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A letter from
theSociety of Gynecologic Oncologists of Canada
September 10, 2007
GOC Responds To Public Concerns Regarding HPV Vaccine
And Cervical Cancer Prevention
In Ontario, as of September 2007, the HPV vaccine will be freely
offered through the school system, for the next three years, to
girls entering into grade eight. Distribution of the HPV vaccine
will be through a voluntary immunization program that will leave
parents and their children with the decision of whether to vaccinate
or not.
The recent media blitz surrounding the HPV vaccine, although welcomed
for the attention given to the often neglected issue of cervical
cancer, has been profoundly negative. In fact, the rhetoric by its
very tone has the potential to derail a major advance in public
health and cervical cancer prevention. It is imperative that a fair
and balanced view of the HPV vaccine be presented so that parents
and children can make informed decisions.
The burden of cervical cancer, and its precursors, has often been
misrepresented as affecting only 1,400 women yearly, from which
400 will die.
Some critics have suggested
that there is no epidemic of cervical cancer in Canada
that requires a move to HPV vaccination at this time. They contend
that the problem is effectively dealt with by routine cervical screening
with the Pap test, and this strategy is sufficient to keep the disease
at bay. They would argue that the HPV vaccine should not be introduced,
as proposed, until more research regarding dosing schedules and
long term effects are fully understood – essentially maintaining
the status quo for the time being.
However, one must look a little deeper at the true burden of the
disease to realize that the current prevention strategies are limited
in the light of new technologies.
Prevention of cervical cancer comes at a very high price, in both
human and financial terms. The current
approach, a secondary prevention strategy (i.e. identifying a disease,
or its precursors, and treating it while it is still curable) is
based on Pap test screening. When a Pap test is abnormal, as is
the case for approximately 400,000 Canadian women each year, cervical
abnormalities are identified and results must be followed-up.
This requires further
Pap testing, additional visits to the doctor, and in many cases
treatment to eradicate the cellular abnormalities. While treatment
is typically localized to the cervix, and is successful at eradicating
pre-cancerous abnormalities, it is not without problems. For some,
treatment has resulted in infertility, for others pain, infection
or bleeding - sometimes an urgent middle of the night visit to the
local hospital emergency is required.
Treatment for pre-cancerous
abnormalities of the cervix results in anxiety, inconvenience, and
intrusion, all of which may have a significant overall negative
psychological impact.
While this secondary prevention strategy has been successful in
reducing cervical cancer incidence since the early 60’s, there
has been minimal or no reduction of cervical cancer in the last
15 years. Up to 25% of Canadian women are seldom or never screened
and these include women from the most vulnerable populations –
this is an issue of equity and access.
Our current approach of testing over and over in the hope of picking
up early abnormalities is based on a
redundancy paradigm that was fuelled originally by a lack of understanding
of the cause of cervical cancer. It works only at great cost, estimated
at approximately 300 million dollars per year, and the need for
an
infrastructure within the health system to screen virtually every
woman.
In Canada, we have not
been able to mount the political will to take this process to the
next step where it will become more effective.
Over the past 30 years, three major Canadian reports have recommended
organized cervical screening
information systems at the provincial/territorial and/or national
levels. Such a system would keep track of
individual Pap test results, the need for repeat tests or updated
tests, and would ensure that each eligible woman and their doctor
would be sent reminders about when to have a Pap test. The need
to move from a spontaneous system, where a patient gets a Pap test
only if they turn up to receive one, to that of an organized electronic
system, was advocated in each of the three national reports. Despite
the overwhelming amount of evidence of the benefits of organized
screening approaches, and repeated advocacy efforts, cervical cancer
prevention using a secondary approach has been stalled for many
years. Yes, overall rates have been reduced over time with the Pap
test, but unless change occurs, cervical cancer rates will go no
lower. It is now known that the cause of cervical cancer is an oncogenic
cancer-causing HPV viral infection that is transmitted sexually.
For the first time it is possible to employ a primary prevention
strategy through the HPV vaccine.
The HPV vaccine acts to
stimulate the immune system to prevent the infection responsible
for cervical
cancers, and related pre-cancerous lesions, before they can develop.
