Cervical Cancer Screening, HPV Vaccine Schedule and Price

Cervical cancer can be eliminated because almost every case starts with a persistent infection by a high-risk type of human papillomavirus (HPV), and both the infection and the precancerous stage it causes can be prevented or treated. HPV vaccination in childhood, regular cervical cancer screening with a Pap smear or HPV DNA test, and treatment of precancerous lesions together stop the disease before it becomes invasive.

Dr. Punyashree R M, a consultant gynaecological oncosurgeon at Fortis Hospital, CG Road, Bangalore, calls cervical cancer her favourite topic for that reason: it is highly preventable, and her team does a great deal of preventive oncology and awareness work. This article sets out the cause, the HPV vaccine schedule and price, the cervical cancer screening schedule, how to act on an abnormal Pap smear and how treatment changes with stage. The wider picture of all the gynaecological cancers is in the complete guide to gynaecological cancers.

Why cervical cancer can be eliminated

What makes elimination possible is that the cause is singular and known. In 99% of cases the cause is persistent infection with an oncogenic HPV type. The disease then moves through a predictable sequence: a healthy cell becomes abnormal, the abnormal cells form a pre-invasive lesion, the lesion becomes invasive cancer, and the cancer spreads. Screening works because it intervenes in that sequence before symptoms appear.

The prize is large. Cervical cancer remains the most common gynaecological malignancy in developing countries and the fourth most common cancer in women worldwide. More than 600,000 women are diagnosed each year, and more than half that number die of it. The most common type is squamous cell carcinoma.

HPV: how the virus causes cancer

HPV is a family of more than 200 viral types. Low-risk types cause benign, non-cancerous skin and genital warts, which are very common. High-risk, or oncogenic, types cause cancer. Types 16 and 18 account for more than 70% of cervical cancers.

The virus is mainly sexually transmitted, and penetrative intercourse is not required: secretions alone can transmit it. Infection is close to universal. Around four in five women are infected at least once in their lives. Most infections clear: in 90% of women the infection is transient and resolves within one to two years. The remaining 10% develop persistent infection, and it is this group that progresses to precancer and, if not detected and treated, to invasive cancer.

HPV is not only a women's disease. High-risk types also cause vulvar and vaginal cancers, and a large share of penile and oropharyngeal cancers, in men as well as women. Dr. Punyashree noted that, with changing sexual behaviour, HPV-related oropharyngeal cancers are increasingly common. In some countries, notably the United States, they now outnumber cervical cancers.

Risk factors for cervical cancer

• Persistent HPV infection
• Multiple sexual partners
• Tobacco use
• Multiparity
• A weakened immune system and poor immunity
• Prolonged use of oral contraceptive pills, for more than 5 to 10 years
• Poor diet, poor nutrition and poor lifestyle
• Family history, which plays a role in fewer than 1% of cases

Symptoms: why early cervical cancer is silent

The most common symptom of early cervical cancer is no symptom at all. Dr. Punyashree was emphatic on this point: a woman who arrives with symptoms is usually already at stage 2B or beyond. The only reliable way to find early disease is to examine the cervix and offer screening, whatever the reason for the visit.

When symptoms do appear, two deserve particular attention:

• Persistent vaginal discharge, often foul-smelling, that does not resolve with repeated courses of medication.
• Post-coital bleeding. She advises asking specifically whether the woman has noticed blood on a condom or bleeding after intercourse.

Any abnormal bleeding, whether heavy, irregular, intermenstrual or persistent, should raise suspicion. Bleeding after menopause also points to endometrial cancer, whose work-up is set out in endometrial cancer and the 4 mm endometrial thickness rule. Advanced disease adds pelvic pain, lower back and leg pain, fatigue, loss of appetite and unexplained weight loss.

HPV vaccine schedule: how many doses, and at what age

Children aged 9 to 14 need two doses of the HPV vaccine, six months apart; people aged 15 to 45 need three. HPV vaccination is the primary means of prevention, alongside changes in behaviour and lifestyle. Quadrivalent vaccines (covering four HPV types) and nonavalent vaccines (covering nine) are available.

