Presented by: Oliver Dorigo, MD, PhD
Associate Professor of Gynecologic Oncology
Stanford University Medical Center
August 22, 2013
Ovarian cancer affects about a quarter million women worldwide each year. When detected early on—when still confined to just the ovaries—it is a highly curable disease. However because it has no distinct symptoms, ovarian cancer is usually detected at a late stage. Once it metastasizes, survival rates are about 30 percent after five years. It is the 10th most common cancer in the United States and the fifth most common cause of cancer death.
New understanding of the basic biology of ovarian cancer has led to more accurate diagnosis and specialized treatments that are based on the location of the cancer and its cellular anatomy.
“There are several kinds of cells in the ovaries, and each cell type can generate a different tumor type with different prognosis and response to chemotherapy,” said Oliver Dorigo, MD, PhD, a professor of gynecologic oncology, who spoke at a presentation sponsored by the Stanford Hospital Health Library. “Even within each group there are different subtypes, so not every cancer is treated the same.”
Most ovarian cancer arises from the epithelial cells, which cover the surface of the ovaries. However it can also originate in the germ cells that produce eggs, in the stromal cells that produce hormones, or in the lining of the abdomen (peritoneum).
Though it’s not clear what causes ovarian cancer, at some point a genetic mutation turns normal cells into abnormal cells that grow and multiply out of control. As abnormal cells accumulate, they form a tumor, and cells can spread to nearby tissues and metastasize throughout the body.
Current Treatment Strategies
Treatment usually involves surgery followed by chemotherapy based on a detailed analysis of the genetics, genomics, and pathways of the disease. Scientists are consolidating their research in the Cancer Genome Atlas (TCGA), a National Institutes of Health-sponsored effort to study molecular aspects of human cancer to improve diagnosis, treatment, and prevention. “It’s a database for new knowledge,” said Dr. Dorigo. “The project will be extremely useful for developing future therapies, when we will have a different way to classify cancer based on specific genetic mutations.”
Currently initial treatment usually involves site reduction—an extensive operation to remove both ovaries, fallopian tubes, and the uterus as well as nearby lymph nodes and abdominal tissue known as the omentum, where ovarian cancer often spreads. Surgery involves the use of extremely accurate, minimally invasive robotic surgery techniques that require very small incisions and shorter recovery times.
“The first surgery is of utmost importance because the more cancer disease is removed the better the prognosis,” Dr. Dorigo said.
For almost all ovarian cancer patients, surgery is followed by several cycles of chemotherapy to destroy any remaining cancer cells, usually comprising a combination of a platinum drug and a taxane, such as Taxol. Chemotherapy can be done either intravenously through a vein or directly into the abdomen using intraperitoneal chemotherapy, which increases tumor exposure to the drugs.
Researchers are tracking patients and working with animal models in the laboratory to refine all aspects of chemotherapy, from dosage to timing of treatment to new combinations of drugs.
One recent study showed that intraperitoneal chemotherapy resulted in both longer progression-free survival when the disease does not get worse (an average of 24 months cancer-free compared to 18 months with intravenous chemotherapy) and overall survival (65 months compared to 49 months). Another study looked at modifying the timing of conventional chemotherapy (Taxol) from every three weeks to every week, and found marked improvement in survival rates. “The timing of treatment made a big difference,” said Dr. Dorigo.
Most women who undergo a combination of surgery and chemotherapy do go into remission. However 70 to 90 percent will have a recurrence of disease at some point. One of the biggest challenges in treating ovarian cancer is the development of platinum resistance, a change in the cancer cells’ DNA that makes them unresponsive to chemotherapy. Research is providing new insights into the molecular mechanisms of DNA repair pathways in these cells, and studies are looking adding new treatments to the initial therapy to prolong remission or prevent disease from returning.
Dr. Dorigo said there are a number of factors to consider when a cancer recurs, such as platinum resistance and platinum sensitivity, the extent of recurrence, the women’s tolerance for therapy or another surgery, quality of life, and clinical trials that may be available.
The future of ovarian cancer treatments lies in developing new targets based on how cancer cells grow, such as enzyme inhibitors to block growth factor pathways. Some studies are looking at ways to deprive cancer cells of the nutrients they need to grow and thrive. Tumors create an environment that encourages the growth of new blood vessels to deliver nutrients to the site, a process called angiogenesis. One anti-angiogenesis approach combined conventional chemotherapy with antibodies to stop vessels from growing in patients with advanced stage ovarian cancer.
Recently a promising new study combined an oral drug called pazopanib with conventional chemotherapy, and showed an increase in six-month progression-free survival.
Other research is looking at drugs that override mutations in the BRCA tumor suppressor genes. Mutations in BRCA1 and BRCA2 have been linked to an increased chance of developing ovarian cancer. In one study, a new drug called olaparib used BRCA as a biomarker and showed significant tumor shrinkage in subjects with BRCA mutations.
“These drugs use antitumor inhibitors to slow progression and decrease tumors, and appear to be very promising,” said Dr. Dorigo. “They are using completely different mechanisms than have been targeted prior.”
Another approach involves teaching the immune system to recognize and attack cancer. Tumors are able to block the immune system by using the molecule CD47 as a “don’t-eat-me” signal to immune system cells called macrophages. Early studies have shown that anti-CD47 antibodies can block this signal and allow macrophages to destroy the tumor cells.
“The CD47 trial is meaningful because high CD47 levels are associated with poor survival rates. The research showed impressive control of tumor development, and may be a step toward cancer vaccines and personalized medicine,” Dr. Dorigo said. “However these are still very early studies and it will be a while before they are approved as treatment.”
Dr. Dorigo encouraged women to take part in clinical trials to speed the process of refining scientific insights into new therapies and to gain access to treatment options that are not yet available.
About the Speaker
Oliver Dorigo, MD, PhD, is director and associate professor of the Division of Gynecologic Oncology and the director of the gynecologic clinical care program at the Women’s Cancer Center at Stanford. He is also director of the Mary Lake Polan Gynecologic Oncology Research Laboratory. Dr. Dorigo received his MD from the University of Heidelberg Medical School in Germany. He did a residency in obstetrics and gynecology at the University of Munich, followed by a research fellowship in cancer gene therapy at the Sidney Kimmel Cancer Center in San Diego. He completed his PhD in molecular biology at University of California, Los Angeles, and a clinical fellowship in gynecologic oncology at UCLA/Cedars Sinai Medical Center. Dr. Dorigo was an assistant professor at UCLA until he joined the Stanford faculty in 2013.
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