.2) and also concluded that VIA has and higher sensitivity than cytology20.

Claeys [Claeys et al,2003] also compared the performance of VIA and pap smear in Rivas district on 1076 patients, referring only positive patients for referral standard. The comparison was made by calculating relative true and false positive rates. The relative true positive rate RELTPR (VIA to Pap smear) was 1.96 and RELFPR was 5.02 and the ratio was 8.04 depicting that VIA detected twice as much as HSIL and invasive cancer as pap smear, but for high false positive rate they suggested to establish uniform criteria on test postivity21.

 

Ghaemmaghama [Ghaemmaghama et al, 2004] in a study on 1200 eligible women with colposcopy as reference standard and using 4% acetic acid to perform VIA reported high sensitivity and specificity of VIA (74.3% & 94% respectively) and comparable with that of cytology (72% & 90%). He inferred that , ” Use of VIA as a feasible method of screening where cytopathology is limited”22.

Shankarnarayanan [Shankarnarayanan et al 2004a] conducted a cluster randomized interventional trial in 113 village panchayats of Abillikai ,Dindingul district in South India to investigate the impact of single round of screening of VIA on cervical cancer incidence and mortality in 30,577 eligible women. Detection rate per 1000 screened were 8.2 for CIN I,7.3 for CIN II and  2.3 for invasive cancer which was 2-3 fold higher than observed in developed countries. He concluded that VIA is feasible, safe and acceptable in rural settings. Across sectional study was conducted by same author in nine centers in Africa  and  India from 1999-2003 in  Bamako (Mali), Brazzaville (Congo), Conakry Guinea),Jaipur (India) ,Kolkata (India) ,Mumbai ( India), Maimey (Niger) ,Ouagadougou (Burkistan) and Thrivanthapurum  (India).The sensitivity of VIA was 76.8% and specificity was 85.5%, positive predictive value was 9.4% and negative predictive value was 99.5%.They also reported high sensitivity of VIA as compared to cytology but specificity was lower 23,24.

Visual inspection with acetic acid can be performed reliably by trained paramedical workers and doctors. Bhatla [Bhatla  et al 2004] in a cross sectional study compared the test performance of VIA by a doctor and paramedical staff on 100 eligible women at AIIMS, India and concluded that although VIA by nurses had higher sensitivity (100% versus 87.5%) but lower specificity (53% versus 63%) when compared to doctors, but was stastically significant25.

Jeronimo [Jeronimo et al 2005] suggested that VIA can be used in well equipped health centre in Peru as an adjunct or alternative to cervical cytology. A prospective study on 1921 asymptomatic women was performed at a centre equipped with latest generation technology and high trained oncologists. Reference standard (Colposcopy and biopsy) was done only in positive cases and it was observed that positive predictive value of VIA (8.3% Vs 6.3%) was comparable to the convential cytology. Most importantly very few patients with a positive VIA were lost ( only 2.3 % ) to follow up before colposcopy, as compared to conventional cytology (26.3% of the women with a positive cytology)26.

In meta-analysis of three studies conducted by Shankarnarayanan [Shankarnarayanan et al 1999] comparing the ability of VIA, cytology and a number of other tests to identify precancerous lesions. VIA had a substantially higher area under the receiver operating curve (0.85) compared to cytology (0.70) in this study. In these studies reference standard which was colposcopy aided biopsy was done only in those who had positive findings in cervical cytology or positive VIA findings. These studies therefore suffered from verification bias27.

Another study was conducted by Belison [Belison et al 2001] in rural china on 1997 women. He performed the reference standard on all women and found that VIA had a 71% sensitivity and 74% specificity. Compared to cervical cytology, VIA was less specific and sensitive. The authors attributed this to high grade of cervicitis28.

Shankarnarayanan [Shankarnarayanan et al 2003a] indicated that VIA has an approximate sensitivity of 93.4% and specificity 85.1% to detect CIN from a pooled analysis of data from two studies29.

Gaffikin [Gaffikin 2003] meta analyzed eight studies and compared efficacy of Pap smear and VIA in cervical cancer screening. He concluded by saying that, “VIA performs as well as, if not better than Pap smear. Miller [Miller 2000] postulated that VIA appears to be the most promising low-technology alternative to cytology. VIA is currently being investigated for its efficacy in reducing incidence and mortality from cervical cancer30.

Cruze [Cruze et al 2005] studied role of VIA in cervical cancer screening in rural Mexictece region in Oxaca mexico in a randomized trial on 2240 women who were randomly allocated for VIA and VIAM and negative tests were referred to colposcopy and biopsy. Statistical analysis was done by Chi square test. They reported low sensitivity of VIA as compared to VIAM.VIAM had greater sensitivity (P>0.5%) but low specificity ( P < 0.5%)31.

Eftikhar [Eftikhar et al 2005] studied 100 VIA positive and 100 VIA negative selected randomly , using 5% acetic acid. Cytology, colposcopy and referral biopsy was done in all .The sensitivity and specificity was 95.7% and 44.1% respectively for VIA and 10% and 92% respectively for cytology and suggested that VIA can be used as a adjuvant to cervical cytology32.

The current level of evidence available for VIA as a screening test for cervical cancer and its precursors suggest that the test can be used for early detection to investigate symptomatic and high-risk women.

 DISCUSSION

The test performance of VIA suggests that it has similar sensitivity to that of cervical cytology in detecting CIN, but has lower specificity. Further research is required to improve its specificity without compromising sensitivity. Information from ongoing studies regarding its longitudinally-derived sensitivity, efficacy in reducing incidence/mortality from cervical cancer, its cost-effectiveness and safety will be useful in formulating public health policies to guide the organization of VIA-based mass population-based screening programmes in developing countries. A VIA-based screening programme requires a large infrastructure for investigation, treatment and follow-up of the positive screens. It is not known whether cost savings with a cheap test like VIA might be offset by the referral and investigation of a higher proportion of women. Since a programme based on VIA involves a certain level of over-treatment, the efficacy, safety and long-term consequences of such a programme also remain to be fully addressed. Thus, information from ongoing studies on these issues will be crucial in judging how appropriate and feasible it will be to introduce VIA-based cervical cancer screening programmes on a population-wide basis in low-income countries.

VIA good efficacy comparable with that of Pap smear.

CONCLUSION

The burden of cervical cancer is rising in the rural areas where resources and infrastructure is poor. Over and above women’s health is accorded low priority by the community delaying reporting of disease. VIA can be used as one technique that will  prove to be effective in other developing countries and in some centers of India as well. It can be the screening method of choice in the Indian rural setting as an alternative to cytology.

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