Combined Program of Vaccination and Testing for the Human Papilloma Virus Could Eradicate Cervical Cancer

Cervical neoplasia is usually an asymptomatic squamous cell carcinoma caused by human papilloma virus infection (HPV); less often, it is an adenocarcinoma. The recognition that human papilloma virus (HPV) is a cause of cervical cancer has opened new opportunities for the prevention of the disease. Primary prevention is now possible via immunization with highly efficacious HPV vaccines and secondary prevention has gained impetus with the advent of sensitive HPV DNA testing to improve traditional Pap cytology screening programs.

As a result, cervical cancer could be eradicated within the next 50 years. However, according to a cervical cancer screening expert, this can only happen if governments implement national screening programs based on detection of the human papilloma virus (HPV), which causes the disease, together with vaccination programs against the virus.

Professor Jack Cuzick told Europe’s largest cancer congress, ECCO 15 – ESMO 34, (the joint multidisciplinary 15th congress of the European CanCer Organisation and the 34th congress of the European Society for Medical Oncology), meeting in Berlin, Germany (September 20 – 24, 2009) that while the current HPV vaccines protect against two cancer-causing strains of the HPV virus, soon there would be vaccines available that protect against nine types. If vaccination were to be combined with HPV screening (which is much more sensitive than the currently used Pap smear test), then eventually the cancer would disappear in those countries that had successfully implemented national programs. However, this would require political will and effort at both national and European level.

“It’s important to say up front that the HPV is responsible for all cervix cancer,” Cuzick said. “If you can eradicate the virus, the cancer will not appear. So the current vaccine holds the promise of eradicating about 70-75% of cervical cancers (caused by HPV types 16 and 18), and there appears to be some additional cross protection amongst types that are closely related to 16 or 18, in particular 31, 45 and a little bit of 33. There are new vaccines being planned that will vaccinate against nine types. If they are successful, there should be no need to screen women that have been vaccinated at all. That’s the long-term future: vaccination and no screening. After about 50 years, we could see cervical cancer disappearing.”

As the current HPV vaccine only protects against two of the cancer-causing types, vaccinated women will still require screening for the rest of their lives.

“Women vaccinated above the age of about 16 will need to be regularly screened for the rest of their life, because the vaccine is not effective in women who have already been exposed to the virus. Even for girls vaccinated before this age with the current vaccine, there will be a need for some screening to protect from cancers caused by HPV types not in the vaccine, so screening is here to stay for the foreseeable future. However, we need to change to screening for HPV rather than the Pap smear test, and then it will be possible for the tests to be conducted at longer intervals,” said Prof Cuzick, who is the John Snow Professor of Epidemiology and head of department at the Cancer Research UK Centre for Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventive Medicine (London, UK).

The Pap test uses cytology to detect pre-cancerous changes to cells; it relies on subjective assessments by people examining the cells in the smear with a microscope and so is open to human error. Prof Cuzick believes such errors will increase as the proportions of smears with affected cells decline due to increasing numbers of women having been vaccinated. In contrast, the HPV test is almost completely automated, is designed to detect the virus in the smear rather than relying on visual examination, and so is much less likely to be affected by human error.

Prof Cuzick said that countries should be switching to the HPV screening test now. “There’s overwhelming evidence that HPV screening is more effective than the Pap smear test, which misses about a third to a half of all high grade lesions. There are now several available commercial HPV tests and most of these tests show a sensitivity (the proportion of true positives correctly identified) in the order of 95% for high grade lesions, whereas cytology is somewhere between 50-70%. So it would really streamline the service because you could test less frequently, and it’s also been shown that the protection lasts longer so that screening every five to seven years is probably appropriate.”

However, he warned that the European Union and national governments should take the initiative in discussions on implementing screening and vaccination programs, rather than leaving it to pharmaceutical companies to lead the debate.

“The European Commission and Parliament, together with national governments, could be doing more to promote HPV testing. One of the most useful things the EU could do would be to provide a forum for the dissemination of knowledge about the role of HPV both to doctors and to the general public. It could sponsor a major symposium to discuss HPV testing, vaccination and the best strategies for implementing programs in member countries."

“There’s been a lot of concern, particularly with the vaccine, that dissemination of information about HPV has come mainly from the drug companies, and people are, not surprisingly, a little sceptical of pharmaceutical-based education programs. So if the EU was to take this up without pharmaceutical support, I think it would be very appropriate and it would provide a forum that would be extremely legitimate.”

Although current HPV tests are more expensive than cytology tests, Prof Cuzick said the price would go down as the volume of tests increased. In addition, the fact that it’s more accurate and women could be screened at longer intervals meant that switching to HPV testing could save governments money in the long term.

