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New screening, treatments in works for ovarian cancer

Down the hall from his office in the Magee Womens Research Institute in Pittsburgh, Thomas P. Conrads, a scientist in the University of Pittsburgh Cancer Institute, sits daily in front of a tabletop-sized piece of equipment rarely, if ever, found in cancer research centers. It's called a mass spectrometer.

An expert in proteomics, or the study of proteins in a biological system, Dr. Conrads oversees these state-of-the-art instruments while they separate and identify the thousands of proteins in cells from minute tissue samples of early-stage ovarian cancer that were donated by surgical patients at Magee Womens Hospital of UPMC.

The process is a very tiny first step in an collaboration of doctors and scientists devoted to finding an accurate screening test for uterine cancer in its earliest phases.

Right now, according to the American Cancer Society, there are just two established screening tests for ovarian cancer and both are imperfect in finding the disease at an early stage, when a cure is still possible. One is transvaginal sonography, an ultrasound test that can help find an ovarian mass but can't tell if the mass is cancerous. The other is a blood test for CA-125, a protein. The problem with CA-125 is that conditions other than cancer also can produce high levels of this protein. Neither test is recommended for women without known strong risk factors for ovarian cancer, the deadliest gynecologic cancer in the nation.

The scientists and doctors working on the UPMC project hope to find multiple blood markers for ovarian cancer that will make early diagnosis both possible and accurate.

"These biomarkers not only have to give us the correct answer but they also cannot give us the incorrect answer -- we call that false positives and false negatives," Dr. Conrads said. "One of the worst things we can do is tell somebody they're healthy when they're not, especially with a disease like ovarian cancer because the disease is so aggressive and the outcome is so grave."

"The more proteins, the higher predictive value," said Dr. Robert Edwards, director of both UPMC's Ovarian Cancer Center of Excellence and Gynecologic Oncology Research and one of the surgeons who has gathered the tissue for testing. "We're pretty excited about [the study]. We just analyzed our first 20 patients; we've submitted data for a national meeting; and we're hoping we'll get a good response."

The search for the screening test is one of "27-28 [gynecologic cancer] studies open right now" at UPMC, Dr. Edwards added. Four of them, including the screening test trial, were initiated by UPMC investigators, and about 12 of the current studies are what are called "cooperative group studies." The GOG, or Gynecologic Oncology Group, studies are funded by the National Cancer Institute.

The majority of those 20-some trials relate in some way -- but not exclusively -- to ovarian cancer, Dr. Edwards said, "because it's the most deadly of the gyn cancers we treat."

"We have all flavors of trials," he added. "We have screening trials for ovarian cancer; we have therapy trials for all three of the [major gynecological] cancers: ovarian, uterine and cervical cancers.

"And we have a number of investigations -- we call them translational studies: how cancers develop, some involving animal models like mice, where we develop pre-cancer and cancer states in mice and look at the biology of them. Our tissue bank has thousands of tissues we've banked from patient studies over the years and patients who've consented to have their tissues used for research purposes."

Western Pennsylvania Allegheny Health System also is part of GOG, a cooperative group that administers gynecology trials nationwide, said Dr. John Comerci Jr., director of outreach for gynecologic oncology at West Penn and for the West Penn Allegheny system.

The other three trials initiated by UPMC include:

• A search for better drugs to use in intraperitoneal chemotherapy, or chemo that is injected through a catheter right into the abdominal cavity rather than intravenously or through a port implanted in a vein.

"We [are] looking at new drugs that might be better tolerated or more effective than the current older drugs that are given in the abdominal cavity," Dr. Edwards said. Recent national studies have shown intraperitoneal therapy is more effective than traditional chemo. "We're a big center and even before the national studies came out we've been using peritoneal therapy for about 15 years here for ovarian cancer," Dr. Edwards added.

Both of the second two studies are under the guidance of Dr. Anda Vlad, who trained as a doctor in her native Romania before emigrating here, where she got her Ph.D. in immunology. Both studies involve the use of mice models:

• The first involves an attempt to develop a gynecological cancer vaccine by studying, understanding and measuring the immune responses in ovarian cancer treated with either cancer vaccines or immune biologics. The former comprises an antigen, a protein molecule that can induce an immune response. In the study, Dr. Vlad said, "we measure a large spectrum of parameters that will help us better understand this complex disease from an immunological standpoint and will hopefully allow us to design improved approaches for future immune therapy in ovarian cancer."

• The second study involves trying to understand the chronic inflammation in endometriosis, a benign mass of tissue that grows outside the uterus, and the role of immune cells in either fighting off or promoting cancer.

Some studies have indicated that endometriosis can be a precursor to ovarian cancer, much as benign polyps can lead to cancer of the colon. "It's actually an under-studied area and [the study] was prompted primarily because of evidence that women with endometriosis, especially those who have had the disease a very long time, may have higher risk for cancer," Dr. Vlad said.

