Postgraduate Training Course in Reproductive Health 2004

Cervical cancer control in developing countries

See also presentation

Abstract

There are an estimated 500,000 cases of cervical cancer every year worldwide, of which 80% occur in developing countries (1). About 300,000 women die anually, 80% are from developing countries. The objective of this paper is to review the epidemiology , preventive measures and treatment of cervical cancer in developing countries. The review was done by using database from various resourses such as PUBMED, MEDLINE, ONCOLOGY.
The etiology of cervical cancer is not well known, however there is a link between cervical cancer and infections such as HPV, Chlamydia and other chronic cervical infections. Organised screening services have contributed much to the decline of cervical cancer incidence and mortality over the past 50 years. However, women in developing countries are yet to profit extensively from the benefits of screening programs, and recent trends show a resurgence of the disease in developed countries. The past 2 decades have witnessed substantial progress in our understanding of the natural history of cervical cancer and in major treatment advances. Human papillomavirus (HPV) infection is now recognized as the main cause of cervical cancer, the role of co-existing factors is better understood, a new cytology reporting terminology has improved diagnosis and management of precursor lesions, and specific treatment protocols have increased survival among patients with early and advanced disease. Current research has focused on the determinants of infection with oncogenic HPV types, the assessment of prophylactic and therapeutic vaccines and the development of screening strategies incorporating HPV testing and other methods as adjunct to cytology. These are fundamental stepping stones for the implementation of effective public health programs aimed at the control of cervical cancer. Pap smear revealed sensitivity and specificity of 51% and 98%, respectively. Other screening procedures such as VIA and VIAM (with or without) biopsy revealed sensitivity  of up to 96% and specificity up to 97%.It was concluded that VIA /VIAM has almost similar sensituivity to that of cervical cytology, so  VIA may be an effective screening method in developing countries

Introduction

The cervix is the lower portion of the uterus that connects the uterus to the vagina. The opening of the cervix remains small except during labor when it expands to allow the baby to pass from the uterus to the vagina. Cervical cancer occurs when cells in the cervix grow erratically and multiply out of control. As with other types of cancer, it often takes years for cervical cancer to develop. First, normal cervical cells change into pre-cancerous cells. Pre-cancerous abnormalities progress without symptoms and if left untreated, they eventually progress into cancer. When cervical abnormalities are detected and treated during pre-cancerous stages, cervical cancer is preventable.

The etiology of cervical cancer is not well known, however there is a link between cervical cancer and infections such as HPV, Chlamydia and other chronic cervical infections.

The Pap smear which was developed by Papanicolaou in 1943 has been a gold standard for the detection of pre-cancerous lesions of the cervix. In developing countries naked eye visual inspection of the cervix (VIA) and with magnification (VIAM) will likely reduce the high morbidity and mortality associated with cervical cancer. VIA can be easily performed even by a well trained nurse in a village level where there is a health care facility.

By doing so cervical cancer will be prevented as all pre-cancerous lesions will be treated by simple methods such as cryotherapy, LEEP or cervical conisation. In addition, screening will increase the number of women seeking treatment for cervical cancer earlier, as the lesions will be early detected.

When detected early, the five-year survival rate for cervical cancer is approximately 92%. If cervical cancer is detected before it has invaded any surrounding tissues, the five-year survival rate is nearly 100%. Therefore, it is very important that all women begin receiving yearly screening and pelvic examinations at age 18 or when they first become sexually active, whichever occurs earlier.

Objectives

The objectives of this paper are:

• To do a literature review on epidemiology of cervical cancer in developing countries
• To review different screening methods and to find which of them will be appropriate to the developing countries
• To review the management of pre-cancerous lesions and cervical cancer

Methodology

The literature review was done by electronically searching PUBMED, MEDLINE, RHO-ORG, Oncolink, Cochrane library and a general web search, and manual search at the WHO and the Geneva Medical school library.

