Sunday November 19, 2006
The vaccine route to cancer prevention
The first vaccine for cervical cancer was approved in Malaysia a few weeks ago. This vaccine is a huge step forward for science, but will issues of morality stop us from protecting our children and ourselves? TEE SHIAO EEK gleans the facts from a few experts who were in KL recently for the XVIII FIGO World Congress of Gynecology and Obstetrics.
ALL these years, we have tried so hard to battle cancers in our midst.
Success has come in small baby steps. We now have better treatments to destroy the cancerous cells that multiply abnormally in the body, we have ways to control tumours from spreading and we have medicines that can make the side-effects of cancer treatment more bearable.
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Prof Margaret Stanley … ‘Cervical cancer is a rare outcome of HPV infection, but because the infection is so common, the rarity becomes more probable.’ |
Now, all that is changing. A vaccine for preventing a form of cancer in women is finally available in more than 40 countries around the world.
The world’s first cervical cancer vaccine, developed by Merck Co & Inc, was given the green light by the US Food and Drug Administration in June this year, and just received regulatory approval in Malaysia earlier this month.
With this vaccine that targets the most dangerous, cancer-causing types of the human papillomavirus (HPV), women will have some form of immunity against a disease that kills a quarter of a million women around the world every year.
A horrible disease
Every day, more than 650 women around the world die of cervical cancer.
“Isn’t that horrible?” Dr Gregg Sylvester asks. It’s a rhetorical question; few of us need to be reminded of how devastating it is when cancer swoops down to steal a loved one away from us.
“Cervical cancer is only second to breast cancer in terms of cancer deaths in women worldwide,” says Dr Sylvester, who is the Senior Director of Adolescent Medical Affairs of the vaccines division in Merck & Co Inc.
“Every year, half a million women are diagnosed with the disease. The sad thing is, almost half of these women will die.”
“Cervical cancer is a horrible disease,” says Margaret Stanley, professor of epithelial biology from University of Cambridge, echoing Dr Sylvester’s words. She relates the case of a 42-year-old woman, who had been going for Pap smears regularly, but had missed her last one. In that short time in between, she developed cervical cancer.
“Despite radiotherapy and chemotherapy, she died two years after diagnosis,” says Prof Stanley.
What adds to the cruelty of the disease is that it often strikes women in their 30s or 40s, “when a woman’s life is still very much ahead of her,” says Dr Sylvester.
A woman loses 26 years of her life when she has cervical cancer (estimates for the US). In Malaysia, 1,492 women become a part of these statistics every year, with 766 succumbing to the disease.
Cervical cancer is primarily caused by the human papillomavirus (HPV), a jewel-like virus that is sexually transmitted.
The HPV virus
The family of HPV viruses is like the Jackson family. There are a lot of them, and they are very common.
“There are something like 180 known HPV viruses,” says Prof Stanley.
The vaccine that has just been approved is targeted at four types of HPV: 6, 11, 16 and 18.
“HPV 16 and 18 are responsible for more than 70% of cervical cancers worldwide. HPV 6 and 11 cause more than 90% of genital warts,” says Prof Stanley.
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The jewel-like human papillomavirus (HPV) is very common. Types 16 and 18 cause the bulk of cervical cancers worldwide. |
“At least half of sexually active men and women acquire genital HPV in their lifetime. About 80% of women will be infected by the age of 50,” says Prof Stanley, describing how common the infection is.
“You get it when you’re young, between age 18 and 28, and it is acquired reasonably quickly after the onset of sexual activity.”
Even though a woman has only one sexual partner, it doesn’t mean that she won’t be infected, because her partner may have the virus from other sexual encounters during or prior to the relationship.
Fortunately, HPV infections are mostly innocuous. “Most of us get rid of the virus on our own,” says Prof Stanley, giving a thumbs up to the human body’s immune system. “However, a proportion of people actually develop lesions in the cervix, called Cervical Intraepithelial Neoplasia (CIN).”
CINs range from low-grade lesions, which are not worrying, to more severe grades, which are clearly very abnormal.
“The lesions that arise in HPV-infected women are usually low-grade CINs and our immune system can clear these. But in a proportion of people, their bodies will not clear the virus and they will have a persistent infection. It’s those women who are at risk of going on to develop the high-grade CINs, called CIN 2 and 3.”
CIN 2 and 3, loosely referred to as pre-cancers, are more likely to progress to cervical cancer.
“HPV 16 and 18 do not just cause cervical cancer. They also cause vaginal and vulvar cancer, penile cancer, anal cancer, head and neck cancer, and larynx cancer,” Prof Stanley notes.
When women go for Pap smear tests, the small sample of cells taken from their cervix is examined for CINs. Pap smears have always been advocated as a way to treat these early abnormalities and prevent cancer.
However, the Pap smear is still fallible. “In UK, we have one of the best (Pap smear) screening programmes for cervical cancer in the world. Yet we still have 2,000 new cases and 900 deaths a year. We’re as good as we can be, but we still miss out,” says Prof Stanley.
