Advances in screening and treatment for cervical cancer

Cervical cancer has the fourth-highest mortality rate among cancers in women and is also the fourth most common cancer in women worldwide. Every seven minutes a woman in India dies from cervical cancer, resulting in over 75,000 deaths per year. India alone accounts for 20% of all cervical cancer cases worldwide. Telangana is ranked no. 3 for cervical cancer cases, after stomach cancer and breast cancer. Due to a lack of personal hygiene & routine screening programs, in both rural and urban population, women often seek care far too late when cancer has become invasive and is untreatable. “India could be cervical cancer-free by 2079 with accessible prevention programmes such as the human papillomavirus (HPV) vaccine and cervical screening more accessible,” Lancet Study.

At a Glance:

What is cervical cancer?

Cervical cancer is an abnormal growth of cells in the lining of the cervix or the cylinder-shaped neck of tissue that connects the vagina and uterus of a woman.

In most cases, cancer presents in the area of the cervix known as the transformation zone. However, it may also spread to neighboring tissues of the cervix like the vagina or even to the distant organs within the body, such as the liver or the lung. Cervical cancer is treatable and curable if detected early.

Why screening for cervical cancer is important in India?

India bears a significant burden of cervical cancer among women. Two major reasons for this high burden are:

• The inadequacy of effective screening coverage
• Lack of access to preventive therapy

Presumptive testing for the presence of pre-cancer or cancer among asymptomatic or apparently healthy women is called cervical cancer screening. Early detection of pre-cancerous lesions is beneficial since it is easier to treat it at this stage and even avoid cancer altogether. Early screening not only benefits in case of precancerous lesions but also helps in early detection of cancer in an early stage. Treatment of cancer in early stages is highly amenable to cure.

Precursor lesions which are otherwise invisible to the naked eye, lead to cancer of the cervix over a period of time. It is possible to diagnose these precursor lesions by a special investigation known as cervical cytology. The lesions progress in a slow manner, sometimes taking as long as 10 – 20 years before assuming an invasive form.

The World Health Organization (WHO) recommends that cervical cancer should be approached in an all-inclusive comprehensive way for its effective prevention and control. The strategy should include components of:

• Community education
• Social mobilization
• Vaccination
• Screening
• Treatment
• Palliative care

Vaccination of girls in the age group of 9-13 years against Human Papilloma Virus (HPV) at the onset of reproductive activity is the primary mode of prevention of cervical cancer. In addition to this, other recommended interventions for prevention include engaging young boys and girls for:

• Creating awareness and education of youngsters pertaining to the importance of safe sexual practices and delay the start of sexual activity
• Making available and promoting the use of condoms for sexually active individuals

• Creating awareness about the harmful effects of tobacco since it is an important risk factor for cervical cancer and youngsters often get habituated to it

• Male circumcision

Sexually active women should be screened for abnormal cervical cells and pre-cancerous lesions, starting from 30 years of age. Women between 30-49 years are at the highest risk of developing the disease, therefore should be targeted for screening.

If treatment is needed to excise abnormal cells or lesions, cryotherapy i.e destroying abnormal tissue on the cervix by freezing is recommended. If signs of cervical cancer are present, treatment options include surgery, radiotherapy and chemotherapy.

Precursor lesions of cervical cancer have been proven to be of a milder degree in case of younger women under 30 years of age. It has also been substantiated with evidence that these low-grade lesions revert back to normalcy after a certain period of time in such cases. On the other hand, this rate of reversal or regression to normalcy decreases in elderly women. The lesions in older women have a higher chance of progression to high-grade precursors and eventually to cervical cancer. The average age of patients with high-grade cervical cancer or squamous intraepithelial lesion (SIL) is around 30 years and the average timespan of the progression of the precursor lesions to cancer is approximately 10 years. A slow development period of the precursor gives an opportunity to diagnose the disease early.