For the electronic search the following key words were used:

• Epidemiology of cervical cancer
• Cervical cancer
• Cervical cancer screening
• Cervical Neoplasm

References related to the following topics were reviewed:

• The epidemiology of cervical cancer
• Screening procedures and diagnosis of cervical cancer
• Screening in low resource setting
• Management of pre-cancerous lesions and cervical cancer
• The roll of vaccines to prevent HPV infection

Discussion

The findings are discussed under different subtitles below:

Epidemiology

Early epidemiological data demonstrated a direct causal relationship between cervical cancer and sexual activity. Major risk factors observed include sex at a young age, multiple sexual partners, promiscuous male partners and history of sexually transmitted diseases such as chlamydia trachomatis(2). However, the search for a potential sexually transmitted carcinogen had been unsuccessful until the last decade, when a breakthrough in molecular biology enabled scientists to detect viral genomes in cervical cells. Strong evidence now implicates human papilloma viruses (HPVs) as prime suspects, The commonest HPV types are HPV 16 and HPV 18. More than 80% of squamous intraepithelial lesions (SILs) and invasive cervical cancers are associated with previous HPV infection (3,4)
HPV is the most prevalent sexually transmitted infection in the world and it affects almost 75% of sexually active women (8,9). After aquiring the infection it can take up to 20 years for the development of cervical cancer. From this review it is obvious that the progression of cellular changes after HPV infection is as well associated with some factors that play a major role in the formation of cervical cancer. These factors include early-onset of sexual intercourse and change of partners (multiple partners), increases the risk to aquire any sexually transmited infection (9). Persistant HPV infection is one of the factors for the development of cervical cancer (5) as well as a positive family history (10).
Other factors that play a role in the development of cervical cancer inlude smoking (11), long term use of combined oral contraceptives and prolonged use of corticosteroids (12,13). Long term use of corticosteroids leeds to supression of the immune system.
Currently, there is an association between HPV and HIV infection in the development of CIN lesions and cervical cancer (4). Some studies showed that the incidence of HPV-related dysplasia increases as immune function declines in HIV-positive women. Cross-sectional and longitudinal samples of HIV-positive women demonstrate that both rates of HPV infection and high-grade dysplasia increase as CD4 counts lower (7,8).

Prevention of cervical cancer

As mentioned above, HPV is the most prevalent sexually transmitted infection in the world. And, unlike other STIs such as gonorrhea or HIV/AIDS, the use of condoms and other safe-sex practices may not be nearly as effective in preventing this infection. This is because the papilloma virus lives in the skin (squamous) cells covering the pubic area (vulva and shaft of the penis) as well as the interior cells lining the vagina and cervix in women, and urethra and anus in both sexes. Condoms do not cover the entire shaft of the penis nor do they block contact with pubic skin. Therefore, during intercourse, even with a condom, skin cells containing HPV can come in contact with a woman’s vulva or vagina, enabling the virus ultimately to reach the cervix. In addition, the friction during sexual intercourse is believed to cause tiny tears in the vaginal wall, making transmission far more likely. Moreover, even dead cells shed during intercourse can contain the virus and remain infective for days.

The prevention of cervical cancer can be primary or secondary

Primary prevention

Cervical cancer can be prevented by avoiding cigarette smoking, long term use of combined oral contraceptives and early sexual intercose (14).
As far as the disease is much associated with high-risk HPV infection, the step forward is to develop an effective vaccine for primary prevention and if possible for treatment of cervical cancer. Currently, a profilactic vaccine is under development focusing on the induction of effective humoral and cellular-immune responses that are protective against HPVinfection (15,16).

Secondary prevention

This can be achieved by early detection and treatment of cervical pre-cancerous lesions.

Screening

Screening appears to be one of the most preventive measures for cervical cancer, unfortunately in developing countries it is still difficult to do massive cervical screening.

To date, cervical cancer prevention efforts world  wide have focused on screening at-risk women using Pap smears or Visual inspection with acetic acid (VIA/ VIAM), with lugol`s iodine (VILI) and treating precancerous lesions.

Pap smear

This method includes the collection of cervical specimen using cytobrushes or spatulae (wooden or plastic). The specimen is smeared on a glass slide and fixed immediately with alcohol. The introduction of this method has been associated with a 70% decrease of cervical cancer deaths (22). Currently, a liquid based preparation method is introduced in order to increase the sensitivity of the Pap smear. The work in 3 different laboratories in Europe revealed an increase in detection of LSIL by 59% and HSIL by 78.9%;  the rate of detection of ASCUS was reduced to almost 43.4% (23)

Interpretation of Pap smear

In 1943, Papanicolaou described 5 classes of cellular changes in exfoliated cells of the cervix (17) (Table 1). This original classification has been modified into another classification in the 1980s, whereby the British Society of Clinical Cytology (BSCC) introduced a new system of classification. In this system, the term ‘dyscariosis’ was employed and sub-devided into three groups. These correlated with the histological grades of CIN I, II and III (18) (table2). The modification of cytological reporting went on further and in 1988, the national Cancer Institute of America came with a new system – the Bethesda system - for reporting cervical and vaginal cytology (20).  In 1991, the national cancer institute reconvened another workshop and the report was published in the Journal of the American Medical Association in 1992 (20) and in a monographin 1994 (21). In most laboratories in the world, cytological specimens are reported as follows:

