Is It Too Soon to Predict an End to Cervical Cancer? 

Anna Sayburn

Disclosures

February 26, 2020

In January, Professor Peter Johnson, NHS England's national clinical director for cancer, told The Guardian : "we hope that cervical cancer can be eliminated altogether by the NHS in England".

But despite these hopes, rates of new cases of cervical cancer in the UK have barely budged in a decade, at around 2500 a year. Cervical cancer screening is taken up by less than 75% of eligible women in the UK, and rates are much lower in other countries, even where screening programmes are provided.

Scares about vaccine safety have slowed or stalled uptake in some countries, while the cost of the vaccine remains a barrier for others. And in January, public health researchers in the UK questioned whether evidence for vaccine efficacy was really as good as claimed.

So is it too early to talk about eliminating cervical cancer, in the UK or worldwide? And does talk of elimination encourage complacency towards the disease?

We looked at the evidence and talked to experts, to find out.

What Do We Mean by Elimination of Cervical Cancer?

Confusingly, elimination does not mean getting rid of cervical cancer altogether. This year, the WHO (World Health Organisation) is expected to agree a draft global strategy for 'eliminating cervical cancer as a public health problem' within this century. This would require all countries reaching an incidence rate of less than four cases per 100,000 women.

"There are other cancer types that are at that level and we talk about them being rare cancers, because they do still exist," said Karis Betts, health information officer at Cancer Research UK (CRUK).

There were 2591 new cases of cervical cancer in the UK in 2017, making it already one of the less common UK cancers. The rate dropped in the early 1990s but has not changed significantly since 2010.

The WHO strategy says that, to achieve the elimination goal, each country should:

  • Vaccinate 90% of girls against HPV by age 15

  • Screen 70% of women with high-precision tests at 35 and 45 years

  • Treat 90% of precancerous lesions and invasive cancer cases

The strategy assumes that HPV vaccination is both effective against HPV itself and efficacious in preventing cervical cancer.

How Protective is HPV Vaccine Against HPV?

The vaccine currently used in the UK, Gardasil (Merck Sharp & Dohme), offers protection against two strains of HPV (16 and 18) which are thought to cause around 70% of cases of cervical cancer in the UK. It also protects against strains that cause genital warts.

Initial figures in England are encouraging. Public Health England (PHE) has carried out HPV surveillance testing of women aged 16 to 24 attending clinics for chlamydia screening since before the national HPV vaccination programme began. For the age group who were offered the vaccine at age 12 to 13, the prevalence of HPV strains 16 and 18 dropped from over 15% to less than 2%, with no HPV16/18 infections picked up in 16 to 18 year olds in 2018, the most recent year for which figures are available.

And a systematic review published in the Lancet last year found equivalent results in other countries. "After 5–8 years of vaccination, the prevalence of HPV 16 and 18 decreased significantly by 83% among girls aged 13–19 years, and decreased significantly by 66%  among women aged 20–24 years," it reports.

However, HPV 16 and 18 are not the only strains of the virus that cause cervical cancer. "There are 12 oncogenic types but there is not a vaccine against all types," said Professor Allyson Pollock, author of a paper which challenged the evidence around HPV vaccine efficacy, and director of the Institute of Health and Society at Newcastle University. She worries that prevalence and incidence of HPV strains is not clearly established around the world.

"So even if you had developed a really good vaccine against 16 and 18, it could be not so good in those countries where other oncogenic types are more prevalent," she said. She also raised the possibility of  'type substitution', where suppression of HPV16 and 18 could lead to other cancer-causing strains to emerge in their place.

Does HPV Vaccination Prevent Cervical Cancer?

Because cervical cancer takes years – even decades – to develop after a persistent HPV infection, there are no data yet to show whether protection against HPV has reduced cervical cancer rates.

Instead, researchers rely on the relationship between vaccination and pre-cancerous changes to cells, such as cervical intrathelial neoplasia (CIN), graded as 1 to 3. CIN1 is relatively common and frequently does not need treatment. CIN3 is much more likely to progress to full-blown cancer.

Ms Betts said: "The first cohort of girls getting the HPV vaccine are coming up to screening age now [in the UK] so in the next few years we will start to get those results… While we can't say we have seen the effect of HPV on cervical cancer cases, we have seen there is a decrease in the number of people having pre-cancerous cell changes and those cell changes are the things that lead to cancer."

In support of the claim, CRUK sent a paper published in 2010 which showed 96% efficacy of the vaccine to protect against cervical CIN1, based on two 4-year randomised controlled trials.

However, using CIN1 as a surrogate endpoint for cervical cancer is problematic, says Prof Pollock.

"The epidemiology varies, with CIN1 and 2 occurring frequently and unlikely to progress to cancer, and CIN3 being much less frequent and much more likely to progress than the others.

"They've combined end points which are very common and highly unlikely to progress with those end points that are less common and more likely to progress. That has inflated the evidence of the benefits of the vaccine."

However, PHE pointed to a 2019 cohort study carried out in Scotland, which showed that women who were vaccinated against HPV at age 12 to 13 and had a smear test at age 20 were 89% less likely than unvaccinated women the same age to have CIN3 or worse.

