The Gynecologic Oncology Group: Advancing The Prevention And The Treatment Of Gynecologic Cancers
The Gynecologic Oncology Group (GOG), established in 1970 by a group of gynecologic surgeons interested in promoting a “collaborative research effort, not only among institutions but also among the various disciplines involved in the treatment of women with gynecologic cancers,” conducts research that has set the standard of care for many gynecologic cancers and has also addressed issues of quality of life and cancer prevention.1 The work of the GOG encompasses all gynecologic cancers, including cancers of the ovary, cervix, and uterus.
Recently, Philip DiSaia, MD, chair of the organization, took time from a hectic meeting schedule during the GOG’s 2008 summer meeting to talk about the importance of the organization’s research portfolio: “The GOG is the largest clinical trials group studying gynecologic cancer in the world,” says Dr. DiSaia, noting that the GOG now involves 70 university centers with more than 300 affiliates as well as an international group of researchers.
The group’s contribution to important research in the field, Dr. DiSaia says, can be seen in several current studies-like those evaluating the use of the targeted therapy Avastin® (bevacizumab) in advanced ovarian cancer. Avastin targets a protein known as vascular endothelial growth factor (VEGF), which is involved in the growth of new blood vessels; drugs that inhibit VEGF may slow cancer growth and enhance the delivery of chemotherapy to the cancer. Avastin is currently approved for selected patients with advanced colorectal, breast, or non–small cell lung cancer and may provide benefits with ovarian cancer as well. The GOG is also evaluating the role of maintenance therapy in ovarian cancer, which involves additional, modest doses of chemotherapy after initial treatment.
The GOG holds two major meetings each year to discuss ongoing research and establish future research priorities. This year’s summer meeting-held in Chicago-began with a symposium on cervical cancer. The first half of the symposium addressed the management of invasive cervical cancer, and the second half explored issues related to human papillomavirus (HPV) vaccination and cervical cancer prevention. Discussion of research priorities for other cancers-including ovarian cancer-were provided at focused workshops during the subsequent two days.
Management of Invasive Cervical Cancer
In 2008 more than 11,000 U.S. women will be diagnosed with invasive cervical cancer (cancer that has spread beyond the surface of the cervix to deeper areas of the cervix or other parts of the body).2 Very early-stage invasive cancer can often be treated with surgery or radiation alone, but more extensive cancer typically requires a combination of treatment approaches.
Treatment of Locally Advanced Cervical Cancer
Locally advanced cervical cancer refers to cancer that has spread beyond the cervix but not to distant sites in the body. This includes cancers that are Stage IIB to Stage IVA. Large Stage IB or IIA cancers may also be considered locally advanced.
A standard approach to the treatment of locally advanced cervical cancer involves a combination of chemotherapy (generally with Platinol® [cisplatin]) and radiation therapy. Building on this standard approach, the GOG is currently conducting a Phase III clinical trial (GOG 219) that will evaluate the addition of the drug tirapazamine to standard therapy with Platinol and radiation. The rationale for the study is that cancer cells are often hypoxic (have low oxygen levels). Hypoxia can interfere with the effectiveness of some cancer treatments, but tirapazamine is designed to work under hypoxic conditions. It is hoped that the combination of tirapazamine and Platinol will result in a lower risk of cancer recurrence than Platinol alone. The trial will enroll 750 women with Stage IB2, IIA, IIB, IIIB, or IVA cervical cancer. Approximately 260 women have been enrolled in the study thus far.
Systemic Therapy for Stage IVB and Recurrent Cervical Cancer
Metastatic cancer refers to cancer that has spread to distant sites in the body (Stage IVB). Recurrent cancer refers to cancer that has returned following treatment.
For many patients with advanced cervical cancer, treatment with the chemotherapy drug Platinol, sometimes in combination with a second drug such as Taxol® (paclitaxel), is a standard approach to treatment. Even with the best available chemotherapy regimens, however, survival with metastatic or recurrent cervical cancer remains suboptimal.
With the goal of improving outcomes among women with advanced cervical cancer, GOG researchers are preparing to launch a Phase III clinical trial known as GOG 240. Expected to begin enrollment in fall 2008, this study will evaluate two important questions:
- Can a non-Platinol-based chemotherapy regimen result in better outcomes than standard Platinol-based chemotherapy?
- What is the effect of adding the targeted therapy Avastin?
Study participants will be assigned to one of four treatment groups:
- Platinol plus Taxol
- Platinol plus Taxol plus Avastin
- Hycamtin® (topotecan) plus Taxol
- Hycamtin plus Taxol plus Avastin
The study will enroll 450 women with Stage IVB or recurrent/persistent cervical cancer.
Cervical Cancer Prevention: HPV Vaccines
Human papillomaviruses consist of more than 100 different viruses. Some types of HPV cause warts on the hands or feet, others cause genital warts, and some have been linked with cancer, most notably cervical cancer. The types of HPV most commonly linked with cervical cancer are HPV 16 and HPV 18, but several other high-risk types contribute to cancer as well.