• within normal limits:

  • atypical squamous cells cells of undetermined significance (ASCUS)

• cellular changes suggestive of :

  • Low-grade Squamous Intraepithelial Lesion (LSIL)

  • High-grade Squamous Intraepithelial Lesion (HSIL)

Visual inspection with acetic acid

Given the difficulty of ensuring high quality cytology-based services in many settings, there is significant interest in new, simpler approaches for dysplasia screening. Of these, visual inspection of the cervix appears to be a promising option, especially for low-resource settings.  Visual inspection the cervix after application of 4%-8% acetic acid (vinegar) solution highlights pre-cancerous cellular changes by turning them white.  Many comparative studies have been done which suggest that VIA is as effective as cytology in early detection of cervical neoplasia. In 1998 Sankaranarayan R, et al (24) published the reslts of  the 3,000 women in the study, 298 (9.9%) were positive on VIA, 307 (10.2%) had atypia or dysplasia on Pap smears, and 182 (6.1%) were positive on both VIA and cytology. An additional 215 women (7.2%) were referred to colposcopy because they were identified as having an abnormal cervix on speculum exam, although they were negative on VIA and Pap. Of the 51 true positive cases, VIA detected 46 (90.1%) and cytology 44 (86.2%). The approximate specificities were 92.2 percent for VIA and 91.3 percent for cytology. The authors conclude that if VIA continues to show satisfactory results, this technique is likely to be useful in developing countries where it is not feasible to introduce cytology screening and in developed countries as an adjunct to improve sensitivity of cervical cytology. 

In a study conducted between January 1996 and December 1999, Tayyeb et al (25) 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 was 93.9% and of Pap smear was 46.9%. Corresponding specificities were 30.4% and 69.5%. The author concluded that the results indicate that VIA is more sensitive and has a higher accuracy as compared to Pap smear. It could, therefore, be valuable in detection of precancerous lesions of cervix. Low cost, easy applicability and immediate results make VIA a useful screening test in developing countries like Pakistan as compared to Pap smear.
In 1999,the University of Zimbabwe and JHPIEGO (26) published the results of their project involving 10  934 clients and it was found that VIA was more sensitive but less specific than cytology. The sensitivity for VIA was 76.7% (95% Cl.70.3-82.3) and for cytology was 44.3% (95%Cl,37.3-51.4). The specificity for VIA was less than that of cytology (64.1% versus 90.6%)

Aided visual inspection with acetic acid (VIAM)

This approach uses a low-power (4x-6x), hand-held visual inspection device (an AviScope), with a built-in light source, or the doctor uses a colposcope, which is a special type of microscope designed to look closely at the cervix, to detect areas of abnormal cells. Normally this procedure follows VIA, that is after application of acetic acid.

Singh V et al (27) reported the findings of aided visual inspection using 5% acetic acid and of cytology evaluated among 402 women against colposcopic findings and/or histologic reports. The sensitivity of cytology (75.3%) was higher compared to that of acetic acid application (52.0%) for mild dysplasias. On the other hand, the sensitivity for detecting moderate dysplasia was 78% for cytology and 81.6% for acetic acid; for severe dysplasia/carcinoma in-situ it was 73.3% for cytology and 86.7% for acetic acid. For invasive cancer, the sensitivity for acetic acid application and cytology (95% for both modalities) was comparable. The specificity of cytology (99%) was higher compared to that of acetic acid application (94.3%). The false positive rate for cytology was 1.0% as against 5.7% for acetic acid application. The results of acetic acid application also showed a remarkable improvement in the sensitivity of unaided visual inspection for early cancerous lesion which was about 60% for early cancerous lesion and only 12% for mild dysplastic and 20% for moderate and severe dysplastic lesions in our earlier experience. It also reduced the false positive rates from 12% by unaided visual inspection to 5.7% by acetic acid application.

Visual inspection with Lugol`s iodine (VILI) or Schiller`s test

Immediately after VIA, the iodine solution is applied over the cervix, areas of healthy tissue will stain brown (mahogany brown) while areas of abnormal cells would turn white or yellow. In case of immature squamous metapalasia, there will be a partial iodine uptake (28).The application of acetic acid or iodine highlights the area with abnormalities and enables the clinician to take biopsies in the affected area of the cervical epithelium.

