Patients with advanced, recurrent, or persistent cervical cancer that was not curable with standard chemotherapy who received the drug bevacizumab (Avastin?; Genentech/Roche) lived 3.7 months longer than patients who did not receive the drug according to findings from a large, randomized Phase III clinical trial (GOG240).[1]

These results were released, based on an interim analysis, in February 2013, and updates were presented today by Krishnansu Sujata Tewari, MD,a professor of obstetrics andgynecology attheUniversity of California, Irvine Medical Center as part a the Plenary Session [2] of the 49th annual meeting of the American Society of Clinical Oncology(ASCO), being held in Chicago, May 31 – June 4, 2013. The trial was sponsored by the National Cancer Institute (NCI) and conducted by a network of researchers led by the Gynecologic Oncology Group (GOG).

Cervical cancer is caused when cells of the cervix, the lower part of the uterus, become cancerous. According to the American Cancer Society, cervical cancer can often be found early and sometimes even prevented entirely by having regular Pap smears and human papilloma virus (HPV) tests. There is a dramatic difference in survival rates between early and advanced cervical cancer.

When localized, at least eight out of 10 women will live for five years following diagnosis. However, when the disease is advanced (metastatic) then the number of women who will live for five years or longer, drops to below one in seven women.

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It is estimated that more than 12,000 new cases of cervical cancer will be diagnosed in the United States in 2013.Chemotherapy regimens are largely ineffective against advanced cervical cancer. As a result,approximately 4,000 women in the U.S. die from the disease each year; worldwide cervical cancer takes afar higher toll, claiming 250,000 women?s lives every year. This is the first study showing that a targeteddrug that blocks blood vessel formation in the tumor (angiogenesis) can prolong survival for women withgynecologic cancers.

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Adding bevacizumab to standard chemotherapy improves survival for women with advanced cervical cancer.


?Women with advanced cervical cancer don?t have many options. We finally have a drug that helpswomen live longer,? said lead study author Tewari said.?This is also possibly a first steptoward turning cervical cancer into a chronic disease, helping women live longer and allowing time foradditional treatments that could further slow the cancer?s progression and improve survival.?

Study design
The GOG240 trial was designed to answer two important questions: Whether topotecan in combination with paclitaxel was superior to cisplatin and paclitaxel in combination, and whether the addition of bevacizumab to either regimen improved overall survival in women with advanced, Stage IVB, cervical cancer, or cervical cancer that persisted or recurred after standard treatment. The primary endpoint of the study was OS.

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. Patients were randomly assigned to one of four treatment groups; two of the treatment groups received bevacizumab. In an analysis conducted in 2012, it was determined that topotecan plus paclitaxel was not superior to the standard therapy of cisplatin plus paclitaxel and researchers, investigators and patients were notified of the finding at that time.

Blocking the blood supply
The purpose of bevacizumab is to block the blood supply that feeds the tumor. The drug originally was approved for certain types of metastatic cancer in combination with chemotherapy and is designed to bind to and inhibit vascular endothelial growth factor (VEGF). VEGF is a protein that plays a critical role in tumor blood vessel growth.

The study showed that the addition of bevacizumab to standard chemotherapy extended the lives of women with advanced cervical cancer, compared to chemotherapy alone. The study met its primary endpoint of improving overall survival (OS) with a statistically significant 29% reduction in the risk of death for women who received bevacizumab plus chemotherapy compared to those who received chemotherapy alone (HR=0.71, p=0.0035).

Living longer
The patients, whose median age was approximately 47 years old, received a dose of 15 milligrams per kilogram (mg/kg) of body weight of bevacizumab administered in the vein with their chemotherapy treatment and continued with this dose one day every three weeks until disease progression or unacceptable toxicity occurred.

The study results show that women who received bevacizumab plus chemotherapy lived a median of 3.7 months longer compared to those who received chemotherapy alone; the median OS was 17.0 months with bevacizumab plus chemotherapy compared to 13.3 months for chemotherapy alone. No new safety signals related to bevacizumab were observed and overall safety was consistent with that seen in previous pivotal studies of bevacizumab across different tumor types.

Progression Free Survival
Women who received bevacizumab plus chemotherapy experienced a 33% reduction in the risk of disease worsening or death (PFS;progression-free survival) compared to chemotherapy alone. This survival difference was highly statistically significant. The progression free survival was 8.2 months for those who received bevacizumab vs. 5.9 months for those who received chemotherapy alone (median PFS: 8.2 months vs. 5.9 months; HR=0.67, p<0.002). Bevacizumab plus chemotherapy further shrank more tumors (response rate) than chemotherapy alone (48% vs. 36%, respectively, p=0.0078).

Adverse Events
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, gastrointestinal events, hematologic events (neutropenia or low white blood cell count and bleeding), and thromboembolism, or formation of blood clots. Quality of life during the trial was also measured and there was no significant difference reported by patients between those who received bevacizumab and those who received chemotherapy alone.

In conducting the study, researchers did not observe new safety signals and the overall safety was consistent with that seen in previous pivotal studies of bevacizumab across tumor types. There was no increase in treatment related deaths in the bevacizumab plus chemotherapy group as compared to the chemotherapy alone group.

“The findings in this clinical trial are important because they are likely to change clinical practice and provide an opportunity to improve outcome in patients with recurrent cervical cancer who have previously had very limited treatment options,” Tewari noted.

Generally, the results indicate thatsurvival benefit associated with bevacizumab did not come at the cost of diminished quality of life.?Treatment options for women with recurrent or advanced disease have been insufficient for far too long.
This study clearly shows how our nation?s investment in clinical cancer research pays off, offering thefirst ever treatment to extend the lives of women with aggressive cervical cancer,? said Carol Aghajanian,
MD, gynecologic c
ancers expert andASCO spokesperson.

Welcome News
In commenting on the trial results, Jeff Abrams, M.D., clinical director of NCI?s Division of Cancer Treatment and Diagnosis said: “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.”

Bevacizumab is currently approved by the U.S. Food and Drug Administration (FDA) for use in several advanced cancers, but has not to datereceived approval in any gynecologic cancer.

For more information
– Full Prescribing Information on bevacizumab.

References
[1] NCT00803062– Paclitaxel and Cisplatin or Topotecan With or Without Bevacizumab in Treating Patients With Stage IVB, Recurrent, or Persistent Cervical Cancer
[2] Tewari KS, Sill M, Long HJ, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ, Leitao MM, et al. Incorporation of bevacizumab in the treatment of recurrent and metastatic cervical cancer: A phase III randomized trial of the Gynecologic Oncology Group. J Clin Oncol 31, 2013 (suppl; abstr 3)

For more information:
Abstract #3: Incorporation of bevacizumab in the treatment of recurrent and metastatic cervical cancer: A phase III randomized trial of the Gynecologic Oncology Group.
Plenary Session
Study Author: Krishnansu Sujata Tewari, MD, University of California Irvine Medical Center
Date: Sunday, June 2, 2013, 2:50 ? 3:05 PM CDT
Location: Room: N Hall B1 Orange, CA

Photo: Krishnansu Sujata Tewari MD. Photo Courtesy: ? ASCO/Silas Crews.

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