With new options for early detection, treatment, and management of ovarian cancer, researchers are back in the race.

By Cathy Dunn

Without warning, ovarian cancer robs a woman of her health and, often, her life. That’s a fact Linda Stokman knows all too well.

“One day I was teaching my elementary school class, the next I was told I had advanced ovarian cancer and needed major surgery immediately,” says the 53-year-old wife, mother, and grandmother from Osceola, Indiana, whose doctor found the tumor during her annual physical.

“I was tired and had some indigestion, but I didn’t think anything was seriously wrong,” she adds. “The diagnosis was devastating.”

About 25,000 women receive the same news each year, and more than half of them die within a year or two. Late-stage diagnosis and few symptoms make this cancer even more elusive.

But the disease is encountering a formidable foe: Researchers dedicated to its defeat.

“Like all cancers, the earlier ovarian cancer is detected, the easier it is to treat,” says Robert Ozols, MD, PhD, senior vice president of medical sciences, Fox Chase Cancer Center, Philadelphia. “This disease is particularly difficult to catch in early stages because most women have minor symptoms—or no symptoms—until the cancer has reached an advanced stage.”

Selma Schimmel, founder and CEO of Vital Options® International TeleSupport Cancer Network and host of The Group Room cancer talk radio show, was diagnosed with stage IA ovarian cancer (see sidebar, page 25) in September 2003 during what was to have been a prophylactic removal of her ovaries (oophorectomy). Schimmel knew she was at high risk for getting ovarian cancer, having been diagnosed with breast cancer 20 years ago at age 28, only a few years after her mother died of ovarian cancer. In addition, Schimmel tested positive for the BRCA1 gene.

“I did the only things that are now available to women in terms of screening and follow-up,” she says. “My tumor markers for ovarian cancer were normal, and I had ultrasounds every three months. An insignificant but lingering ovarian cyst helped speed up my decision to have a prophylactic oophorectomy, and it saved my life.”

Setting the Stage
The four stages of ovarian cancer are characterized by the size of the tumor and whether the disease has spread to other organs. Stage I, confined to one or both ovaries, is usually treated by surgery followed by chemotherapy in high-risk patients.

Stage II tumors have spread to surrounding areas in the pelvis, such as fallopian tubes, bladder, or womb and generally require more extensive surgery and follow-up chemotherapy.

When the cancer reaches stage III, it has spread outside the pelvis to peritoneal surfaces, surrounding lymph nodes, or upper abdomen. In addition to surgery and chemotherapy, radiation therapy may be used if isolated cancer cell colonies recur after treatment.

In stage IV, the cancer has spread outside the abdomen, affecting organs throughout the body. When the disease becomes this advanced, patients may benefit from a combination of standard and experimental treatments. Cancer vaccines, monoclonal antibodies, and new drug treatments are currently being tested against ovarian cancer in clinical trials worldwide.

Ovarian cancer may occur in three types of cells. The most common, epithelial carcinoma, arises from the cells covering the surface of the ovary and accounts for 85-90% of all ovarian malignancies. Germ cell cancers (developed from eggs) and ovarian stromal tumors (formed in supportive tissue) are more rare.

The grade of a cancer, which refers to the appearance of the cancer cells under a microscope, also determines treatment because it tells oncologists how quickly the tumor will grow. Grade 1 (low) cells look like regular ovarian cells. They often grow slowly and rarely spread. Grade 2 (moderate) and grade 3 (high) cells appear abnormal and are more likely to grow quickly and spread rapidly.

“Although Linda was diagnosed at stage III, her cancer had not affected major organs or invaded her lymph nodes,” says her oncologist, Michael Method, MD, director of oncology research, St. Joseph’s Regional Medical Center, South Bend, Indiana, and former chairman of the National Ovarian Cancer Coalition. “She was very lucky.”

Complexities of Chemotherapy
After surgery in 2000, Stokman received one of the standard chemotherapy combinations for the treatment of ovarian cancer, six rounds of Taxol® (paclitaxel) and Paraplatin® (carboplatin). Some of her friends remained active during their treatments, but toxicity sidelined Stokman.

