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103 Issue 3 Interview Transcript(2)

Kristine Crane: Welcome to the JNCI Podcast. I'm Kristine Crane. Invasive cervical cancer is a leading cause of death among women in developing countries. But HPV DNA screening is increasingly being shown to rapidly reduce cervical incidents and mortality. I talked with Dr. Philip Castle of the American Society for Clinical Pathology. Dr. Castle, along with his colleague, Julia Gage of the National Cancer Institute wrote a recent editorial on HPV screening. Why don't we start by just talking about HPV? Not all HPV strains pose a risk for cancer. Which do and how and when are those generally contracted?

Philip Castle: Well all HPV infections are sexually transmitted and so HPV infections are predominantly found in younger women. As we'll discuss most of them go away. The key types, the types that cause cancer, there's 12 of them, the most important of which is HPV 16 which causes about 55 percent of cervical cancer worldwide.

Kristine Crane: And it's also-- it's not just the strain but also the duration of infection that can be indicative of cervical cancer risk, is that correct?

Philip Castle: Correct. Most infections go away and most people who are sexually active are exposed. Fortunately most of those infections go away. However, in a small subset of people those infections persist and when they persist they present a risk of the development of cervical pre cancer and if the pre cancer is not detected and treated, invasive cervical cancer.

Kristine Crane: So tell me a little bit about the review that you conducted.

Philip Castle: Well the review that we conducted was to try to put into context what we know about HPV testing as an alternative to the traditional Pap smear or a cervical cytology for cervical cancer screening. Our goal was sort of expert opinion on what we see is the promise of HPV DNA testing, that is testing for the DNA of the virus versus the older technology of cervical cytology and also some of the concerns and limitations of introducing HPV DNA testing.

Kristine Crane: Can you talk a little bit about some of those, first of all the benefits and then the concerns and limitations?

Philip Castle: So the benefit of HPV DNA testing is it's very, very sensitive for cervical pre cancer and cancer. So when a woman tests negative for HPV DNA even at one time point she's reassured against cancer for ten years or more. If she tests positive, it doesn't mean that she has pre cancer or cancer, it just means that we do more work up of her to find out what's going on. So there has to be a diagnostic step or assay that defines her risk of pre cancer. The limitations of HPV DNA testing is that more women will test positive than by Pap smears. The other limitation is the misuse of the test. When you have a very sensitive test with the kinds of predictive values that we see in the clinical trials in epidemiologic studies and in true practice, you don't need to screen every year or two years or even ever three years which is the current recommendation but what we're seeing now is that clinicians are using HPV DNA testing not according to guidelines. So a third of everybody that's using HPV DNA testing is using it every year and another third of the folks are using it every two years as opposed to the three year recommendation.

Kristine Crane: What do you think that the most cost effective public health strategy would look like? Would it be every three years?

Philip Castle: Well we already over screen and now we're going to increase the over screening by using HPV DNA testing every year. What happens is of course more women are told that they've screened positive and there's a psychosocial impact of that. I mean nobody responds well to being told they have a positive test. So we have to minimize that and that's the challenge of introducing a new technology is how to convey the right messages to the patients so that they don't over interpret the results and don't panic. The other consequence is that with more women testing positive, more women will undergo diagnostic procedures which are imperfect. And because they're imperfect they will classify some women with cervical pre cancer and that will trigger treatment. And treatment has an impact on reproductive outcomes. Specifically it contributes to pre term delivery. So we have to do a good job of using HPV DNA testing or any screening test thoughtfully so that we balance the benefits to harms.

Kristine Crane: What about in the developing world, I mean we know that cervical cancer is a leading cause of death, largely because women don't have access to screening? So what kind of evidence is out there showing that screening could actually impact mortality significantly?

Philip Castle: Well in the last year and a half there have been to seminal studies. The first study was in India showing that a single round of HPV DNA testing with management can reduce mortality by 50 percent. So put that into context, it was in India in a high risk unscreened population, a single round of HPV DNA testing reduces mortality by 50 percent over a seven to eight year period. That's a remarkable finding. And the other part of that was that cytology and VIA did not reduce mortality. So VIA is a visual inspection of the cervix, is another screening test. The second seminal study was in South Africa showing that a HPV screen and treat program-- what I mean by screen and treat is if they're HPV positive and there are no contraindications, the woman would be immediately treated by cryotherapy, showed a much better performance this visual inspection of the cervix in reducing the incidence of precancerous lesions. Put together it really suggests that a single round of HPV DNA testing by a simplified screen and treat program really could impact the incidence of cervical cancer in developing countries. The key issues are wide coverage, so not just screen people who are already being screened but getting everybody and also the availability of a low cost test. And there are several low cost tests that are in development or have undergone some validation and so we're very hopeful that over the long term there will be these robust low cost HPV tests that cou

Kristine Crane: And what about vaccines, just in general there's been a lot of talk recently about the HPV vaccine and when to take it and more vaccines in development? So what is sort of the optimal time for a vaccine to be taken and in what context?

Philip Castle: The current HPV vaccines are prophylactic vaccines. So they only prevent infection, they don't treat infection or the related disease. So the optimal time to deliver HPV vaccines is before women become sexually active. In the United States the median age of sexual debut is around 16 or 17. So the best time to really catch the entire population is around the ages of 11 and 12 which is what is recommended by the American Cancer Society and the ACIP, so the CDC Committee. As you vaccinate older and older women you're going to get less benefit because either they have the infection already and the vaccines are not going to impact that or they've already been exposed to that HPV type and are probably immune to it. So from a public health standpoint to get the maximum benefit to cost ratio, one wants to vaccinate women around the ages of 11, 12 when most have not begun having sex. The impact of delivering HPV vaccine to the cervical cancer prevention program in the United States could be quite profound in that it reduces the population risk of cervical cancer if there's wide coverage. And right now there's very poor coverage as been reported by the CDC. But if there's a significant uptick then one could delay screening until ages of 25 or even 30 and screen much less because the risk of cervical cancer's gone down by about 70 percent. The vaccines target the two types that cause 70 percent of cervical cancer.

Kristine Crane: To what extent do you think that this issue or cervical cancer prevention generally could-- crystallizes a lot of what's going on in the health care debate or just trying to make medicine more cost effective?

Philip Castle: I think this is, certainly for cancer prevention, this is the flagship. We have great tools now. We have better and better screening tools. We have a prophylactic vaccine. We need to figure out ways to integrate the two in a cost effective manner without increasing the risk of cervical cancer and this can be done. My main concern is that we're just going to put vaccine on top of screening which will be done every year and as a consequence we're not going to really change the rates of cervical cancer in this country which are about 11,000 per year but what we will do is send the cost of doing cervical cancer prevention soaring. So we have to be very thoughtful. But if we can figure out to do this for this disease then we can provide leadership on how to do this for other cancers and other diseases.

Kristine Crane: That was Dr. Philip Castle of the American Society for Clinical Pathology. For information on this podcast or for a transcript or to listen to other JNCI podcasts please visit our Web site at You can also follow us on Twitter at jnci_now. I'm Kristine Crane. Thank you for listening. #### End of Castle.mp3 ####