Screening programmes can successfully achieve their aim by:

• Detecting and treating the pre-invasive stage of the disease to reduce the incidence of cancer
• Reducing the mortality and morbidity associated with cervical cancer
• Reducing healthcare costs with early diagnosis and treatment

What are cervical cell changes that are detected in cervical cancer screening?

Cells of the cervix, known as squamous cells and glandular cells appear abnormal on examination with a microscope in presence of precancerous changes. The abnormal changes within the cells of the cervical tissue even though not cancer may eventually lead to cancer.

Human papillomavirus (HPV) of certain types cause cervical cell changes. An association between cervical malignancy and HPV infection has been scientifically established. In more than 90% of cases of cervical squamous carcinomas, carcinomas in situ and adenocarcinoma HPV DNA is identified.

One of the major challenges with HPV is that it has a very hard structure making it stable and difficult to eliminate by sterilizing instruments. HPV also possesses a relatively high resistance to agents like ether and acids.

 Cervical cell changes are of two main types:

In many commonly identified cervical precancerous lesions, the abnormal changes are noticed in the squamous cells and the glandular cells.

The Bethesda system is a newer type of classification wherein, the precursors are termed as squamous intra-epithelial lesions (SIL). These are further divided into two different types, namely the low-grade SIL that is similar to Cervical intraepithelial neoplasia (CIN I) and the high-grade SIL similar to Cervical intraepithelial neoplasia (CIN II and CIN III).

High-grade abnormalities usually do not cause symptoms, but they have a high probability of developing into cervical cancer within a span of 10 to 15 years if not detected and treated early. Any such changes if observed should undergo further testing. High-grade abnormalities necessarily need to undergo treatment.

Who should go for cervical cancer screening?

Since a majority of cervical cancer cases in India are reported after 30 years of age, the Federation of Obstetric and Gynaecological Societies of India (FOGSI) recommends that healthcare settings with adequate resources should begin screening at 25 years and those with fewer resources should begin screening at 30 years.

What are the screening options for cervical cancer?

The common screening options include:

• Pap test (Cytology) every 5 years: In some cases, women need to undergo a repeat Pap test after a few months to determine if the abnormality still persists.
• HPV testing every 5 years: Since HPV is the underlying cause of many abnormalities the doctor may recommend testing of the cervical cells for HPV. In certain types of HPV infections, the condition may resolve on its own and these would not lead to any precancerous changes or cancer, however, certain others in absences of clearance by the body tend to cause cancer.
• Colposcopy with or without a biopsy: This test allows the doctor a better visualization of the cervix under magnification. This could be followed by removing a sample from the suspected region in the cervix followed by laboratory examination.
• Cervical biopsy: This involves removing a sample from the suspected region in the cervix followed by laboratory examination.
• Endocervical + Endometrial sampling: This involves removing a sample from the endometrium, or uterine lining followed by laboratory examination.
• VIA: Visual inspection of the cervical area is done with acetic acid.

The Pap test has the potential to identify abnormal cells in the cervix that are suspected to turn into cancer. In the HPV(human papillomavirus) test the causative virus for cell changes is identified. Pap tests are useful in the early detection of cervical cancer. When diagnosed in this stage, the chances of complete cure of the cancer are quite high.

While HPV testing is considered to be the best available method, other screening tests i.e HPV, cytology, combined testing with both HPV and cytology, and VIA, are considered to be valid options for screening.

What are the screening recommendations for the early detection of cervical cancer?

