June 1, 2009 (Orlando, Florida) — There is no survival benefit from early treatment based on an elevated cancer antigen (CA)-125 level alone, in the absence of symptoms, among women with recurrent ovarian cancer. Even though chemotherapy was started nearly 5 months sooner, there was no difference in outcome from those who began treatment when they became symptomatic.
The results of the study were presented during the Plenary Session here at the American Society of Clinical Oncology 45th Annual Meeting.
"This is a study that can affect the lives of all women with ovarian cancer," said Eric P. Winer, MD, chief of the Division of Women's Cancers at the Dana–Farber Cancer Institute in Boston, Massachusetts. "This is the kind of research that is often very difficult to do, but it is very important."
The results of this study can not only influence treatment and improve the lives of women with ovarian cancer, it also has the potential to substantially reduce healthcare-related costs, added Dr. Winer, who moderated a press briefing during which these results were presented.
More than 21,000 women develop ovarian cancer each year, and most will be diagnosed with advanced disease. "A rise in the level of CA-125 is an early signal of cancer recurrence, but its meaning is not known," said lead author Gordon Rustin, MD, professor of oncology at Mount Vernon Cancer Center in Hertfordshire, United Kingdom.
"About 80% of patients with advanced disease will relapse after first-line chemotherapy, and most of them benefit from further therapy," said Dr. Rustin. "Serial measurement of circulating tumor markers has the potential for earlier detection, but it is unknown if it will lead to better outcomes."
CA-125 is a valuable assay for the diagnosis and monitoring of ovarian cancer, and it is common for women to undergo periodic CA-125 testing while they are in remission. Testing can occur as frequently as every 3 months for several years following their initial treatment, explained Dr. Rustin.
No Survival Advantage and Poorer Quality of Life
The OV05/EORTC 55955 trial was designed to investigate the benefit of early chemotherapy for relapsed disease on the basis of CA-125 levels alone, as opposed to treatment after symptom onset. The primary outcome of the study was overall survival, and secondary outcomes included time to second-line chemotherapy, time to third-line treatment or death, and quality of life.
The study participants were drawn from 59 sites in 10 countries between 1996 and 2005. Of the 1442 patients registered for the trial, 529 were randomized to either immediate treatment on the basis of rising CA-125 levels or delayed treatment (after the onset of symptoms).
CA-125 levels were measured every 3 months, but patients and the research team were blinded to the results, which were only monitored by the trials units. If the levels exceeded twice the upper limit of normal, the patients were randomized to immediate treatment or to continue with the blinded CA-125 measurements with treatment delayed until symptom recurrence.
Median survival from registration was 70.8 months, which occurred about 6 months after diagnosis, explained Dr. Rustin. "The time from registration to randomization was a median of 9 months."
Patients in the early-treatment group started second-line chemotherapy 4.8 months earlier than the delayed-treatment group, and Dr. Rustin pointed out that this difference between the 2 groups was highly significant. Third-line chemotherapy was begun 4.6 months sooner in the early-treatment group.
"The results showed that earlier chemotherapy did not induce a longer time to remission," said Dr. Rustin. Patients who received second-line chemotherapy earlier also received third-line treatment earlier, and these patients also did not benefit from a longer remission.
Follow-up was 56.9 months and, during that time, 379 (72%) patients died. "There was absolutely no difference in survival outcomes in the 2 groups," he said. The hazard ratio was 1.00 (P = .98).
Earlier treatment was also associated with a deterioration in global health scores. "Early treatment did not improve quality of life; it actually made it worse," Dr. Rustin said.
Change Standard of Care?
Women can now be offered a choice in follow-up care: no routine CA-125 or regular CA-125 surveillance. "Even if the CA-125 rises, chemotherapy can be delayed," said Dr. Rustin. "For the first time, women can be reassured that there is no benefit from early treatment based on CA-125, and that chemotherapy can be safely delayed until signs and symptoms appear."
These results are important and may change our standards of care, commented Beth Karlan, MD, director of the Women's Cancer Research Institute at Cedars-Sinai Medical Center in Los Angeles, California. "This study makes us question why we perform intensive CA-125 surveillance if it doesn't improve survival or quality of life," said Dr. Karlan, who served as a discussant of the paper. "If early intervention with additional chemotherapy does not improve survival and may in fact impair quality of life, then why are we doing it?"
Although the study had strengths and limitations, overall, Dr. Karlan feels that these results can change clinical practice. "We need to educate clinicians and patients about the level I evidence provided by the trial and recommend less frequent monitoring," she said. "We should consider delaying palliative chemotherapy until clinical recurrence."
During the daily Highlights Session, Robert L. Coleman, MD, from the Department of Gynecologic Oncology at the University of Texas MD Anderson Cancer Center in Houston, pointed out that patients might want to continue having CA-125 testing.
"Patient expectation is high and patients demand this test," he said. "We have a very hard time telling patients that it is not important."
The study was conducted by the MRC/NCRI and EORTC Gynae Cancer Intergroups. Dr. Rustin has disclosed no relevant financial relationships. Dr. Karlan has received honoraria from Eli Lilly and research funding from Amgen, AstraZeneca, Genentech, the Gynecologic Oncology Group, Marshall Edwards, and Unither Pharmaceuticals. Dr. Coleman has consulted and/or served in an advisory role for Celgene, Genentech, GlaxoSmithKline, Merck, Morphotek; and has received research funding/honoraria from GlaxoSmithKline, Lilly, Ortho Biotech, Sanofi-Aventis, and Novartis.
American Society of Clinical Oncology (ASCO) 45th Annual Meeting: Abstract 1. Presented May 31, 2009.
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