Who should be vaccinated, and how many doses:

• Ages 9 to 14: the best time to vaccinate, for girls and boys. Two doses, six months apart. Dr. Punyashree said no booster is needed after this course.
• Ages 15 to 45: catch-up vaccination for women and men. Three doses, at 0, 2 and 6 months.

Each dose is 0.5 ml, so one vial vaccinates one person per dose.

Efficacy, in the figures Dr. Punyashree presented:

• About 90% reduction in cervical cancer.
• 80 to 85% reduction in vaginal, anal, vulvar and penile cancers.
• About 90% reduction in benign genital warts.
• More than 90% reduction in recurrent respiratory papillomatosis, a condition in which infants born to HPV-infected mothers develop growths in the airway, when the mother has been vaccinated.

What Australia's programme shows

The first HPV vaccine was licensed in 2006. Australia added HPV vaccination for girls to its national immunisation programme in 2007, and in 2013 extended it to boys, recognising that boys carry and spread the virus as adults. Australia is now on course to be among the first countries to eliminate cervical cancer as a public health problem, a milestone projected for around 2035. Dr. Punyashree cited it as evidence of how effective the vaccine is.

HPV vaccine price in India, and access

The Indian-made quadrivalent HPV vaccine costs about ₹2,000 per dose, roughly half the price of imported quadrivalent vaccines, in the market prices discussed on the call. The cost of the HPV vaccine is one of the main barriers to programmes in low-resource settings, and it was the focus of a question from a doctor in Tanzania on the call.

India now manufactures its own quadrivalent HPV vaccine, introduced about two years before the session. Dr. Punyashree's price comparison:

• Indian quadrivalent vaccine: about ₹2,000 per dose.
• Imported quadrivalent vaccine: about ₹4,000 per dose, so the Indian vaccine costs roughly half as much.
• Gardasil 9 (nonavalent): about ₹10,000 per dose.

Supply is constrained. About 60% of the Indian vaccine's output goes to the government, which gives it free to girls in the target age group, prioritising underprivileged populations who would not otherwise reach a health facility. Only about 40% reaches private and corporate hospitals. For now, Dr. Punyashree said, the Indian vaccine is given only in India, and she was not sure that export would happen in the near term.

Its long-term efficacy is still being measured. Because it is new, she expects it will take about another decade to establish precise figures. Its virus-like particles are similar to those of the established vaccines, which is the basis for confidence that it will prove effective.

Why adoption still lags

Dr. Punyashree identified the obstacles as scale and awareness rather than science. In a very large population the resources required are very large, and awareness has to be created among people who often will not attend even a cancer awareness talk. Stigma keeps many from listening. In her view, governments, medical societies and non-governmental organisations all have to act, starting with awareness, and the decision to make vaccination universal sits with governments. Doctors and organisations in India are pressing for the Indian-made vaccine to enter the national immunisation schedule for girls and boys. As awareness grows, her outpatient clinic sees more people arriving simply to be vaccinated.

Cervical cancer screening schedule: Pap smear, HPV DNA and co-testing

Cervical cancer screening starts at 21 with a Pap smear every three years; from 30, an HPV DNA test or co-test every five years is an alternative, and screening stops at 65. Screening is the second line of prevention. Three tests are in use:

• Pap smear (cytology): examines cervical cells for abnormality. It can be conventional or liquid-based cytology (LBC); LBC is more sensitive.
• HPV DNA test: detects the DNA of high-risk HPV types.
• Co-test: a Pap smear and an HPV DNA test together, which Dr. Punyashree regards as the best option because it shows both whether abnormal cells are present and whether HPV is present.

When to screen, and how often:

HPV DNA testing starts only at 30 because, between 20 and 30, most sexually active women carry some HPV infection, most of it transient. Testing earlier would generate positive results that cause needless anxiety and intervention.

Either approach is acceptable for screening. HPV DNA testing is more sensitive and, because it is repeated only every five years, more acceptable to many patients. It is also more expensive than a Pap smear, so the choice is made with the patient. A normal Pap smear does not require an HPV test. An abnormal Pap smear does: a borderline result (ASC-US) is triaged with an HPV DNA test, and higher-grade abnormalities go straight to colposcopy.