The general recommendations for screening for cervical cancer are as under:

• Cervical cancer testing should start at age 21: Testing in case of women under age 21 is usually not suggested.
• Women between the ages of 25 and 29: Women of this age group should undergo a Pap test every 3 years. HPV testing in this age group should be reserved in case of an abnormal Pap test result.
• Women between the ages of 30 and 65: Women of this age group should undergo co-testing, i.e Pap test, and HPV test every 5 years. Even though co-testing is preferred, alternately a Pap test alone every 3 years can be carried out.
• Women over age 65: Women of this age group should not be tested in case they have undergone regular cervical cancer testing with normal results in the preceding 10 years. Testing should not be commenced again if it has been stopped once. In case of women who have a positive history of a serious cervical pre-cancer, testing should continue for a period of at least 20 years after that diagnosis, even though they cross the age limit of 65 years.
• Immunocompromised women:
  • Screening/testing should begin within 1 year of initiation of sexual activity
  • HPV testing / co-testing / cytology / VIA are recommended
  • Testing should be done every 2 -3 years
• A woman who has undergone a total hysterectomy i.e removal of uterus and cervix for reasons unrelated to cervical cancer and without any earlier history of either pre-cancer or cervical cancer is not recommended to undergo tests.
• All women who have been vaccinated against HPV: Women of this category despite being vaccinated, should still undergo screening as per the recommendations for the age groups they belong to.

In certain cases, women with specific health history like HIV infection, organ transplant, exposure to Diethylstilbestrol (DES) etc may require an individualized screening schedule for cervical cancer. Women with such a history should definitely consult their doctor.

What are the treatment options for precancerous cervical lesions?

In women tested positive for the presence of a precancerous cervical lesion, certain treatment options are available that can help reduce the chances of the conversion of the lesion into cervical cancer. Some of these treatment options include:

• Loop electrosurgical excision procedure (LEEP): The suspected lesions in the cervix are removed with a thin, electrically charged wire.
• Freezing (cryotherapy): A cold probe is used to destroy some precancerous cervical lesions by freezing. Once destroyed, the dead tissue eventually shed off from the cervix.
• Laser treatment: A beam of laser light is cast on the suspected lesion to destroy it.
• Conization: This entails surgical removal of the suspected abnormal tissue in a conical i.e a cone-shaped form.

What are the treatment options for cervical cancer?

The treatment options for cervical cancer are undergoing rapid improvisations. With many options now available, the most suitable choice for an individual will depend on several factors like:

• The stage of the cancer
• Whether or not cancer has spread to other parts of the body
• The size of the cancerous lesion or tumor
• A woman’s desire to bear children in the future
• Underlying medical condition and other health factors

Fertility concerns for younger women

Fertility-sparing surgery is often a preferred treatment option for women with early cervical cancer. Fertility issues for younger women are high on our list of considerations and we make an endeavor to provide support for all women undergoing sexual side effects consequential to cervical cancer treatment through our survivorship support program.

As mentioned before, the type and stage of cervical cancer and other factors like a person’s health, age, and sensitivity to certain medications etc determine the suitable treatment option for cervical cancer. Some of the treatment options that may be used independently or in combination include:

Chemotherapy :

The use of medications to destroy cancer cells is called chemotherapy. Advanced cervical cancer is treated with a therapy known as concurrent chemoradiation which is essentially a combination of chemotherapy with radiation therapy. Chemo augments the effect of the radiation.

Targeted therapy:

This entails making use of drugs that act specifically on cancer cells, leaving aside the normal cells. The cancer cells are selectively destroyed. The underlying principle of targeted therapy is that it identifies and counteracts some unique characteristics of specific cancer cells. The drugs in targeted therapy attach to the receptor proteins of the cancer cells. This property aids in either killing the cells or augmenting other therapies like chemotherapy to work more effectively. Angiogenesis inhibitors are drugs used in targeted therapy that primarily prevent the development of blood vessels by cancer cells that feed tumors.

Immunotherapy:

Immunotherapy makes use of the body’s own immune system in fighting against the disease. Certain drugs which stimulate the immune system to fight specific cancer cells are used in this therapy. Currently, certain such drugs for the treatment of melanoma, kidney and/or lung cancers, have been approved. Clinical trials on a variety of other cancers are underway. It is anticipated that a combination of immunotherapies with other treatments is likely to improve outcomes for some patients.

Radiation therapy:

High-powered energy beams are used to destroy cancer cells. Radiosurgery is an advanced treatment option, also known as stereotactic body radiotherapy. Here intense radiation is used instead of surgery for the removal of cancerous tissues.

