Advances in Preventing and Diagnosing Cervical Cancer

Somewhere in the world, a woman is dying of cervical cancer. In fact, a woman dies of cervical cancer almost every 2 minutes. According to the World Health Organization (WHO), it is the second leading cause of female cancer mortality worldwide, with 288,000 deaths and 510,000 cases each year. The Institutes of Health reports that in the United States, 11,270 new cases of cervical cancer were diagnosed in 2009; in that same year, 4070 women died of the disease. Unlike most cancers, which still have us searching for their causes, how to prevent them, and how to diagnose them before they become life threatening, we have essentially found these answers when it comes to cervical cancer.

Advances in screening and the approval of vaccines against the human papillomavirus (HPV), which causes 70% of cervical cancer cases, have brought us to a turning point with cervical cancer, just as Papanicolaou’s (Pap) test did in the 1940s. Although Georgios Papanicolaou invented the Pap smear in the late 1920s, it did not find acceptance in the medical community until the 1940s, at which time there were approximately 26,000 US cervical cancer deaths per year. Just 40 years ago, cervical cancer ranked as the number one cause of cancer death for women. Campaigns in the United States to increase awareness of the need for yearly Pap smears have contributed to a 638% drop in cervical cancer death. Yet, in low-income countries where Pap smears are far from routine, WHO reports that cervical cancer remains the leading cause of cancer death among women.

Who Gets Cervical Cancer?

According to the Centers for Disease Control and Prevention (CDC), 6 of every 10 cases of cervical cancer occur in women who have never had a Pap smear or any cytological test within the past 5 years. A Pap smear detects changes in the cells of the cervix associated with precancerous and cancerous states. The test does not detect HPV, a group of more than 40 virus strains that can infect genitalia and the mouth, and throat. Although we primarily associate just two strains of HPV—16 and 18—with cervical cancer, according to the National Cancer Institute (NCI), these two cause only 70% of cases. The remaining 30% are attributable to other HPV strains with high cancer-causing potential, including types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, and 73.

The American Council on Science and Health estimates that more than 5 million people in the United States become infected with HPV annually. The rate of new HPV infection is highest among sexually active adolescents, but the immune system in this demographic often clears the infection within 1 to 2 years, making cervical cancer rare in women aged <21 years.

HPV Vaccination

In 2006, the FDA approved Gardasil, a vaccine that prevents infection with cancer-causing HPV strains 16 and 18 and strains 6 and 11, which cause 90% of genital warts. Gardasil is approved for females and males aged 9 to 26 years and is administered in 3 doses over 6 months. Although giving the vaccine to boys and young men helps reduce the spread of certain HPV types and protects them against 90% of cases of genital warts. While Gardasil is not approved to prevent HPV-related cancers in males, evidence shows the virus is responsible for some cases of penile, anal, and head and neck cancers in males.

Studies have suggested that it is not cost-effective to immunize males against HPV, and few insurers provide coverage for HPV vaccination in this group. Analyses of the cost-effectiveness of HPV vaccination males assumes that most eligible females are getting properly vaccinated with Gardasil and this alone will suffice to reduce HPV-related cancers, but that is not the case. According to Tina Tan, MD, an infectious disease specialist at Children’s Memorial Hospital who serves on an advisory board on HPV in males for Merck and Co. (Gardasil’s manufacturer), less than 20% of females aged 13 to 17 have received all 3 doses of the vaccine.

Recent data presented at the annual meeting of the Society of Gynecologic Oncologists in March showed that Gardasil might also benefit women who already have HPV by protecting against recurrence of the virus in the first few years following their surgeries for HPV-related cancer. Other studies have suggested vaccinating women older than 26 if they are sexually active, with multiple partners, and HPV testing indicates that they are negative for HPV.

Last year, the FDA approved another HPV vaccination, Cervarix,which is used to prevent cervical cancer and precancerous lesions caused by HPV types 16 and 18. The vaccine is approved for use in girls and women aged 10 to 25 years. Cervarix is also administered in 3 doses over 6 months.

