Cervical Cancer: paradigms at home and abroad

Cervical cancer, a disease that will affect more than 12,000 women in the United States this year and more than a half million women worldwide,  leads to significantly fewer deaths when effective early detection methods are available, either via a Pap smear or with a test for presence of the human papilloma virus (HPV).  However, such tests aren’t readily available to many women in low-resource settings, and even for those women with access to health care services, compliance with recommendations for testing is not assured. For example, among women with access to care, 50 percent of those who developed invasive cervical cancer had not been screened three years prior to their diagnoses. Until screening usage is widespread in all populations and incidence rates drop dramatically, there will be far too many deadly cases of this disease, and these cases will more likely be found in women from low-resource settings, both domestically and abroad.

If cervical cancer is caught sufficiently early, it often can be cured. Conversely, for those women who present with late-stage disease, there remains a need for better therapies. At this year’s plenary session at the annual meeting of the American Society of Clinical Oncology in Chicago on June 2, 2013, issues related to cervical cancer were front and center. NCI was a large part of this discussion, having sponsored a clinical trial that will have an important impact on the treatment of late-stage disease, and also having funded a screening trial in India using a network of community outreach workers to offer low tech-screening by direct visualization of the cervix coated with dilute acetic acid (vinegar), a process known as VIA.

Cervical cancer microvessel density showing blood supply to tumor

Discussants for the findings presented at ASCO were Ted Trimble, M.D., director of NCI’s Center for Global Health, and for the screening trial, Sarah Kobrin, Ph.D., program director in the Process of Care Branch of the Behavioral Research Program, NCI.  Trimble and Kobrin traveled to India to meet with a team of doctors, nurses, and community health workers, as well as two patients who had been in the trial (Reference: “Effect of visual inspection with acetic acid (VIA) screening by primary health workers on cervical cancer mortality: A cluster randomized controlled trial in Mumbai, India,” by Surendra Srinivas Shastri, M.D., of Tata Memorial Hospital, India, and colleagues).

Commonly used in the U.S. and higher-resource countries, the Pap smear is a relatively sophisticated test that requires trained cytologists to examine the cells retrieved from the cervix and consistently identify samples that are abnormal.  Shastri’s study looks at the less sophisticated technique of VIA that relies on direct visualization of the cervix after it is swabbed with vinegar.  His challenge was not only to identify a test that works, but also to find a method to get the test to women in communities where health care facilities and transportation may present challenges.

In the trial, local health workers and community residents were identified and trained to provide VIA to women who needed screening. More than 75,000 women from 10 communities had multiple rounds of VIA.  The screened women were compared to over 76,000 women from 10 similar communities where women were informed about cancer risks and the available screening facilities, were given vouchers for free cervical cancer screening at Tata Memorial hospital, but were not offered the outreach system with VIA performed by community health workers. The trained outreach workers also helped ensure that women with abnormalities were escorted to Tata Memorial hospital, where they underwent re-examination with colposcopy (which uses a tool to provide an illuminated, magnified view of the cervix) and then received appropriate diagnostic testing and treatment.  The findings from this study showed that the community screening group had a 31 percent reduction in death due to cervical cancer, which is significant.

The success of this trial in reducing death can be attributed to the combination of the VIA test and the outreach system Shastri’s team developed. Interim results from this study were published in the International Journal of Cancer (Reference: “A cluster randomized, controlled trip of breast and cervical cancer screening in Mumbai, India: methodology and interim results after three rounds of screening.” 2010:126:976-84. Indraneel Mittra, Gauravi A Mishra, et al).  Other studies that incorporated the VIA test did not show such positive results, perhaps because they had different systems of follow-up.

In Western populations, new cases of cervical cancer are not frequently seen at an advanced stage because early-stage detection is much more common and effective, via either a Pap smear or HPV test. Where not identified at an early, curable stage, cervical cancer can spread locally and into distant organs. Advanced cervical cancer is difficult to treat and is life-shortening for the generally young women who are diagnosed with it. At ASCO, Trimble also discussed key findings of an NCI-supported clinical trial (Reference: “Incorporation of bevacizumab in the treatment of recurrent and metastatic cervical cancer: A phase III randomized trial of the Gynecologic Oncology Group”).  Preliminary results from this trial were announced by NCI in February 2013 (see http://www.cancer.gov/newscenter/newsfromnci/2013/GOG240).

Bevacizumab (Avastin) is a drug designed to bind to the VEGF (vascular endothelial growth factor) protein. Bevacizumab may block a tumor’s ability to tap into nearby blood vessels and may prevent the tumor from connecting to the blood supply it needs for continued growth. This Gynecologic Oncology Group study used bevacizumab, along with other conventional chemotherapy agents, in women with advanced, recurrent, or metastatic cervical cancer that was not curable. The trial compared women who received bevacizumab plus chemotherapy with those who received chemotherapy alone and found those who received bevacizumab had lower mortality, with a nearly four month longer survival.  This is a significant survival advantage for an advanced cancer that can progress rapidly.

Specifically, a total of 452 patients in the United States and Spain with metastatic, recurrent, or persistent cervical cancer not curable with standard treatment were enrolled between 2009 and 2012. The trial was designed to answer two questions. First, it looked at two combinations of chemotherapy drugs, in an attempt to determine whether topotecan in combination with paclitaxel was superior to cisplatin and paclitaxel in combination. The study then examined whether the addition of bevacizumab to either regimen improved overall survival.

Patients who received bevacizumab lived a median 3.7 months longer than those who did not receive bevacizumab. Progression free survival, meaning that after treatment the disease did not worsen, was 8.2 months for those who received bevacizumab vs. 5.9 months for those who received chemotherapy alone. However, patients receiving bevacizumab experienced more side effects than those who did not. These side effects were consistent with side effects previously known to be associated with bevacizumab and included hypertension, neutropenia (a low white blood cell count), and thromboembolism, or formation of blood clots.  Quality of life during the trial was also measured and there were no significant differences reported between those who received bevacizumab and those who received chemotherapy alone.

“This is welcome news, as progress has been very difficult against this cancer, and GOG physicians and patients who participated have made an important contribution,” said Jeff Abrams, M.D., clinical director of NCI’s Division of Cancer Treatment and Diagnosis.

The trial in India of acetic acid and the trial in the United States of bevacizumab would seem, on the surface, to be unrelated. The facts are more nuanced. Vinegar is inexpensive but bevacizumab, like many advanced chemotherapy agents, is relatively expensive. Visualization of the cervix using acetic acid to improve early diagnosis combined with effective patient assistance and appropriate follow-up can make a difference in places where cervical cancer is the leading cause of women’s cancer and women’s cancer deaths. Bevacizumab is an option for therapy of already advanced disease.  

“NCI’s hope is that the research reported at ASCO this year with acetic acid visualization will ultimately make the need for use of bevacizumab and chemotherapy agents, as well as for studies in advanced cervical cancer, a much reduced occurrence,” said Elise Kohn, M.D., head of the gynecologic program in NCI’s Clinical Investigations Branch.