Prevention is better than cure

CN Purandare, Alka Kriplani & Neerja Bhatla

IN India, cervical cancer is the second most common cancer in women, accounting for nearly one-fourth of the global burden of cervical cancer, with an estimated 122,800 new cases and 67,500 deaths annually, which is more than the number of deaths due to maternal mortality. Since these women are usually in their 40s and 50s, it is estimated that the years of life lost are greater in cervical cancer. Globally, cervical cancer accounts for 528,000 cases including 445,000 cases in low and middle income countries (LMICs). 

Epidemiology

The age-standardised incidence rate of cervical cancer varies between 5.6 and 24.3 per 100,000 women in different regions of India. Although a gradually declining trend in the cervical cancer incidence has been observed in different regions of India over the last two decades, the rates still remain significantly higher than in other Asian countries. In fact, the absolute numbers of both cervical cancer cases and deaths are on the increase due to population growth.

In the West, repeated testing by Pap smear and consequent treatment of precancerous lesions led to a substantial decline in the numbers of cervical cancer cases. In India, with very limited resources to introduce and sustain effective population-based cervical cancer screening programs, there was not much progress in preventing this very preventable cancer. 

The discovery by Nobel laureate Harald zur Hausen that persistent infection with one of the oncogenic, high-risk types of human papillomaviruses (HPV) is the 'necessary' cause of cervical cancer; enabled the development of primary prevention using HPV vaccination.

Presently available vaccines target the two types that are responsible for 70 per cent of cervical cancers worldwide. HPV 16 and HPV 18 and can prevent over 90 per cent of high-grade precancerous lesions caused by these types. In India, there is a greater proportion of these types, making it likely that the impact of vaccination will be better than has been observed already in research studies and in countries that have implemented the vaccine program.

Efficacy of doses

Fewer than three doses of HPV vaccine would substantially reduce costs, improve compliance, ease logistics and facilitate scale up in national immunization programs.  Data to support this has emerged from trials. WHO, after reviewing the available evidence on less than 3-doses, has recommended a two-dose schedule for girls (at an interval of 6 months, which may be extended to 12 months to facilitate vaccination) if vaccination is initiated prior to 15 years of age and a three-dose schedule (at 0, 1-2, and 6 months) if vaccination is initiated after the 15th birthday and for immunocompromised individuals, including those infected with HIV.

Countries implementing Immunisation 

More than 80 countries have introduced HPV vaccine in the national immunisation programs (NIPs), of which 33 are LMICs; in addition, 25 LMICs have introduced HPV vaccination in pilot demonstration programs as a prelude to national scaling up in NIPs. 

In most programs a school-based approach is predominantly used to deliver the vaccine to the targeted adolescents with additional efforts using field clinics, and primary health centres to cover girls who missed vaccination and do not attend schools. Gavi The Vaccine Alliance has been able to markedly reduce the procurement price of both vaccines to Rs $5.  

While Australia, Denmark, USA and Canada were the first high-income countries to introduce HPV vaccination in NIPs in 2007, Panama (2008) in Latin America, Bhutan (2009) in Asia and Rwanda (2010) in Africa were the first LMICs that introduced HPV vaccination. Early reports of protection offered by the vaccine at the population level against vaccine targeted HPV infections, genital warts and cervical premalignant lesions have already started coming from countries that introduced the vaccine between 2007 and 2010.

HPV vaccine safety

Extensive data on the safety of HPV vaccines are now available from clinical trials and the population programs. Globally more than 270 million doses have been administered with no serious adverse events linked to the HPV vaccine and with an excellent safety profile. A meta-analysis of vaccine trials concluded that the frequency of serious adverse events (OR 0.99; 95%CI 0.87-1.14) and death (OR 0.91, 95%CI 0.39-2.14) were similar in the vaccinated and control groups.

The majority of deaths reported were accidental in nature, and none was attributable to the vaccines. Various rare syndromes have also been studied and none found to be related to the vaccine. A recently published study from India reported no serious adverse event attributable to the vaccine after administering 34,856 doses of the quadrivalent vaccine to 10-18 year old girls and following them over four years.