However, with the new vaccine that protects against HPV infections and pre-cancerous lesions, we’re not so likely to “miss out” anymore.
Injecting hope
The development of the vaccine began in the 1980s, with several universities and research institutions in US and Australia racing towards their vision of finding the world’s first cervical cancer vaccine.
Towards the end, this effort became tangled with patent disputes and royalty payments. Nonetheless, the vaccine has finally become reality. Now, the real test is in the efficacy of the vaccine.
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How the vaccine works. – Photo illustration courtesy of MSD |
“The efficacy of this vaccine has been evaluated in four Phase II and Phase III clinical studies,” says Dr Sattler, involving a total of over 27,000 women, age 16 to 26 years. On average, study participants were followed for up to four years after enrolment.
Although the goal of the studies was to prove that the vaccine prevents cervical cancer, it was not feasible for the scientists to actually see whether cervical cancer occurred, because the disease can take up to 20 years to develop. So instead of sitting around and twiddling their thumbs for two decades, the scientists decided to look for CIN 2 and 3 instead, which are the immediate precursors of cervical cancer.
Dr Sattler focuses on two of the pivotal Phase III studies, FUTURE I and FUTURE II: “FUTURE I, which enrolled over 5,400 women worldwide (age 16-26), analysed the efficacy of the vaccine against a broad spectrum of HPV-related diseases of the genitalia (cervix, vulva and vagina).
“The women in the study had not been infected with either HPV 6, 11, 16 or 18. They were given either a placebo or the vaccine, and followed for one-and-a-half years.
“The vaccine prevented 100% of HPV 6, 11, 16 and 18-related CINs of any grade, as well as cervical cancer. The vaccine also prevented 100% of genital warts related to these four HPV types,” he notes.
The FUTURE II study, which was the largest study conducted by Merck, enrolled over 12,100 women worldwide who had not been infected with HPV 16 or 18.
“These women were given either a placebo or the vaccine, and followed for one-and-a-half years. The vaccine prevented 100% of high-grade cervical pre-cancers and non-invasive cervical cancers. No cases of CIN 2 and 3 appeared in the vaccine group, compared to 21 cases that appeared in the placebo group,” says Dr Sattler.
A combined analysis of all the four clinical trials shows that the vaccine:
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Dr Carlos Sattler … ‘The quadrivalent vaccine prevented 100% of cervical pre-cancers and non-invasive cervical cancers.’ |
“With this vaccine, we’ve also demonstrated the longest duration of efficacy of any cervical cancer vaccine to date. We saw that through five years of follow-up, the vaccine prevented 96% of HPV 6, 11, 16 and 18-related infections and disease,” says Dr Sattler.
What will happen beyond the five-year point, nobody knows yet. Would women need a booster shot?
“We don’t know,” he admits. However, he is encouraged by the fact that the vaccine has shown the capacity to induce immune memory, which is a hallmark of long-lasting protection after vaccination.
“Ultimately, long-term evaluation of the vaccine is going to be required by following study participants ? for at least 10 years.”
From the studies, the vaccine appeared to be well tolerated. The most common adverse experiences were mild or moderate discomfort, pain and swelling at the injection site.
One for the books
If nothing is done to intervene in the course of cervical cancer, including vaccination, the disease burden will probably increase by about 40% by the year 2020.
Prof Stanley is fully in favour of using the cervical cancer vaccine as a major public health initiative to avoid this calamitous epidemic.
Few health authorities are going to argue otherwise. So far, this quadrivalent vaccine has been approved in over 40 countries, including Malaysia.
“In many countries, the vaccine has been approved for use in females from nine to 26 years of age. There are many countries (including New Zealand, Australia, Mexico and European Union) that have also approved the vaccine in males nine to 15 years,” says Dr Gregg Sylvester.
The US is one step ahead in providing recommendations for use of the vaccine.
“The Advisory Committee on Immunisation Practice of the Centers for Disease Control has recommended that all 11- and 12-year-old girls should be vaccinated. They also said that females aged 13 to 26 who have not been previously vaccinated with this vaccine should also be vaccinated. For nine- to 10-year-old girls, they said that vaccination should be up to the doctor to decide,” Dr Sylvester elaborates.
In Malaysia, the vaccine has just received regulatory approval. However, MSD, Merck’s subsidiary in Malaysia, was unable to confirm details beyond that. It is expected that the vaccine will be available soon, but only in private clinics and hospitals initially.
Fit For Life asks Dr Sattler what it has been like to be a part of this development. His face is grave as he considers this question. “It’s incredibly fulfilling from a professional standpoint. It’s an honour to be able to somehow contribute to such an incredible public health intervention,” he says.
The cervical cancer vaccine has elicited unabashed praise from the medical community.
“I think the vaccine is a remarkable breakthrough,” says Dr Saunthari Somasundaram, Honorary General Secretary and Executive Director of the National Cancer Society of Malaysia.
“In my personal opinion, I think it’s the biggest and most important step in vaccines since polio vaccination,” Prof Stanley ventures to say.
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