The outlook for patients with advanced ovarian cancer brightened in the 1980s with the development of cisplatin and carboplatin and again in the 1990s, when paclitaxel, or Taxol®, emerged from clinical trials. But even with these advances, only a fraction of patients with stage III disease by far the most common stage at diagnosis survive five years.
Where the next advance will appear remains, therefore, an urgent question. What new strategy or strategies could be ready for large, randomized, studies? There is no overwhelming consensus on this issue, but in recent journal articles, experts propose several candidates for phase III trials.
Best known and perhaps most controversial of these candidates is high-dose chemotherapy with stem cell transplant. In this rigorous therapy, the transplant is used to restore bone marrow destroyed by the high doses of chemotherapy drugs.
High-dose chemotherapy and transplantation first with bone marrow and later with stem cells gained attention and supporters in the late 1980s and early 1990s, when it produced high response rates in early trials. The use of transplants began to grow, both outside of trials and in an ongoing stream of small, phase II studies. Many oncologists and patients became convinced of its benefits.
"People have very strong feelings about it, they believe in it," said Gisele Sarosy, M.D., an ovarian cancer researcher at the National Cancer Institute.
But skeptics point to problems with transplantation. They note the riskiness of high-dose chemotherapy plus the high cost of patient care and low quality of life during treatment. They also point out that transplantation has not so far been shown to prolong survival in a large, randomized trial.
Such a trial, comparing transplants to the best available standard therapy, is urgently needed, according to Patrick Stiff, M.D., and colleagues of Loyola University, Maywood, Ill. In a report in the Oct. 3 issue of the Annals of Internal Medicine, these longtime transplant researchers suggest a randomized trial in relapsed patients whose tumors are sensitive to the platinum-based drugs (cisplatin and carboplatin) and who have only very small tumors remaining after surgery.
This subgroup appears to have a good chance of benefitting from transplant, they say. That conclusion is based on an analysis of outcomes in 421 patients in the Autologous Blood and Marrow Transplant Registry. The analysis showed that 39 percent of a subset of transplant patients with relapsed, platinum-sensitive disease survived at least two years after diagnosis, results that the authors say "seem superior to those seen with conventional salvage chemotherapy."
One small phase III transplantation trial for ovarian cancer is currently under way in France and should be completed by the end of this year, but there is none in the United States. An NCI-sponsored trial closed recently, according to Edward Trimble, M.D., who coordinates gynecologic cancer trials and heads the surgery section in NCI's Cancer Therapy Evaluation Program. Trimble said that despite vigorous efforts to promote this trial, only 20 patients were enrolled in two and a half years.
"Without compelling data from phase III trials in other solid tumors, such as breast cancer," said Trimble, "I am pessimistic that we could successfully mount another phase III trial evaluating high-dose chemotherapy in women with ovarian cancer."
However, there are several other candidates for phase III trials. In an editorial that accompanies the Transplant Registry analysis, Sarosy and Eddie Reed, M.D., chief of the Medical Ovarian Cancer Section at NCI. propose several less toxic approaches that they consider at least as promising.
New Drug Strategies
One of these approaches, the use of newer drug combinations, has raised hopes because the drugs appear to overcome the platinum-drug resistence that develops in many ovarian cancers after initial treatment. In an article in the June issue of Seminars in Oncology, Trimble reviews the newer drugs oxaliplatin, epirubicin, liposomal doxorubicin, topotecan, oral etoposide, gemcitabine, and vinorelbine each of which has produced a response in ovarian cancer patients when used alone. They are now being tested in two-drug and three-drug combinations, said Trimble.
Also promising in early studies, say Sarosy and Reed, is the use of a second, or consolidation, round of standard-dose chemotherapy for patients whose tumors have responded well to the first round. They propose further study of consolidation with a combination of drugs that includes paclitaxel.
Sarosy and Reed also suggest more phase III trials for intraperitoneal therapy, in which drugs are delivered directly to the abdominal cavity and its lining (peritoneum), the places where most ovarian cancers first spread. Like transplantation, this strategy has been used for some time without being fully studied.
Phase III intraperitoneal trials with various combinations of drugs have taken place, but the results have not shown clear-cut benefits over traditional chemotherapy, Trimble says. Currently, several studies of combination regimens are under way.
The Gynecologic Oncology Group, one of the NCI-sponsored Clinical Trials Cooperative Groups, has recently completed a phase III trial comparing standard intravenous carboplatin and paclitaxel to intravenous paclitaxel and to intraperitoneal cisplatin and paclitaxel. The results will be available in two to three years, Trimble said.
Other innovative approaches to advanced ovarian cancer are in the pipeline. Trimble mentions several that are promising though not yet ready for phase III trials therapeutic vaccines, gene therapy, and anti-angiogenic agents, which cut off the blood supply to tumors. To this list, Sarosy and Reed add graft-versus-tumor types of transplantation, in which the transplant may stimulate the patient's own immune system to fight the tumor.
The high number of investigational treatments is welcome in a disease in which current therapy is not curative, Trimble writes. "Based on this multitude of investigational questions and the low cure rates currently achieved, all women with advanced ovarian cancer should be offered participation in clinical trials."