Thus, there is the need to implement this new strategy, based upon
a biological paradigm, whereby the majority of the disease is prevented
before it can occur. Not only does primary prevention have the potential
to increase the standard screening interval from once every two
to three years, to perhaps once every five years, but more importantly,
the vaccine has the potential to greatly reduce the number of abnormal
Pap tests, with the associated follow-up and treatment implications.
There can be no argument, even from the opponents of HPV vaccination,
that the tenets of primary prevention are vastly superior to that
of secondary prevention.
The implications of this biological paradigm argue strongly not
only for vaccination programs to reduce the
burden of the disease, but also for a fundamental shift in monitoring
and testing for specific viruses. Secondary prevention strategies
will still be needed under this new paradigm; however it is hoped
that this will occur through linkages with existing cervical cancer
screening programs and networks, and over time their focus will
be revised. The efficacy data around the HPV vaccine are sound and
compelling. A systematic review of randomized trials (reported in
the August 2007 issue of the CMAJ) clearly shows almost 100% protection
from HPV infection and related disease caused by four major HPV
subtypes (6,11,16,18). These subtypes account for 70% of all cervical
cancers and 90% of all genital warts. The vaccine has been shown
to be effective over five years of follow-up.
The argument that cervical cancer was not an endpoint in these studies,
and as such cannot justify the
implementation for cervical cancer prevention, is not valid. Endpoints
in the trials were carefully chosen with the input from regulatory
agencies including the U.S. Federal Drug Administration (FDA). These
endpoints were surrogates for cancer (i.e. high grade precancerous
lesions and infections with high grade risk types) simply because
the long duration of the natural history of cervical cancer (decades)
would make the endpoints of cervical cancer unmanageable and unethical
in these studies.
The argument that investigation on about 1,200 girls aged 9 to 15
years of age cannot justify the use of the
vaccine in the recommended 9-13 age cohort does not tell the whole
story. All of the trials to date report data on outcomes of disease
or infection for thousands of women between the ages of 15 and 26
years of age. With FDA approval, the younger age group was chosen
only for immunogenicity data (i.e. to look to see whether this group
would make antibodies against the HPV subtypes to a level equal
to or greater than the 15 to 26 year age group) and not on efficacy
(which addresses protection against infection). This is not only
understandable but is practical as well. It would be unethical to
submit younger girls to biopsies and examinations, especially when
this age group generally does not have exposure to HPV infection.
In the immunogenicity studies, the antibody responses were much
higher than in the older age group. These data predict well for
persistence of protection over time, and also provides the rationale
for inoculation at an earlier age. Also, the vaccine was most effective
when given prior to exposure to HPV infection.
In addition to the efficacy data established in the randomized trials,
large ongoing phase IV trials (some groups being followed for life)
are being conducted. These groups are five or more years ahead of
any population implementation that we would choose to do now in
Canada. The data from these groups will be shared worldwide to further
inform issues regarding HPV vaccine implementation.
The issue of whether a booster will be necessary is important, and
while there is presently growing evidence of long-term immunity,
that data will need to be monitored prospectively. The situation
is not unlike the precedent of the hepatitis B vaccine that is now
routinely administered in schools, and one that uses the same vaccine
technology with similar long-term protective effects. In addition,
there are also ongoing reports from the various trials of immune
memory responses in which women that are challenged with the HPV
antibodies after 5 years are showing that they are able to mount
a response.
The randomized trials, which were very tightly monitored for safety
events, showed that there were more minor adverse events such as
pain, redness, or swelling at the injection site associated with
the vaccine. However, there were no differences in the number of
serious adverse events or in deaths between those who received the
HPV vaccine and those who received an inert placebo injection. These
compelling data show that severe adverse events, even death, can
occur in a study population, or in the real world, even when there
are no reasons for such
reactions (such as a placebo injection).
The HPV vaccine has also
been subjected to ongoing rigorous review by regulatory bodies around
the world including Health Canada and the U.S. FDA. There is consensus
by experts about the safety of the vaccine. With over seven million
doses of the vaccine distributed in the USA alone, rates of serious
adverse events have been less than expected, at approximately five
percent of the 2,531 adverse events reported to date (U.S. VAERS
database). This is lower than the average 10%-15% event rate seen
with other
similar vaccines. To date there has been a lack of causality related
to the vaccine for the serious adverse events that have occurred.
Based on this data, the American Advisory Committee on Immunization
Practices has recently confirmed their support for the safety of
the vaccine.