“For younger women we think HPV testing should happen every five years starting at age 25-30; by the time they’re 50, if they’ve been negative, they could probably be screened every eight years. So there’s a lot to be gained, both in terms of better protection and less frequent screening, which will save time and money. If women can go less often and get more protection it makes a lot of sense.”

For more information:

• Oncopolicy session: Drug and lifestyle mediated prevention initiatives in Europe. Thursday 11.15-12.15 hrs CEST (Hall 3)
• Merck Manuals for Healthcare Professionals

Also read these Pubmed Abstracts

• Franceschi S, Cuzick J, Herrero R, Dillner J, Wheeler CM. EUROGIN 2008 roadmap on cervical cancer prevention. Int J Cancer. 2009 Jun 11;125(10):2246-2255. [Epub ahead of print]
• Breitenecker G. [Cervical cancer screening : Past - present - future.] Pathologe. 2009 Sep 16. [Epub ahead of print] German.
• Dinas K, Nasioutziki M, Arvanitidou O, Mavromatidis G, et al. Awareness of human papillomavirus infection, testing and vaccination in midwives and midwifery students in Greece. J Obstet Gynaecol. 2009 Aug;29(6):542-6.
• Lynge E, Antilla A, Arbyn M, Segnan N, Ronco G. What's next? Perspectives and future needs of cervical screening in Europe in the era of molecular testing and vaccination.
  Eur J Cancer. 2009 Oct;45(15):2714-21. Epub 2009 Aug 18.
  Franco EL, Coutlée F, Ferenczy A. Integrating human papillomavirus vaccination in cervical cancer control programmes. Public Health Genomics. 2009;12(5-6):352-61. Epub 2009 Aug 11.
• Ginsberg GM, Edejer TT, Lauer JA, Sepulveda C. Screening, prevention and treatment of cervical cancer-A global and regional generalized cost-effectiveness analysis.
  Vaccine. 2009 Jul 31. [Epub ahead of print]
• Barzon L, Giorgi C, Buonaguro FM, et al, Guidelines of the Italian Society for Virology on HPV testing and vaccination for cervical cancer prevention. Infect Agent Cancer. 2008 Dec 16;3(1):14

Information for your patients:

• Genital HPV Infection - CDC Fact Sheet
• Virus del papiloma humano genital (VPH)
• Center for Young Women's Health
• Merck Manuals (Home Edition) for Patients and Caregivers: Cervical Cancer
• Onco'Zine - The International Cancer Network

Images courtesy American Society of Clinical oncology (ASCO).

New diagnostic procedures: a new, quick test for prostate cancer

Prostate cancer is the most common cancer diagnosed in men in the UK and many other developed countries, including the United States. In the UK 35,000 men are diagnosed each year with prostate cancer. To emphasis the gravity of the disease, one man dies every hour of prostate cancer in the UK. African Caribbean men are three times more likely to develop prostate cancer than Caucasian men. In the United States, the estimated number of new cases prostate cancer is more than 192,000 with 27,000 deaths.

A new, fast, diagnostic procedure
Researchers have developed the test by using light energy to measure the level of citrate in fluid samples from the prostate gland. The technique could provide the basis of a rapid means of detecting prostate cancer in the future. Almost a quarter of male cancers in the UK are diagnosed as prostate cancer and more than 10,000 men die from the disease each year.

Scientists, led by Prof David Parker from Durham University’s Chemistry Department, have worked with experts from the University of Maryland, USA to develop the technique that measures the wavelength of light as it is shone through diluted samples of body fluids.

The research team, funded by the North East Proof of Concept Fund and the EPSRC, believe that the technique which can measure, with speed and accuracy, how citrate levels fall in the prostate gland as cancer develops, could also find use for the diagnosis of other medical conditions, associated with poor kidney function.

Prof Parker said: “Citrate provides a significant biomarker for disease that may provide a reliable method for screening and detecting prostate cancer, and for the monitoring of people with the disease. This technique could form the basis of a simple screening procedure for prostate cancer that could be used in outpatient departments at local hospitals.”

His team have shone light into over 100 different chemical structures to see how they function and respond to the presence of certain important bioactive species. They have looked particularly closely at how citrate and lactate bind to luminescent structures within fluids. Citrate and lactate are vital for our bodies’ metabolism for normal function. Citrate provides energy for cells and the amount found in the prostate varies considerably due to an enzyme called m-aconitase which transforms it. This enzyme is very sensitive to zinc and, in prostate cancer sufferers, zinc levels are depressed and the enzyme switches on again.