Diagnosis (Histological)

The diagnosis of cervical cancer is usually confirmed by histopathological examination of a tissue from the lesion.The following are some of the methods used by doctors to diagnose cervical cancer (28).

• Biopsy :This is a simple procedure whereby a tissue sample is taken from the cervix and examined by a histopathologist under a microscope.

• Endocervical curettage (ECC):  In this procedure, a spoon-shaped instrument called curette is used to scrape tissue from the area within the opening of the cervix, which cannot be seen during  colposcopy.

Management of pre-cancerous lesions (Secondary prevention)

For the various pre-cancerous conditions of the cervix, treatment usually includes methods in which the area of abnormal tissue (usually the outer-most layer) is cut off or directly destroyed using some of the following methods (28):

·Cryosurgery (cryotherapy)
This is a simple procedure that does not require anaesthesia, where an instrument is used to freeze the outer layer of cervical tissue, thus destroying the area of abnormal cells. Usually it is recommended to clients with CIN I & CIN II lesions involving less than 75% of the transformation zone, and if the lesion does not extend into the endocervix.

Cauterization
This is a procedure similar to cryosurgery, except instead of freezing the outer layer of the cervix, the abnormal cells are killed by burning them with a very "hot" instrument.

Laser surgery
In this procedure, the area of abnormal tissue is cut off and/or destroyed by directly pointing an intense, beam of light. As in cryosurgery or cauterisation, the use of anaesthetics may not be necessary

LEEP or electrosurgical excision procedure
In this treatment method, an electric wire loop is used to slice off a thin layer of outer tissue from the cervix. This tissue will then be viewed under a microscope to determine whether it is cancerous or not. In most women, there is no need for further treatment after this procedure, provided the tissue removed is abnormal but not cancerous. The LEEPprocedure is quick and simple because it is done under local anaesthesia.

Conization
This procedure, otherwise known as cone biopsy, consists of removing a deeper sample of tissue from the cervix. The sample will be examined by a pathologist under a microscope to detect the presence of abnormal cells in deeper layers of the cervix. Sometimes the surgeon may remove an entire area of tissue, making it a viable treatment of pre-cancerous lesions. Since the procedure can be a bit painful, it does require the use of local or general anaesthesia. In many centres pre-cancerous lesions are managed using cryotherapy or LEEP (Table 3). Cryotherapy is preferred to LEEP as it can be performed even in a remote area where there is no electric power. Olatunbosun (29)  published the results of a study of 73 women diagnosed with CIN treated by cryosurgery. After a five-year follow-up period, the cure rate was 90 percent, excluding 22 women lost to follow-up. The authors characterized these results as comparable with those reported for other destructive methods and recommended cryosurgery as a simple, low-cost, outpatient treatment approach, without serious side-effects or effects on pregnancy outcome.  They emphasized, however, the importance of proper pre-treatment evaluation and the need for long-term follow-up of patients. They also recommended against the use of cryosurgery for CIN with glandular involvement, given its limited depth of destruction.

Treatment of cervical cancer (tertiary prevention)

In developing countries, the treatment of cervical cancer is a very big problem, some countries do not have the units or hospitals where cancer patients can be treated, other countries have either one or two units, and most of the patients cannot afford the travel costs to reach the places. Not only that but olso in some countries the treatment of cervical cancer is so expensive, and many poor women can not afford and die without treatment. Normally the treatment of cervical cancer varies with the stage of the disease (30). For early invasive cancer, surgery is the treatment of choice. In more advanced cases, radiation combined with chemotherapy is the current standard of care. In-patients with disseminated disease, chemotherapy or radiation provides symptom palliation.

Treatment of stage 0 ( carcinoma in situ)
Carcinoma in situ is treated with local ablative measures such as cryosurgery, laser ablation, and loop excision (30, 31,32). Hysterectomy should be reserved for patients with other gynaecologic indications to justify the procedure.
The 5-year survival rate after treatment is 90%-100%.

Stage 1A
The standard treatment for microinvasive disease is total hysterectomy.  Lymph node dissection is not required if the depth of invasion is less than 3 mm and no lymphovascular invasion is noted. Selected patients with stage IA disease but no lympho-vascular space invasion who desire to maintain fertility may have a therapeutic conization with close follow-up, including cytology, colposcopy and endocervical curettage.  Patients with medical comorbidities who are not surgical candidates can be successfully treated with radiation.
The 5 year survival rate is 90%-100%.  

