Combining drugs and radiotherapy improves the survival chances of women receiving treatment for cervical cancer. These are the conclusions of Cochrane Researchers who carried out the most comprehensive study of the effects of combined drug and radiotherapy in cervical cancer treatment to date.

Cervical cancer is the second most common cancer in women worldwide. Treatments for the disease have changed markedly over the last decade as a result of guidelines issued by the National Cancer Institute (NCI) in 1999, which stated that chemoradiotherapy should be considered as an alternative to radiotherapy. Chemoradiotherapy combines chemotherapy (drug treatment) and x-ray treatment, whereas radiotherapy is just x-ray treatment.

“We saw clear evidence that adding chemotherapy to radiotherapy improves survival, as well as disease free survival,” said Claire Vale, of the Medical Research Council Clinical Trials Unit in London in the UK. “These are effective, affordable treatments that provide a benchmark for other potential treatment approaches.”

The researchers analysed data from 15 trials involving a total of 3,452 women. They found that compared to women who had radiotherapy alone, women receiving chemoradiotherapy were more likely to live for longer after treatment. Five years after receiving treatment, 66 out of every 100 women survived with chemoradiotherapy compared to 60 out of 100 with radiotherapy. In addition, treatment with chemoradiotherapy reduced the chance of the cancer coming back or spreading to other areas. Crucially, their analysis showed that the benefits of chemoradiotherapy were not just restricted to the platinum-based drugs recommended by the NCI.

Based on a small subset of the data, there was also an indication that continuing drug therapy after chemoradiotherapy could improve survival rates even further, although the researchers say more studies are required to confirm this. “We suggest that new trials are needed to find out whether giving extra chemotherapy is better for women with cervical cancer or not,” said Vale.

An article published Online First in The Lancet Oncology reports that human papillomavirus (HPV) DNA testing prevents more invasive cervical cancer compared to cytology screening alone. It detects persistent high-grade lesions which lead to cervical cancer at an earlier time. Consequently, HPV testing should become the main screening tool for women aged 35 years or older at longer screening intervals, with cytology reserved for triage of women who test positive for HPV.

DNA testing for HPV is widely recognized as superior in detection of precancerous lesions called high-grade cervical intraepithelial neoplasia (CIN2 and CIN3) compared with cytology. However, HPV testing is less exact. It also results in more false-positive tests than conventional Pap smears. However, it is unclear whether shifting to HPV testing from standard cytology in cervical cancer screening programmes increases their effectiveness in preventing invasive cervical cancer. This is particularly true in developed countries where advanced cervical cancers are rare among screened women.

Guglielmo Ronco and colleagues from Italy led The New Technologies for Cervical Cancer (NTCC) screening study. It reviewed the benefits and risks of introducing HPV testing for cervical cancer screening and evaluated the most appropriate age for initiating HPV testing.

Two rounds of screening were done for two separate recruitment phases. Women, aged 25 to 60 years, were randomly assigned to conventional cytology only or to HPV testing plus cytology (first phase) and HPV testing alone (second phase). During both phases all women with an abnormal cytology result were referred to colposcopy. In the HPV group, during phase one all women who were HPV-positive and aged 35 to 60 years were referred to colposcopy, whereas women aged 25 to 34 years were referred to colposcopy only if cytology was also abnormal or if HPV testing was persistently positive. During phase two, women in the HPV group were referred for colonoscopy if the HPV test was positive.

A similar number of invasive cancers were detected in each group according to the findings in the first round of screening. There were nine in the cytology group compared with seven in the HPV group. But in the second round no cancers were detected in the HPV group compared with nine in the cytology group. This suggests that HPV-based screening is more effective than cytology at preventing invasive cervical cancer, probably because of earlier detection and treatment of CIN.

Significantly, for women aged 35 years or older, the combination of HPV testing with cytology did not increase the sensitivity of screening. This indicates that increased detection of CIN3 was primarily due to HPV testing.

On the other hand, among younger women aged 25 to 34 years, HPV testing led to over-diagnosis and treatment of regressive CIN2 lesions which is associated with increased risk of pregnancy-related morbidity.

The authors explain: “Our data support the use of stand-alone HPV testing as the primary screening test. The extremely low detection of CIN3 at round two in the HPV group (2 per 10 000) indicates that HPV-based screening at extended intervals is safe.”

They say in conclusion: “Further follow-up is needed to define how long screening intervals can be safely extended. Research is needed to define the optimum management of HPV-positive women…to minimise the costs related to increased referral to colposcopy and overdiagnosis of regressive lesions.”

In an associated comment, Philip Castle and Hormuzd Katki from the National Cancer Institute in the USA write in conclusion: “HPV testing shows a great deal of promise to revolutionise cervical cancer screening…We advocate that clinical management be based on estimating a woman’s individual risk of cervical precancer, rather than complex algorithms. Data from the current study could be used to develop risk estimates to make the promise of more effective and cost-effective cervical cancer prevention a reality.”

“Efficacy of human papillomavirus testing for the detection of invasive cervical cancers and cervical intraepithelial neoplasia: a randomised controlled trial”

In observance of National Cervical Health Awareness Month, The American College of Obstetricians and Gynecologists (the College) has an important message for women: All women should have an annual well-woman exam, but not all women need annual Pap tests. For many women, the College now advises Pap testing at regular intervals instead of every year, based on their age, risk factors, and previous cervical screening test results.