Surgery & medical procedures:

Hysterectomy or surgical removal of the uterus, Cervicectomy or surgical removal of the cervix, with or without removal of lymph nodes, cryosurgery & cervical conization are some of the surgical options for treating cervical cancer.

It is possible to remove only the affected tissue by the gynecologist if a woman wishes to preserve her fertility. However, this may not be always possible, especially in cases with more complex diseases. Fertility-sparing procedures should be discussed with the doctor before beginning the personalized treatment plan.

Palliative care:

Intended to improve the quality of life of cancer patients with the terminal disease who may not be amenable to treatment.

Can cervical cancer be prevented?

Even though eliminating the complete risk of cervical cancer may not be possible, certain preventive measures can be taken:

Primary Prevention:

Healthy lifestyle choices should be made alongside creating a conducive environment that assists individuals in making healthy choices. Women should:

• Preferably not smoke or make efforts to stop altogether if they do. Women smokers are more susceptible to cervical cancer than non-smoker women as per current evidence.

• Human papillomavirus and other sexually transmitted diseases should be prevented from spreading by using barrier methods during intercourse.

• Reproductive activity should be delayed until an older age.
• Sexually transmitted diseases should be managed effectively.

• Undergo family planning to avoid many children as giving birth more than once or multiparity, is also associated with a higher risk for cervical cancer and HPV infection.

Secondary prevention:

The objective of secondary prevention is early detection and treatment of precursor lesions. Cervical cancer is preventable. Federation of Obstetric and Gynaecological Societies of India (FOGSI) endorses the recommendation of the World Health Organization (WHO) that in the preferred age group of under 15 years, two doses of vaccination can be administered at an interval of 6 months for primary prevention. The vaccination charts by WHO also lay down the recommendations for older girls, women and special cases. It is reiterated that screening should not be discontinued after vaccination.

Does HPV vaccination show benefit in preventing cervical cancer?

Primary prevention for cervical cancer with the HPV vaccine is strongly recommended.

Infection control related to the Human Papilloma Virus (HPV):  The strong association between cervical malignancy and HPV infection has been established scientifically. As mentioned earlier, Sexually transmitted HPV infection is thought to cause the majority of cervical cancers. In more than 90% of cervical carcinomas in situ, squamous carcinomas, and adenocarcinoma, HPV DNA is isolated.

“The risk of HPV and other sexually transmitted infections remains a factor should your risk status change — for example, a new partner, or any illness which suppresses your immune system,” Dr. Nikhil S Ghadyalpatil

When comparing HPV test and Pap test, a negative HPV test indicates a far lower risk for cervical cancer and greater assurance of low cervical cancer risk than a negative Pap test.

HPV vaccination in young girls and young women is shown to be of benefit when administered:

• Between ages 9 – 26 years
• Before first sexual intercourse takes place

References:

• Population Services International (PSI). Cervical Cancer Control and Prevention. Available at: https://www.psi.org/program/cervical-cancer-control-prevention/. Accessed on 25th February 2019.
• Cancer Council.Cervical cancer. Available at: https://www.cancercouncil.com.au/cervical-cancer/#sPOi2j2EPtOwRiRU.99. Accessed on 25^th February 2019.
• FOGSI gynaecologic oncology committee. Screening and Management of Preinvasive Lesion of Cervix and HPV vaccination. Available at: http://www.fogsi.org/wp-content/uploads/2018/03/FOGSI-GCPR-Final-March-2018.pdf. Accessed on 25th February 2019.

About Author –

Dr. Nikhil S Ghadyalpatil, Consultant Medical Oncologist, Yashoda Hospitals – Hyderabad
MD, DNB, DM (Medical Oncology)

Dr. Nikhil S Ghadyalpatil has more than 8 years of experience and has specialized in chemotherapy, targeted therapy and immunotherapy and bone marrow transplantation for solid and blood malignancies.