Sooner the better

India is the largest contributor to the global burden of cervical cancer. Several regions of India still have rates higher than most Asian countries and the absolute number of cases is on the increase due to population growth. Fewer than 5 per cent of eligible women in India have ever been screened. The only government sponsored population based cervix screening program so far is in Tamil Nadu where one round of VIA screening has been offered to women through the Government health services. However, adequate screening requires repeated three to five-yearly interventions with coverage of at least 70 per cent of the target population and involves a number of steps including quality assurance of selected test method, diagnosis by biopsy, treatment and regular follow-up to be truly effective. Introducing such efficiently organised population-based cervical cancer screening programs requires substantial resources and could be a challenging task. However, vaccination and screening are complementary strategies, which when implemented in tandem can substantially improve results. 

Cervical cancer affects socioeconomically disadvantaged women, so feasible and effective intervention has to be provided to them through the public health services if we wish to prevent a tragedy that affects not only the women but their families as well.  A pragmatic approach is introduction of an HPV vaccination program targeting a single year cohort of girls aged 9-13 years with a two times intervention at 6 months interval. This will eventually build up a cohort of women at very low risk of HPV 16 and HPV 18 infection and consequently, at a low risk for cervical cancer. One or two rounds of screening in these women may then suffice to provide effective protection. 

The high burden of cervical cancer and the high efficacy and safety of HPV vaccination justify its introduction in the Indian NIP.

— Prof Purandare is the president of the International Federation of Gynecology and Obstetrics (FIGO), Prof Kriplani is the president of the Federation of Obstetric and Gynaecological Societies of India (FOGSI) and Prof Bhatla is the chairperson of gynecology oncology committees of FIGO & FOGSI.

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Age of Vaccination

The vaccine is most effective when administered to pre-adolescent and adolescent girls. Both the vaccines have demonstrated high immunogenicity in girls aged 9-14 years with antibody titres 1.7-2.0 fold higher than in the 15-26 year old women in whom the protective efficacy of the vaccine against infection and disease were already established.

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CERVICAL CANCER

Cervical cancer starts in the cells lining of the cervix -- the lower part of the uterus (womb). 

Can it be detected early ?

• These cells do not suddenly change into cancer. The normal cells of the cervix first gradually develop pre-cancerous changes that turn into cancer. 
• These changes can be detected by the Pap test.

Can it be prevented?

• Yes, if one finds and treats pre-cancers before they become true cancers
• Prevent the pre-cancers by getting an HPV vaccine, stop smoking and use condoms 

The culprit

• Human papillomavirus (HPV)
• Over 200 HPV types have been identified 
• There are 12 high-risk HPV types including 16 and 18
• HPV can also cause anogenital, head, neck cancers and genital warts 

RISK FACTORS

• Smoking and avoiding fruits and vegetables
• Overweight & weak immune system 
• Taking oral contraceptives  for a long time and unprotected sex

INDIAN SCENARIO

• 2nd most common cancer in women
• Accounts for 25% cases globally
• Annually 122,800 new cases
• 67,500 deaths;  in 40-50s age group 

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A VEXED ISSUE 

The HPV vaccination has become a controversial issue after the Punjab government decided to provide “life saving vaccine” to prevent cervical cancer among school going girls of six grade. It made the vaccine a part of the immunisation programme by launching inoculation in November this year. The decision was based on a cost-effectiveness study by the Postgraduate 

Institute of Medical Education and Research (PGIMER), Chandigarh. 

POINTS OF DISCORD

• Scientists Vivian Suman and Jacob Puliyel challenged PGIMER study
• The vaccines are meant to prevent only two out of a dozen cancer causing HPVs 
• Only two vaccines - Cervarix (by GlaxoSmithKline) and Gardasil (by Merck) - are available in India
• A vaccine is allegedly linked with deaths of some tribal girls in Andhra Pradesh

HOPE FOR AN ACCORD

Pune-based Serum Institute of India is developing an HPV vaccine that will be significantly cheaper compared to multinational brands, hence cost-effective.