“The chemotherapy destroyed my blood platelets and caused bone pain so severe I could hardly walk. I couldn’t take hormone replacement therapy either, so I had hot flashes 24 hours a day,” she recalls.

“The Taxol/carboplatin combination is a very effective first-line treatment for ovarian cancer, but it can cause debilitating side effects, such as neuropathy,” says Alan Gordon, MD, director of research in gynecology, US Oncology, Dallas. “Newer chemotherapies like Taxotere produce less nerve damage but may result in increased incidences of neutropenia.”

The Taxol/carboplatin regimen, widely used in ovarian cancer, provides a small number of advanced epithelial ovarian cancer patients (10-15%) long-term survival. These patients, the platinum-sensitive group, many times can be successfully re-treated with the same regimen. However, for patients whose disease seems to be resistant to the initial regimen, secondary treatments are needed.

Taxotere® (docetaxel) inhibits tumor growth by blocking cancer cell division, resulting in cell death. The drug received initial approval by the U.S. Food and Drug Administration (FDA) in 1996 as a treatment for breast cancer but has also been studied in a number of clinical trials in ovarian cancer.
Given by itself, Taxotere causes shrinkage of disease in up to 40% of patients. Taxotere has also been evaluated as part of a combination regimen with carboplatin, with 34 (81%) of 42 patients treated in one trial showing disease regression. These trials led to a larger international trial of more than 1,000 women.

One advantage to the Taxotere regimen was that the patients did not experience as much nerve damage as those treated with the Taxol regimen. However, patients who received Taxol/carboplatin appeared to be at less risk of developing infections or fevers from low blood cell counts.

Despite being diagnosed early and having all disease removed surgically, Schimmel is following medical recommendations of adjuvant Taxol/carboplatin because her tumor was identified as grade 3.

“In my favor is that my cancer was an incidental finding, I was optimally staged, and the malignancy was contained to one ovary. I may very well be disease-free already, but adjuvant chemotherapy is my best insurance policy.”

The Next Approach
The goal for treatment remains the best response with the fewest side effects. For that reason, researchers are constantly searching for better ways to deliver what have been shown to be effective drugs.

Doxil® (doxorubicin) encloses Adriamycin® (doxorubicin) in a bubble of fat called a liposome that evades immediate detection and destruction by the immune system, making it more likely to reach the targeted tumor, where the drug is released.

Doxil received FDA approval in 1999 for the treatment of refractory ovarian cancer based on three clinical trials that included 176 patients with metastatic ovarian cancer, most of whom (145) had developed a resistance to Taxol and carboplatin or cisplatin. Twenty of the 145 patients (13.8%) were responsive to Doxil, which is associated with side effects such as reduced blood cell counts and redness and swelling in the hands and feet.

The tolerability of Doxil makes it optimal for combination regimens. In current clinical trials, physicians are testing Doxil both by itself and in combination with Taxol and carboplatin.

Hycamtin® (topotecan) is the first of a new class of drugs called topoisomerase 1 inhibitors, which block the enzyme topoisomerase 1, a component of the machinery required for DNA replication. When this enzyme is inhibited, cell division cannot continue.

Initial studies with Hycamtin in patients resistant to Taxol or platinum agents showed that some experienced remission of their disease. The most common side effect was lowered blood counts.

The FDA approved Hycamtin in 1996 for women with metastatic ovarian cancer who had failed initial or subsequent chemotherapy treatments. Currently, there is great interest in using Hycamtin as first-line chemotherapy for the treatment of ovarian cancer. In some trials, Hycamtin replaces Taxol. In others, Hycamtin is being incorporated as a third agent with Taxol and platinum compounds to possibly improve the time of remission.

Gemzar® (gemcitabine) belongs to a group of drugs called antimetabolites and was initially approved by the FDA in 1996 for the treatment of locally advanced or metastatic pancreatic cancer. Like Hycamtin, Gemzar was initially tested in patients resistant to standard treatment and produced low response rates. However, combination regimens proved much more successful, particularly in patients who were newly diagnosed.