Future research and trials may lead to more effective HPV vaccinations, predicts Katina Robison, MD, Women’s Reproductive Health Research Scholar and Assistant Professor, Program in Women’s Oncology, Department of Obstetrics & Gynecology at The Warren Alpert Medical School of Brown University in Providence, Rhode Island. “There are currently trials under way evaluating vaccines that prevent up to 8 of the high-risk HPV genotypes,” said Robison.

“Eventually, I believe we will see an HPV vaccine that prevents the majority, if not all, high-risk genotypes. In addition, vaccines will be developed that do not require 3 injections—to allow for a more effective global vaccination effort.” Robison said it is clear researchers must continue to work on developing vaccines that not only prevent most high-risk HPV infection, but ones that are cost-effective and easy to administer.

HPV Testing

All vaccinations carry some risk of adverse effects, and research is still forthcoming regarding how long HPV immunization lasts and if booster vaccines are needed years later to provide prolonged immunity. In addition, the vaccines may not always be available in the areas where they are most needed and many parents have elected not to vaccinate their daughters because of fears that it has negative health and/or moral implications. Long latency between initial HPV infection and the onset of cancer requires more immediate measures to screen the generation of women born before HPV vaccination was available. For women who have been vaccinated, because neither vaccine protects against all strains of oncogenic HPV, testing remains necessary.

In 2003, prior to Gardasil’s approval, the FDA approved Digene, a rapid, standardized gene test that relies on DNA/RNA probes and monoclonal antibodies to identify 13 high-risk types of HPV. Digene is approved as a primary adjunctive screening with a Pap smear in women aged ≥30 years to identify cervical intraepithelial neoplasia (CIN) grades II an III, and thus indicate the need for colposcopy. It is also approved astriage for women with abnormal Pap results, to determine appropriate follow-up. A major benefit of the test is its ability to identify these HPV strains before any visible changes occur in the cervical cells. This might eventually allow women who are HPV-negative to get Pap smears less frequently. Pap smears have a fair number of false positives, leading to unnecessary expense for repeat tests or additional procedures. Women who test positive might need more frequent Pap smears than their HPV-negative counterparts, to watch for changes in the cells of the cervix.

In April 2009, the New England Journal of Medicine(Sankaranarayanan, et al) published results of a cluster-randomized clinical study involving cervical cancer screening of 131,746 healthy women in villages in Osmanabad India. Trial results showed that a single round of HPV screeningreduced the incidenceof advanced cervical cancer and cervical-cancer mortality within8 years—much more than a single conventional cytologic test orvisual inspection of the cervix with acetic acid (VIA). The women, aged 30 to 59 years, were randomly assigned to 4 groups of 13 clusters each. The groups assigned to undergo screening included 34,126 women who had HPV testing, 32,058 who underwent cytologic testing, 34,074 who had VIA, and a control group of 31,488 women who received standard care. In the HPV-testing group, cervical cancer was diagnosed in 127 subjects, with 39 cases ≥grades II. Cervical cancer was detected in 118 subjects in the control group, with 82 at advanced disease (hazard ratio [HR] for detection of advanced cancer in HPV-testing group, 0.47; 95% confidence interval [CI], 0.32-0.69). In the HPV-testing group, 34 women died of cervical cancer compared with 64 in the control group (HR, 0.52; 95% CI, 0.33-0.83). Researchers found no significant reductions in the numbers of advanced cancers or deaths between the cytologic-testing group or in the VIA group compared with the control group.

A two-phase study involving women aged 25 to 60 years was published this March in Lancet Oncology (Ronco, et al). In the first phase, women were randomly assigned screening with conventional cytology or HPV testing combined with liquid-base cytology. Nearly all the women underwent a second round of screening in phase one with cytology only. Women aged 35 to 60 years who were HPV-positive were referred for colposcopy; women aged 25 to 34 years underwent colposcopy if cytology testing was abnormal or if HPV testing was persistently positive. Testing identified 9 cases of invasive cervical cancer in the cytology group compared with 7 in the HPV group (P= .62).