At Magee Womens Hospital and the Hillman Cancer Center, 14 investigators are involved in seven projects under the Shapira Family Foundation Program in BRCA-Related Malignancies.

BRCA1 and BRCA2 gene mutations "are inherited mutations that can be passed through families on either the mother's or the father's sides to male or female children," said Dr. Kristin Zorn, a gynecologic oncology surgeon who also works in counseling for women at high risk for ovarian cancer. That type of mutation is called autosomal dominant.

"When that gene is passed on in families it puts women at high risk for breast and ovarian cancers in particular, but also pancreatic cancer and other types of cancer," Dr. Zorn added.

"Increased cancer risk also can be seen in men with mutations, including breast cancer."

The BRCA mutations show up more frequently in Ashkenazi Jews. As a result, Dr. Zorn said, "it's a very active area of research [in Pittsburgh] because there is a large Ashkenazi population."

The seven projects funded by the $2 million Shapira grant, she added, are aimed at BRCA1- and BRCA2-associated breast cancers.

"What we're looking for is being able to predict which women will be likely to get cancer and whether there is any way to intervene to prevent cancer or, alternatively, get it as early as possible."

Many women known to carry the mutated genes decide to have prophylactic mastectomies and salpingo-oophorectomies, or removal of the fallopian tubes and ovaries.

"It's a drastic step," Dr. Zorn said. "But currently it's the best option we have for them. What we're hoping is to offer less drastic interventions in the future, such as a preventative medicine."

Another goal of the research, she added, is "to figure out why certain mutations result in cancers affecting certain organs. For example, why do BRCA1 and BRCA2 mutations [lead to] ovarian and breast cancer while HNPCC, or Lynch mutations, are associated with colon, endometrial and ovarian [cancers]?"

Earlier studies, meanwhile, have resulted in new treatments for ovarian cancers, treatments that are extending the lives of patients.

"The treatment of ovarian cancer in the 1970s, it was considered like pancreas cancer or liver cancer -- some of the tougher cancers to have an effective treatment for," Dr. Edwards said. "But from the 1970s till the first part of the new millennium, the treatments have radically improved survival, and what we call disease-free or progression-free survival has been extended by these advances.

"So we've taken [ovarian cancer] patients with Stage 3 cancer [Stage 4 is the most advanced], the most common type, which used to live six to eight months and now the median survival rate is four years.

"And that's just the median survival for the group," Dr. Edwards added. "We have many, many patients now that are out 10 to 15 years disease-free and a lot of that has to do with the use of aggressive surgery and giving the chemotherapy in the abdominal cavity [peritoneal chemotherapy]."

The "aggressive surgery" can take many hours or several different procedures.

"We take out portions of the bowel if they have a tumor on them," Dr. Edwards said. "We strip the lining of the abdomen, called the peritoneal lining, and do sometimes six, seven, eight surgeries to remove any little implants of cancer. We remove or burn them off. It can take hours of tedious [work] and we find that makes a difference in outcome."

Dr. Zorn noted that "there's more opportunity to do surgery laparoscopically. Recovery time is much shorter and we've become more and more expert at it. It's commonly an option for folks now."

The West Penn Allegheny system also makes use of intraperitoneal chemotherapy, Dr. Comerci said. He credited the introduction of the therapy for having a "major impact on survival."

"Two large, Phase 3 trials demonstrated a greater than one-year survival advantage in patients with advanced-stage ovarian carcinoma," Dr. Comerci said.

"Intraperitoneal chemotherapy is associated with a greater number of side effects and is not for every patient, but for the young women with most of their tumor removed, it's an option that should be considered and patients should discuss it with their oncologist."

West Penn also has a surgical robotics program suitable for use in cervical, endometrial and early-stage ovarian cancer.

"The advantages are a quicker recovery, less pain and a shorter period until the patient can start additional therapy if needed," Dr. Comerci said.

At Allegheny General, Dr. Jan Seski, director of gynecology in the department of human oncology, has extended to his ovarian cancer surgical patients the bloodless medicine and surgery program he developed 30 years ago for Jehovah's Witnesses, who are not permitted to accept blood transfusions, not even their own.

Rather, he devised a technique that optimized blood count before surgery and surgical techniques that limit blood loss during the procedure.

"There is an example of something new in cancer of the ovaries that is not necessarily a result of research. We've shown if red blood transfusions [aren't necessary] you can improve survival. ... It's foreign protein that overwhelms the immune system. If the immune system is impaired, you have less ability to fight off cancer shares," Dr. Seski said.

For more information about ovarian cancer and uterine cancer, contact the medical malpractice lawyers of Pittsburgh, Pennsylvania