Prof Pollock still believes that the data for the effect of the vaccine on cervical cancer is not yet convincing. "It's just too early to say. They're using surrogate endpoints in very young women. What it does point to is the importance of having good, comprehensive cancer registration. If we've got good cancer registries we should be able to answer this in part," she said.

However, she points out, many countries in which the vaccine is being rolled out do not have cancer registries, so are not in a position to judge the effect of the vaccine.

What About Confidence in the Vaccine?

In England in 2018/19, around 84% of eligible girls received both doses of the HPV vaccine, but some other countries have much lower rates. The vaccine has had a 'bumpy' ride since its introduction a decade ago, says Professor Heidi Larson, director of The Vaccine Confidence Project and professor of anthropology, risk and decision science at the London School of Hygiene and Tropical Medicine.

"It's very context specific," she said. "Some countries are struggling with concerns and others have done better. I think we have got quite a way to go before we get global uptake."

She pointed to Japan, where 7 years ago the Government suspended its proactive recommendation for states to offer HPV vaccination (although it is still available for those who ask) after what turned out to be unfounded fears about chronic pain symptoms.

In lower-income countries, access depends partly on funding. Gavi, the Vaccine Alliance (a public-private partnership that promotes access to vaccines in developing countries), provides some access, but funding is not always the issue.

"Armenia, which has pretty strong vaccine confidence in general and high uptake of childhood vaccines, got Gavi funding to roll out HPV vaccine targeting 90% of relevant age group and only managed to get 6% to show up for it. So there are cases like that, and on the other hand places like Rwanda and Zimbabwe that are doing OK." India is another country where fears about vaccine safety have made it impossible to achieve widespread national vaccination, she said.

Prof Larson says the situation is particularly frustrating because "every time [reports of harm from the vaccine] have been investigated, we find most of the symptoms being reported are at the same rate among the girls who haven't been vaccinated".

She is hopeful, however. "I think the overall trajectory is of increase with a bumpy road, but there are more girls getting HPV vaccine in the world today than there were certainly 10 years ago and probably 5."

She says that increasing confidence in HPV will not be easy. "I don't think more and more data is going to fix this. This is a highly emotive issue… We need to look in each setting at what it is that will make the difference. In some cases it will take a lot of local engagement, getting peer influencers who believe in it to start nudging."

What's Happening with Cervical Screening?

The UK screening programme has historically identified pre-cancerous cell changes and referred women with lesions for investigation or treatment to prevent lesions progressing to cancer. A recent change means that, in future, women will be tested first for HPV, and their sample will only be sent for cytology if it tests positive for high-risk strains of the virus.

However, only around 70% of eligible women in the UK have had an adequate screening test result recorded in the past 3 years, and there is concern that rates may drop. Confusion over whether women who have been vaccinated still need to be screened may be partly to blame.

"The major challenge the programme is currently facing is the fall in coverage rates," said PHE in a statement. "It is a great concern about the number of people who choose not to take up their screening invitation."

Ms Betts says this worries CRUK too. "I think that is a common myth. People think I'm fine, I'm vaccinated, I won't need to be screened. That is a myth. We urge people not to be complacent. If you are between 25 and 64 and you have a cervix then cervical screening is for you, regardless of your sexual history or your vaccination status." She urged healthcare professionals to talk about the benefits and risks of screening to all eligible women.

She points out that the vaccination programme and screening are about reducing risk, not a guarantee against cancer. "Even if you have the vaccine, that is not 100% effective because it doesn't protect against all HPV strains," she says. "The vaccine is going to greatly reduce your risk but it's not a guarantee."

Prof Pollock believes the messages about HPV vaccination and elimination of cervical cancer could worsen the decline in screening rates.

"I think people are bound to be puzzled if they are told on the one hand that we've got this vaccine that is going to eliminate cervical cancer, and then on the other told 'but you must still attend screening'," she said. "This is one big concern, that people take the vaccine and think they are protected so they don't need to go for screening."

PHE said in a statement that screening was likely to change and evolve as the effects of the HPV vaccination spread, and that longer screening intervals (5 years instead of the current 3 years) might be appropriate once HPV vaccination was fully implemented.

Conclusion: Is Elimination of Cervical Cancer a Realistic Goal?

Prof Larson believes the WHO goal of elimination is "an ambitious agenda" but should not be watered down.

"I think it's fine to have that ambitious goal but we have to be a little more realistic with the time frame. I would say don't drop the ambition, but let's look harder at where the interventions will make the most difference," she says. She said it was important to have both screening and vaccination on the agenda.

Ms Betts agrees that "HPV vaccination is sadly not this magical thing that will solve all our problems – we will still need screening". She points out that the estimates of lives saved and cancer cases prevented "are based on models of people having the vaccine and continuing to get screening… If people stop doing those things, that undoes it".

She added: "We are talking about something that is decades away."

A statement from PHE agreed that: "Although the long-term goal is to eliminate cervical cancer, this is still many years away."

While a combination of vaccination and screening in the UK seems likely to have an effect in future, the WHO goals and the requirements to achieve them seem some way off for many countries in the world. In addition, the UK will need to ensure screening levels do not slip, if it is to meet the goal. And we will not know the full effect of vaccination on cancer rates for many years to come.

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