In 2009, an estimated 11,270 new cases of cervical cancer were diagnosed in the US, and the disease caused over 4,000 deaths. The Pap test is a highly effective tool in detecting cervical cancer at its earliest and most treatable stages. In fact, regular cervical screening tests can actually find precancerous changes before they become dangerous and turn into cancer.

Getting regular, but less frequent, Pap tests is a safe option for many women, according to new evidence-based guidelines issued in December 2009 by The American College of Obstetricians and Gynecologists. The College now recommends that Pap testing start at age 21 and that women ages 21-29 be screened every two years; women age 30 and older can be screened every three years. However, women with certain risk factors and health issues may need more frequent screening.

The College acknowledges that reducing the frequency of Pap tests may be met with resistance by many women, but the bottom line is that research has shown less frequent cervical screening to be just as effective in preventing cancer as annual screening. Consequently, overscreening for cervical cancer may actually do more harm than good and can lead to unnecessary treatment and future childbearing implications.

One of the reasons why cervical cancer is more common among poorer women could be because they start having sex at a younger age than more affluent women, scientists have said.

Although deprived women are twice as likely to get cervical cancer as more affluent women, research has shown that their levels of infection with the human papillomavirus (HPV) – which is responsible for the majority of cases of cervical cancer – tend to be similar.

Researchers at the International Agency for Research on Cancer investigated the link between deprivation and higher cervical cancer risk. Until now, experts thought that the difference in cases of the disease could be just because poorer women were less likely to go for cervical screening.

Although screening uptake had an effect, this latest international study looked at many countries without screening programmes and found that poorer women were still more likely to develop the disease.

The researchers looked at how many years a woman had been in education, which gave them an indication of their socio-economic status.

As expected, researchers found that the least educated women were more likely to develop cervical cancer than the most educated women.

But the study also showed that the age at which a woman started having sex and the age at which she had her first baby were the most important factors explaining this increased risk.

Commenting on the study, which is published in the British Journal of Cancer, Dr Silvia Franceschi, lead author from the International Agency for Research on Cancer, said: “We weren’t sure why cervical cancer is more common in poorer women.

“Levels of HPV infection were approximately the same across the board and, in some countries, even higher among the richest women.

“We now think that it’s because in our study, poorer women had become sexually active on average four years earlier.”

Dr Franceschi suggested that this exposure to HPV at an earlier age may give the virus “more time to produce the long sequence of events that are needed for cancer development”.

The researcher also explained: “In a previous large international study, we also showed that this trend was not restricted to adolescence and that the risk of cervical cancer was also higher in women who had their first sexual intercourse at 20 rather than 25 years.”

Dr Lesley Walker, director of cancer information at Cancer Research UK, said that the study raises some interesting questions.

“Although women can be infected by HPV at any age, infections at a very young age may be especially dangerous as they have more time to cause damage that eventually leads to cancer,” she explained.

“Importantly, the results back up the need for the HPV vaccination to be given in schools at an age before they start having sex, especially among girls in deprived areas.

“We strongly advise all women to attend cervical screening when invited. Women should also visit their doctor without delay if they have symptoms – such as bleeding between periods or after the menopause and pain during sex.”

In the 1980s, Harald zur Hausen and his co-workers discovered that specific types of human papillomavirus (HPV) cause cervical cancer. Scientists soon found out how these pathogens cause cells to degenerate. It is known today that the main culprits are viral proteins E6 and E7. Both proteins switch off different cellular control functions, thus promoting cell growth.

Professor Dr. Frank Rösl and his co-workers at DKFZ have now discovered another mechanism by which the E6 oncoprotein of high-risk HPV16 promotes carcinogenesis. The oncogene silences production of an immune protein called interferon-kappa. Interferons are proteins which are part of our immune system and are responsible primarily for stimulating the immune response to viruses and tumors. Interferons are produced by white blood cells and other cell types. Interferon-kappa is relevant for HPV infections, because it is produced mainly in cells of the skin and mucosa (keratinocytes) which are the preferred hosts of the viruses. If interferon-kappa is not working in cells, other proteins involved in immune defense also cease to function properly.

Dr. Bladimiro Rincon-Orozco of Rösl’s team has now shown for the first time that HPV16 switches off the interferon-kappa gene by biochemical modification of DNA. Such alterations of the genetic material are called epigenetic mutations. Studying HPV infected cells in a culture dish, the research team observed that interferon-kappa is epigenetically silenced. They were later able to confirm this result in cervical cancer tissue samples.

“Interferon-kappa is an important part of what is called innate immunity,” Frank Rösl explains. Using this evolutionary old defense mechanism, the body can defend itself immediately after being infected with pathogenic agents, while formation of the specific “acquired” immune system may take some time. “By switching off the interferon production, the viruses prevent infected cells from being destroyed by this type of immune response,” says Rösl, explaining the strategy of the virus that causes cancer. In the next step, the researchers are planning to investigate whether administering interferon-kappa can slow down the growth of cervical cancer cells and may thus support treatment of the disease.