Survival rates weren't significantly different between those who started chemotherapy once high serum concentrations of CA125 were detected, and those whose treatment was delayed until they had clinical symptoms (median survival 25.7 months versus 27.1 months), Ann Marie Swart, MD, of Medical Research Council Clinical Trials, and colleagues reported online in The Lancet.
"Our results challenge the widespread belief that earlier treatment for recurrent cancer must be better, particularly for cancers for which recurrent disease is disseminated and curative options few," they wrote
In general, early treatment is usually associated with improved outcomes. But data from trials looking at the timing of therapy are conflicting with respect to early treatment for patients with metastatic disease.
For women with ovarian cancer, blood concentration of CA125 often rises several months before clinical symptoms of relapse appear. The marker is also used for initial diagnosis and monitoring of response to chemotherapy.
Patients often see good response with treatment after recurrence, but it is rarely curative and has side effects, the researchers said.
So to assess the benefits of early treatment on the basis of increased CA125 concentrations, the researchers assessed women whose ovarian cancer was in complete remission after platinum-based chemotherapy. They also had normal CA125 concentrations.
These women had a clinical exam and CA125 level checks every three months.
If their blood concentration exceeded twice the upper limit of normal, they were randomly assigned to either early or delayed chemotherapy.
A total of 1,442 women from 59 centers around the world registered for the trial, and 529 were randomly assigned to treatment groups -- 265 to early treatment, 264 to delayed.
Over a median follow-up of 56.9 months, 20% of the women had a rise in CA125 within six months of first-line chemotherapy, 33% saw the rise between six and 12 months, and 45% had it after 12 months.
About 70% of the women died. Of the 370 deaths, 186 occurred in the early treatment group and 184 in delayed treatment. Thus, the researchers said, there was "no evidence of a difference in overall survival between early and delayed treatment" (HR 0.98, 95% CI 0.80 to 1.20, P=0.85).
Median survival was 25.7 months for those on early treatment and 27.1 months for those on delayed treatment.
The women on early treatment started chemotherapy 4.8 months earlier than those on delayed treatment. A higher proportion of those in early treatment received six or more chemotherapy cycles than those in the delayed treatment group (64% versus 51%).
More patients in delayed treatment received platinum-taxane combinations (39% versus 34%), and fewer received single-agent platinum (25% versus 29%).
More early-treatment patients started third-line treatment (67% versus 54%). The median time from randomization to third-line treatment or death was 12.5 months in the early group and 17.1 months for the delayed group, "showing that women assigned to early treatment needed further treatment for clinical progression, on average 4.6 months earlier than those assigned to delayed."
The finding was significant at P=0.0001.
Additionally, there was no deterioration in patient quality of life by delaying therapy, the researchers said.
They added that the findings may be explained by the fact that the lead time between elevated CA125 levels and clinical recurrence -- particularly for rapidly growing, more chemosensitive tumors -- might be too short for early introduction of chemotherapy to have a beneficial effect.
But they said there was no evidence that early chemotherapy had a greater effect in those with a short time from the end of first-line chemotherapy to randomization.
In an accompanying editorial, Robert T. Morris, MD, of Wayne State University in Detroit, and Bradley J. Monk, MD, of Creighton University in Phoenix, said the study should be interpreted cautiously.
They point out that it took a long time to enroll patients, which suggests a clinician bias to not register patients who were considered likely to benefit from early treatment with chemotherapy or surgery.
Also, most of the patients enrolled had a worse prognosis and would be unlikely to benefit from the chemotherapy used in the trial.
"Only those with long platinum-free intervals, i.e., those not randomized in this trial, would be likely to benefit from early therapy when recurrent disease is small and asymptomatic," they wrote.
In addition, newer agents such as bevacizumab and other combinations weren't available during the course of this study.
Morris and Monk wrote that using this marker to predict which candidates would be optimal for surgery needs to be addressed, and Swart and colleagues acknowledged that in their study.
Still, Morris and Monk concluded that the trial "should be appreciated for its bold challenge to the assumption that early treatment of relapsed disease must be better than delayed treatment."