A study of 24 previously untreated patients treated with Gemzar, Taxol, and carboplatin resulted in disease remission in 100% of patients tested, with complete disease eradication seen in 60% of patients. In a recent study, Gemzar given in combination with carboplatin appears to be more effective than carboplatin alone. Gemzar can also cause a reduction in platelet counts, which may predispose a patient to bleeding.

“Doxil, Hycamtin, and Gemzar may be effective against recurrent disease,” Dr. Gordon says, “but their side effects range from painful skin problems to serious blood disorders such as neutropenia.”

The Newest Weapons
In addition to the progress being made in the treatment of ovarian cancer using standard chemotherapy agents, novel targeted therapies offer the advantage of generally being less toxic than standard therapies because they target cancer cells and leave most healthy cells intact.

One such monoclonal antibody therapy, R1549 (pemtumomab), contains a mouse antibody that binds to an abnormal form of mucin (MUC1), a protein on the cell surface common to many solid tumors. Chemically paired with Yttrium-90 radioisotope, pemtumomab targets and destroys cancerous cells.

Stokman has returned to teaching, adding a second profession: helping other women with ovarian cancer through her outreach efforts.

“Cancer is sometimes just a part of life,” she says. “Learning to live with it and keep going is an important part of defeating it. Supportive family, friends, and specialists like Dr. Method have made all the difference in my recovery.”
Medical experts note that managing ovarian cancer may be a lifelong process because women are living longer with the disease.

“In the 1960s, only about 30 percent of women with ovarian cancer survived five years,” Dr. Ozols says. “Today, more than 50 percent reach that benchmark, living full lives while coping with the illness daily.”

“Our first priority is to cure cancer,” says Dr. Gordon, “but until that time, we’re seeking ways to treat it like a chronic disease. We don’t want to overmanage with medications because treatments carry their own risks.”

Shaping the Future
Following the less-is-more philosophy, researchers have begun clinical studies testing the effectiveness of lower dosages of chemotherapy and less frequent treatments. They are also developing more effective screening methods and trying alternate drug-delivery methods such as intraperitoneal therapy, in which the abdominal cavity (also referred to as peritoneal area) may be flooded with chemotherapy to prevent the implantation of tumor cells.

Derived from the toxin of poisonous jack-o’-lantern mushrooms, irofulven (MGI-114) is showing great promise as a treatment for recurrent advanced ovarian cancer patients who have had limited success with more traditional therapies like Taxol.

“Irofulven is rapidly absorbed by cancer cells,” says Eddie Reed, MD, director of the Mary Babb Randolph Cancer Center at West Virginia University in Morgantown and principal investigator for the drug’s phase II clinical trials. “Once inside the cells, the toxic compound attaches to DNA and proteins, preventing tumor cells from reproducing. Eventually, apoptosis occurs because tumor cells cannot replicate.

“Preliminary clinical trial results have been encouraging,” he adds. “In one study, five of 15 women with recurrent ovarian cancer experienced at least a 50 percent reduction in tumor size. This is significant because ovarian cancer patients who have failed first-line standard therapy are considered the toughest group to treat. Further evaluation is needed to confirm our findings.”

The compound has side effects similar to traditional chemotherapy, including nausea, vomiting, and fatigue. To minimize these effects in phase II studies, researchers have switched to an every-other-week dosage.

Another promising drug is BMS-247550, an epothilone B analog derived from the microorganism myxobacteria. Epothilones, like taxanes, attack a tumor’s microtubulin system where cancer cells grow and divide. Epothilones disrupt cell division through the same chemical pathway as Taxol, but they also are equally effective against taxane-resistant cancer cells.

“We’ve made a lot of progress in treating ovarian cancer in the last decade but we’re still not where we want to be,” Dr. Ozols admits. “We clearly need more effective tools for diagnosis and treatment.”