There are other issues that must also be addressed. One is that
the HPV types not covered by the vaccine may take the place of the
viruses that we are protecting against. This is considered by most
experts to be a theoretical concern only, but to be safe, ongoing
surveillance will be necessary. It has also been speculated that
girls may be more sexually promiscuous because they have had a vaccine
to prevent against some types of HPV. This is wild speculation at
best; it may very well be that greater awareness of sexually transmitted
infections may have the exact reverse effect.
Other concerns focus on how to ensure equitable access to the vaccine,
especially in under-serviced areas or on the impact to the screening
system. Will women forget to get screened, or will the lack of a
cervical screening registry become more of an issue? How do we tell
who has been vaccinated and who has not? How do we make sure that
girls and women will get the actual three doses and not just one
dose? Are two doses as good as three doses? What about the cost?
Is it cost effective? Is it the best way to spend our health care
dollars to protect the health of women against this disease? Do
we have the educational tools required to provide women, girls and
parents with enough information to make an informed decision in
a voluntary vaccination process? All these questions can be addressed
through the ongoing integrated monitoring of vaccine implementation
programs. Therefore, what is the impact of waiting 10 to 20 years
to see the results of cervical cancer rates drop before implementing
the vaccine? What is the impact of a generation of adolescents not
protected against the virus while we have the technology available
to us? That needs to be figured into the equation.
These questions all fall
into the realm of implementation science, the next part of the story.
Critics are correct; the data of how to do this
right and for the best cost-effectiveness are not complete. This
issue has received tremendous focus by experts across Canada leading
to many documents outlining the strategies required for appropriate
data gathering and infrastructure required to answer some of these
questions.
As far as the cost-benefits are concerned, several modeling studies
have quantified the possible impact of
vaccination. Most of these studies show cost-effectiveness in favour
of vaccine implementation versus other
traditional strategies. The recent August 2007 CMAJ article by Brisson
et al. reports that the number needed to vaccinate to prevent a
cancer death with the HPV vaccine is actually superior to similar
numbers than for the influenza, the meningococcal and the varicella
vaccines. A rush for needles into arms however is not the simple
answer. Implementation must be done in concert with enhancing existing
cervical screening programs, including the ideal of a cervical cancer-screening
information system, advocated for over 30 years, and a parallel
integrated strategy for the systematic monitoring of vaccine uptake
and immunization outcomes. An information system would not only
monitor adverse events and ongoing efficacy issues, but also provide
information on implementation datasets needed to advance our knowledge
(long
term efficacy, optimum dosing, the need for boosters, impact on
the health system, etc). To date the rhetoric has focused on other
issues but in reality a key missing piece to the puzzle is to advocate
for an organized implementation infrastructure. This part of the
process will need to have the highest profile as the biological
approach to this disease eradication unfolds. Will we have to wait
another 30 years for the infrastructure pieces to fall into place
to complete this puzzle? This is the drum-beat that should be used
by all stakeholders, from across the many different perspectives,
to advance the state of the art in this very important women's health
issue.
The controversy in the lay and medical press belie the multitude
of perspectives on this issue – socially charged as it crosses
sexual issues, religious issues, women/girl’s issues, health-related
politics, federal and provincial politics, big pharmacy, and not
least money. While it is easy to see how viewing these incomplete
datasets around implementation as a lightning rod for opposing perspectives,
one must not lose sight of the big picture. The burden of disease,
the stalled nature of cervical cancer prevention, and the impact
of primary prevention have created not a perfect storm, but a perfect
opportunity to galvanize the various stakeholders. What is now needed
is to put our shoulders behind the eradication of cervical cancer
not as a possibility but as a reality. With the HPV vaccine, the
ongoing monitoring, follow-up, and integration with existing cervical
cancer prevention practices will provide a lasting framework for
success in the reduction of the burden of cervical cancer.
THE SOCIETY
OF GYNECOLOGIC ONCOLOGISTS OF CANADA
Michael Fung-Kee-Fung, M.D., BS, FRCSC
Secretary-Treasurer
Joan Murphy, M.D., FRCSC
Chair, GOC Cervical Cancer Task Force
Marie Plante, M.D., FRCSC
President-Elect
Society of Gynecologic Oncologists of Canada
780 Echo Drive, Ottawa, ON K1S 5R7 Canada | 800.561-2416 / 613-730-4192
ext. 250
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