Abnormal Pap smear: what happens next

Any abnormal Pap smear, other than a borderline (ASC-US) result with a negative HPV test, should be referred for colposcopy, a magnified examination of the cervix, with or without biopsy. Before that, the first check on any Pap smear report is whether the sample was satisfactory, meaning adequate for interpretation. The second is whether abnormal cells are present. Whether to biopsy is decided using a colposcopic scoring system such as the Swede score or the Reid colposcopic index, whichever the centre follows. Multiple punch biopsies are the ideal sample. One rule is absolute: if a lesion is visible on the cervix, do not take a Pap smear; take a punch biopsy.

LSIL and HSIL: observe or treat

Cervical intraepithelial neoplasia (CIN) is precancerous change in the lining of the cervix, graded 1 to 3 by how much of the lining is affected. Cytology and histology group it in two tiers:

• Low-grade squamous intraepithelial lesion (LSIL), or CIN 1: usually needs no treatment, only observation, provided the HPV DNA test is negative. Many of these lesions regress.
• High-grade squamous intraepithelial lesion (HSIL), or CIN 2 and CIN 3: needs treatment and regular follow-up. Untreated CIN 3 progresses to invasive cancer in about 30% of women over 30 years, and about 1% of HSIL lesions already harbour unsuspected invasion.

HSIL is treated by excision, which is both diagnostic and therapeutic and preserves fertility: loop electrosurgical excision (LEEP, also called LLETZ), laser conisation or cold knife conisation. The procedure can be repeated if the margins are positive. In an older woman who has completed her family, or who has other uterine problems, hysterectomy is also an option.

Cervical cancer treatment by stage

Treatment depends on the stage, and cervical cancer has a bimodal age pattern: it occurs in women in their thirties and in women in their sixties, so fertility is often a live consideration. Microinvasive disease is cancer that has invaded less than 5 mm deep, in the FIGO staging system the team follows.

Microinvasive cancer (stage IA1 and IA2). For stage IA1, a simple extrafascial hysterectomy is enough on its own, without adjuvant therapy, and in a young woman who wants to conceive, conisation can be offered. Stage IA2 also needs assessment of the pelvic lymph nodes, by sentinel node biopsy or dissection, alongside a simple or modified radical hysterectomy, or a radical trachelectomy, which removes the cervix with the parametrium and preserves the uterus.

Early macroscopic cancer (stages IB1, IB2 and IIA1). Dr. Punyashree's team performs a type C1 modified radical hysterectomy, which is nerve-sparing, with either pelvic lymph node dissection or sentinel lymph node biopsy. Depending on the size and type of the tumour, radiation may follow surgery. A woman not fit for a major operation receives chemoradiation instead, tailored to her. The surgical detail, including how sentinel mapping is done and how often bladder problems follow, is in the complete guide.

Locally advanced cancer (stages III and IV). Treatment is chemoradiation. Squamous cell cancers are radiosensitive, and chemotherapy is given alongside radiation as a radiosensitiser to improve the response. One alternative sequence is neoadjuvant chemotherapy, then surgery, then chemoradiation; the other is direct chemoradiation, depending on response. International guidelines (NCCN, ESGO) treat concurrent chemoradiation as the standard for locally advanced disease, and neoadjuvant chemotherapy followed by surgery has not matched it in randomised trials.

Residual or metastatic disease. Where disease remains after chemoradiation and the patient's performance status is good, the team will still operate to remove it: a radical hysterectomy, or an anterior, posterior or total pelvic exenteration (removal of the involved pelvic organs), depending on where the tumour is and how large it is. Stage IV disease with distant metastases needs systemic therapy, and immunotherapy has been shown to improve overall survival.

The cost of the operation for women travelling for surgery is on the radical hysterectomy cost page. Questions from doctors in Uganda, Ethiopia and Tanzania on screening, advanced disease and vaccine programmes are answered on the Live Discussion page. Dr. Punyashree's profile is at Dr. Punyashree R M.