The second phase of the study involved HPV testing alone. A total of 33,851 women from the cytology group and 32,998 from the HPV-testing group had a second round of screening. Among women aged 35 to 60 years, at round 1, the relative detection of HPV versus cytology was 2·00 for CIN II (95% CI, 1·44-2·77), 2·08 for CIN III (95% CI, 1·47-2·95), and 2·03 for CIN II and III together (95% CI, 1·60-2·57). In round 2, the detection of CIN II-III was much lower in the HPV group versus the cytology group. In both the HPV and cytology groups, similar numbers of cervical cancers were detected in the first round. In the second round, 9 additional women in the traditional cytology group had a cervical cancer diagnosis, even though all 9 had demonstrated normal cytology in round 1. No women in the HPV screening group were found to have cervical cancer in round 2 (P= .004).

“In addition, 44% of these cancers were adenocarcinomas, which is much higher than the incidence in the general population,” noted Robison. “These lesions were likely to be in the endocervical canal, and cytology would be more likely to miss these. In my opinion, this is the most important finding in this study because the goal of cervical cancer screening is to prevent cervical cancer. This study suggests adding HPV testing to cytology could actually prevent cervical cancers,” said Robison.

A longitudinal study published this April in the British Medical Journal(Anttila, et al) confirmed the benefits of HPV testing. This recent routine-organized program showed that primary HPV screening with a cytology triage is more sensitive than conventional cytology in detecting cervical cancer and the most severe, grade III CIN lesions, across all study age groups. Between 2003 and 2005, 58,283 women aged 30 to 60 years were included in the screenings. The study was based on a maximum follow-up of 5 years from index invitation from 2003 to 2007, within the population-based screeningprogram for cervical cancer in southern Finland.

In this study, 50% of participants received screening with HPV DNA testing and the other half received conventional cytology screening. After randomization, 107 women were excluded from the HPV arm and 99 from the conventional arm. In total, there were 191,218 womanyears at risk (67.0% in the HPV armand 66.3% in the conventional arm). More women experienced a positive screeningepisode, defined as any diagnosis of CIN or cervical cancer, in the HPV screening arm (110) thanin the conventional screening arm (72) and more in the HPV arm (1244) than in the conventional screening arm (1053) were recommendedfor intensified screening at the index screen. Compared with the conventional arm, the relativerate of grade III CIN in the HPV arm was 1.44 (95% CI,1.01-2.05) in all women invited to participate. The relative rate ofcervical cancer in the HPV arm compared with the conventionalarm was 0.75 (95% CI, 0.25-2.16) in invitees and 1.98 (95% CI, 0.52-9.38)in attendees (women who were screened and gave a cervical sample). Among invitees there were 6 cases of cancer in the HPV arm compared with 8 cases in the conventional arm; and for attendees, there were 6 cases in the HPV arm and only 3 in the conventional arm. Based on probability of progression of these types of lesion in women aged ≥35 years, the benefit of primary HPV testing could certainly be life saving.

Results from these trials and others that are currently in progress will further determine the best processes for screening and diagnosis of cervical cancer. “The ideal method for screening and diagnosis of cervical cancer is likely to vary based on geographic region and resources available,” said Robison. In October of 2009, the International Federation of Gynecology and Obstetrics released guidelines for cervical cancer screening and treatment, which Robison said vary based on resources available.¹ “In my opinion, HPV testing will become the method of screening globally,” she added. “It will likely become the primary screening modality in resource-poor areas, but potentially only be performed once in a woman’s lifetime. It is a more sensitive method of screening.” She envisioned a different testing scenario for women in North America. “I feel HPV testing will be used in conjunction with cytology, and its use will likely vary based on the age of the patient. I think as HPV testing becomes more cost effective, cytology may fall out of favor as it is unclear that it adds a lot to the sensitivity of screening,” said Robison.

Imagine the thrill Georgios Papanicolaou would feel today, knowing that advances in liquid-based cytology, vaccinations, and HPV testing have taken his dream of reducing cervical cancer deaths to a whole new level. With widespread adoption of HPV vaccination in females and HPV testing, some countries could potentially see the eradication of this killer disease within the next 50 years.