The types of HPV that cause cervical cancer or genital warts are transmitted sexually. HPV infection is extremely common and generally occurs soon after an individual becomes sexually active. Although most infections resolve on their own, some persist and can lead to precancerous or cancerous changes to the cervix, vulva, vagina, penis, and anus.
Vaccines that prevent infection with high-risk types of HPV have the potential to greatly reduce the occurrence of cervical cancer. The HPV vaccine that is currently on the market is Gardasil® (Quadrivalent Human Papillomavirus Recombinant Vaccine), which targets HPV types 6 and 11 (which are linked with genital warts) as well as the cancer-associated types 16 and 18. Another HPV vaccine that may be approved is Cervarix,™ which targets HPV types 16 and 18 only. Because HPV types 16 and 18 are thought to account for roughly 70 percent of all cases of cervical cancer, widespread use of these vaccines would have the potential to eliminate most (but not all) cases of cervical cancer.
Gardasil and Cervarix each appear to be quite effective, and Gardasil has been approved for use in girls and women between the ages of nine and 26 years. Important remaining questions that were discussed at the GOG scientific session on cervical cancer prevention include the extent of cross-protection provided by HPV vaccines (the extent to which the vaccines protect against high-risk types of HPV other than HPV 16 and HPV 18), the value of vaccinating women over the age of 26, and differences in the composition of Gardasil and Cervarix.
Because different types of HPV share some structural similarities, it’s possible that the current vaccines (which protect against HPV 16 and HPV 18) may also provide a degree of protection against other, related, high-risk types of HPV. This would increase the benefit of vaccination. According to a presentation by Darron Brown, MD, of the Indiana University School of Medicine, there is evidence that both Gardasil and Cervarix provide some degree of cross-protection against related types of HPV.
Vaccination of Older Women
A discussion of the pros and cons of vaccinating older women (those over the age of 26) was led by Kevin Ault, MD, of the Emory University School of Medicine. Vaccination is likely to provide less protection to older women because many older women will already have been infected with HPV. Nevertheless, for women who have not been infected with all the HPV types included in the vaccine, vaccination is likely to provide some protection regardless of age. Dr. Ault noted that “midadult” women remain at risk of HPV infections, and initial looks at efficacy data in these women suggest that vaccine efficacy may be high.
Vaccine Adjuvants: Is Newer Better?
Finally, Levi Downs, MD, of the University of Minnesota School of Medicine and Mark Einstein, MD, of the Montefiore Medical Center debated the merits of two different vaccine adjuvants. An adjuvant is a component of the vaccine that enhances immune response. Cervarix and Gardasil each use a different adjuvant, and this may influence the strength and the duration of protection against HPV. The adjuvant used in Gardasil-amorphous aluminum hydroxyphosphate sulfate (AAHS)-has been used in other vaccines for many years. Cervarix, in contrast, uses a new adjuvant known as AS04, which is composed of aluminum hydroxide and monophosphoryl lipid A. The argument in favor of AAHS focused on its established safety profile. The argument in favor of AS04 focused on the possibility that it may eventually be shown to stimulate a higher or more sustained immune response.
To address the question of immunogenicity, a study is being planned to directly compare the immune responses elicited by Gardasil and Cervarix. Even if Cervarix is shown to produce a higher immune response, however, it may not prove any more effective than Gardasil at preventing cervical disease. Thus far both vaccines appear to be highly effective.
Priorities for Ovarian Cancer Research
Ovarian cancer remains the deadliest gynecologic cancer in the United States. In 2008 an estimated 21,650 women will be diagnosed with ovarian cancer and 15,520 will die of the disease.2 Improvements in survival will require both earlier detection of the disease (which is commonly diagnosed at an advanced stage) and new approaches to treatment. Surgical removal of as much cancer as possible followed by chemotherapy with Paraplatin® (carboplatin) and Taxol is a standard treatment approach for many women with ovarian cancer, but researchers continue to evaluate new drugs and new drug combinations as well as new approaches to drug delivery.
The meetings of the GOG Ovarian Committee focused on proposals for new Phase III clinical trials. The proposed studies focused on two high-risk populations: patients with platinum-resistant disease and patients with suboptimally debulked cancer. Patients are considered platinum-resistant if their cancer doesn’t respond to treatment with a platinum chemotherapy drug such as Paraplatin or if their cancer progresses shortly after treatment.
Debulking refers to the surgical removal of as much ovarian cancer as possible. Patients are considered optimally debulked if very little cancer remains following surgery (no tumors larger than 1 centimeter). If the amount of remaining cancer is greater than this, the patient is considered suboptimally debulked. Patients who are suboptimally debulked tend to have worse outcomes and are in need of new and more-effective treatment options.
The committee discussed several study proposals, and the most promising of these will undergo further protocol development.
The work described here represents just a fraction of the GOG’s current and planned research. During the 38 years of the GOG’s existence, its work has led to new standards for cancer treatment and improved outcomes for patients. From the identification of more-effective and less toxic chemotherapy regimens to the evaluation of newer, targeted cancer drugs, the work of the GOG continues to contribute to better survival and quality of life for women facing gynecologic cancer.