Stage IB or IIA
For patients with stage IB or IIA disease, treatment options are either combined external beam radiation with brachytherapy or radical hysterectomy with bilateral pelvic lymphadenectomy. Most retrospective studies have shown equivalent survival rates for both procedures, although such studies usually are flawed due to patient selection bias and other factors. However, a recent randomised study showed identical overall and disease-free survival rates. Postoperative radiation to the pelvis decreases the risk of local recurrence in patients with high-risk factors.  A recent randomised trial showed that patients with parametrical involvement, positive pelvic nodes, or positive surgical margins benefit from a postoperative combination of cisplatin-containing chemotherapy and pelvic radiation.
The 5 year surveillance rate is 80%-90%

Stage IIB-IVA
For locally advanced cervical carcinoma (stages IIB, III, and IVA), radiation therapy traditionally has been the treatment of choice. Treatment begins with a course of external beam radiation to reduce the tumour mass and enable subsequent intracavitary application. Brachytherapy is delivered using afterloading applicators that are placed in the uterine cavity and vagina.  For treatment with radiation alone, 5-year survival rates reportedly are 65- 75%, 35-50%, and 15-20% for stages IIB, III, and IVA, respectively.

Combined chemotherapy plus radiation therapy for cervical cancer
Recently, the report of 3 well-conducted studies of concurrent chemoradiation has changed the standard of care in this group of patients. In the Radiation Therapy Oncology Group trial, 403 patients with bulky IB and IIB-IVA cancers were randomised to either radiotherapy to a pelvic and paraaortic field or pelvic radiation with concurrent cisplatin and fluorouracil. Rates of both disease-free survival and overall survival were significantly higher in the group that received combination treatment.

The treatment for disseminated cervical cancer primarily is palliative in nature because cure is not possible:
Chemotherapy with single agents such as cisplatin or isofosfamide results in response rates of approximately 20%. Combination regimens have higher response rates and can prolong disease-free survival. However, toxicity is increased and no survival advantage is gained. In addition, the duration of response is usuallyshort. Palliative radiation is often used individually to control bleeding, pelvic pain, or urinary or partial large bowel obstructions from pelvic disease. Invasive procedures such as nephrostomy or diverting colostomy sometimes are performed in this group of patients to improve their quality of life. Special effort should be made to ensure comprehensive palliative care, including adequate pain control for these patients.

Future Directions

There are a number of exciting new developments that may help to improve the prevention of cervical cancer. Some of them include educational efforts that encourage behavioural changes to prevent infection; development of a vaccine against HPV; and testing for HPV during screening efforts.

• In order to prevent the disease we need to recommend on the following things:
• More educational efforts should be directed toward adolescents and health care providers regarding the strong causal link between acquisition of HPV as a sexually transmitted disease and development of cervical cancer and its precursors.
• Delay of the onset of sexual intercourse and the use of barrier methods of contraception in the sexually active women.
• Development of an effective prophylactic vaccine against HPV.

Although experimental animal studies have demonstrated that vaccination against HPV is possible, many conceptual issues must be addressed before the vaccines are available for clinical trials. In addition to the construction of the vaccine, issues such as the immune response following vaccination and the selection of target populations will be complex to resolve. Some clinical trials have used vaccines as part of a therapeutic regimen, but none have used it as primary prevention.

Conclusion

In this review, cervical cancer is considered to be a preventable and treatable disease, and is one of the most common malignancies in women worldwide and 80% of all newly diagnosed women are from developing countries.  Aided visual inspection after application of acetic acid (VIAM) and Lugol`s iodine (VILI) is an effective screening method in developing countries, and treatment of pre-cancerous lesions  by cryotherapy plays a major role in preventing the development of cervical cancer. Not only that, but also it can be learned and performed by trained nurses and midwives.

As a recommendation, the Governments of the developing countries should help to implement screening programs using simple methods (cheaper and sustainable). Governments should introduce or initiate reproductive health programs to young people so as to educate them on safe behaviour such as safe sex which will reduce the incidence of sexually transmitted infections including HPV.

Acknowledgement

I would like to thank the course organisers of the Geneva Foundation for Medical Education and Research, Professor Campana and his team, my sponsors IAMANEH who helped me to attend this wonderful training. I am grateful to all the teachers who worked hard using even their spare time to teach me and answer my questions whenever I was in need. My special thanks to Dr. Vassilakos- my tutor  for supervising me to perform this work.

Table 1. Classification of Pap test

Table 2. CIN classification

Table 3. Two treatment options for Pre-cancerous lesions

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Edited by Aldo Campana,