Prof Leslie Costello from the University of Maryland said: “Citrate is formed in cell metabolism processes which alter as cancers grow. The analysis of the citrate concentration of prostatic fluid can provide an accurate way to screen and diagnose prostate cancer. Since citrate concentrations decrease markedly early in malignancy, this technique makes it possible to analyse what’s happening quickly in the early and treatable stage of prostate cancer. It shows much promise as a clinical tool.”

The new test requires only a microlitre of fluid and the sample can be easily measured in an optical instrument. Using samples from male volunteers, the researchers have developed a portable instrument that can give results in 3 minutes.

The team’s challenge has been how to accurately measure changes in the amount of citrate or lactate in fluid samples using the technique. The early results are promising and the team intends to look at the analysis of other body fluids. A possible way forward is to examine the citrate levels in seminal fluid samples, which are made up of 50% prostate fluid.

Technology Transfer
The University has launched a spin-out company called FScan Ltd to develop the technique and to seek commercial backing. The team has looked at 20 samples so far and verified the analysis in every case. The next stage is to work with a local hospital and examine samples from 200 volunteers to see whether the first Durham results correlate.

Prof Parker says: “It’s been a complex process to develop the technique but we’re very optimistic about it. Ultimately, this could provide an accurate method of screening for prostate cancer in men that could be carried out in 3-minutes once a biopsy has been obtained from the patient at a hospital outpatient department.”

The Prostate Cancer Charity believes that this new, three minute test could effectively help to diagnose prostate cancer.

The discovery follows the invention in 2006 by Durham University Professor Douglas Newton of a Urine Flow Meter. The UFlow Meter helps men to assess if they have a restricted rate of urine flow - one of the warning signs of prostate problems.

The establishment of FScan Ltd is part of the University’s aim to enhance the exploitation of the Intellectual Property generated by high quality research activities.

Tim Hammond, Head of Technology Transfer at Durham University, said: '”We quickly realised the potential of this research and have worked closely with Professor Parker and his team to secure initial proof of concept funding through NorthStar Equity Investors and the North East Proof of Concept Fund and to establish FScan Limited as the vehicle to validate and commercialise the technology.”

John Neate, Chief Executive of The Prostate Cancer Charity, an organization striving for a world where lives are no longer limited by prostate cancer,explains: “This is early stage research, with the citrate levels of only 20 samples being tested. The results of a biopsy take around two weeks to come back to a patient and the main benefit of this new potential test would be one of speed. If the findings of further research in a large group of men remain consistent with these early results, the test could add something beneficial to the diagnostic tools currently available. Men could have a clearer idea of whether they have the disease, before the biopsy results confirm this. The full biopsy results would still be necessary, however, to confirm whether a man has an aggressive or non-aggressive form of the disease."

“The benefit of the test to men living with non-aggressive forms of prostate cancer, who are being treated with active surveillance, is less clear. This new test, which involves the insertion of a needle into the prostate under local anaesthetic, is an invasive procedure when compared to the current practice of monitoring the progression of the disease using the PSA blood test. The researchers hope to able to refine the test by using samples of seminal fluid which may be easier to obtain. If this was the case, it would be easier to see how this test could take a useful place in clinical practice."

“The acceptability of the test as a broader screening tool is problematic, given its invasive nature.”

Process for testing
1. Sample of prostatic fluid taken from patient in hospital using local anaesthetic
2. 200 fold dilution of 1 microlitre of sample with a buffer solution into pre-coated disposable cuvettes.
3. Optical spectroscopy on the sample, using a versatile bench top instrument with easy to use software.
4. Reading of results after 3 min measurement cycle directly reading out actual citrate concentration.

The sample is taken from the prostate gland – this is part of the biopsy procedure during clinical analysis in urology.

For more information, read the following PubMed abstracts:

• Croswell JM, Kramer BS, Kreimer AR, et al. Cumulative incidence of false-positive results in repeated, multimodal cancer screening. Ann Fam Med. 2009 May-Jun;7(3):212-22
• Prorok PC, Andriole GL, Bresalier RS, et al. Design of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Control Clin Trials 2000 Dec;21(6 Suppl):273S-309S.
• Hessels D, Schalken JA. The use of PCA3 in the diagnosis of prostate cancer. Nat Rev Urol. 2009 May;6(5):255-61
• Ferlay J, Autier P, Boniol M, et al. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol. 2007 Mar;18(3):581-92. Epub 2007 Feb 7.

Other resources:

• National Cancer Institute - Factsheet Prostate Cancer
• National Cancer Institute - About Prostate Cancer

Information for your patients:

• National cancer Institute: the online booklet What You Need To Know About™ Prostate Cancer to learn about prostate cancer symptoms, diagnosis, treatment, and questions to ask the doctor.

Fig. 1 : Range of citrate levels measured using the new optical probe