October 7, 2010 — The assumption that ovarian cancer survival would improve with early treatment of relapse (after a rise in CA125 concentration but prior to clinical or symptomatic disease) has been challenged by data showing that overall survival is just as good in women whose relapse treatment begins later.
"Women can now opt for not having routine CA125 measurements during follow-up if well," lead author Gordon J.S. Rustin, from Mount Vernon Cancer Centre, Northwood, United Kingdom, told Medscape Medical News.
These are the findings of the first randomized trial to investigate the timing of treatment for relapsed ovarian cancer. The data from the Medical Research Council OV05 and European Organisation for Research and Treatment of Cancer (EORTC) 55955 trials were published in the October 2 issue of the Lancet.
Major Source of Anxiety
CA125 levels typically rise as ovarian cancer relapse is developing, but how to respond to that indicator has been unclear.
"Concerns about CA125 testing and the implications of raised CA125 concentration are major sources of anxiety," the researchers note. " A woman with a rising CA125 concentration, who remains well, without symptoms or signs of recurrent disease, presents a major management dilemma. Because of this issue, practice varies widely in terms of whether or not regular CA125 measurements are done and in the timing of initiation of second-line chemotherapy."
To address the effect of early vs delayed treatment of relapsed ovarian cancer, Dr. Rustin and colleagues randomly assigned 265 patients with CA125 concentrations more than twice the upper limit of normal to early treatment (within 28 days) or to delayed treatment (once clinical or symptomatic relapse became apparent).
After a median follow-up of 56.9 months, overall survival was similar in the 2 groups, with 186 deaths in the early treatment group and 184 in the delayed group. Median survival after randomization was 25.7 months for patients receiving early treatment and 27.1 months for those receiving delayed treatment.
Quality of life deteriorated sooner in patients treated earlier, with significant disadvantages for role, emotional, social, and fatigue subscales associated with early treatment.
Study coauthor Maria E. L. van der Burg, from Erasmus Medical Center in Rotterdam, the Netherlands, told Medscape Medical News that the researchers were surprised that quality of life was worse in the early-treatment group. "We had expected a better quality of life by delaying symptoms," she said.
The authors conclude that "women should be informed that there is no evidence of a benefit from early treatment on the basis of rising CA125 concentration, and no deterioration in quality of life by delaying chemotherapy. If CA125 concentration rises during follow-up, chemotherapy can be safely delayed until symptoms or signs of tumor recurrence develop. . . . For the first time, women can be given evidence-based advice and can make informed choices about follow-up. . . . The results of this trial suggest that they can opt to forgo routine CA125 monitoring if their disease is in complete remission after first-line treatment."
However, in an accompanying editorial, Robert Morris, MD, from Wayne State University in Detroit, Michigan, and Bradley Monk, MD, from Creighton University School of Medicine in Phoenix, Arizona, note that a number of factors "limit this study's application to management."
These factors include the possibility of clinician bias to not enroll in the trial patients considered likely to benefit from early retreatment with chemotherapy or surgery, an imbalance in platinum-free interval among the study groups, and the high proportions of patients with platinum-resistant disease unlikely to respond to the second-line chemotherapy used.
Dr. Rustin told Medscape Medical News that Drs. Morris and Monk have misinterpreted some of the data in the paper.
"About 20% of randomized patients had a rise of CA125 to double the normal range within 6 months and are wrongly considered platinum-resistant by Morris and Monk. There is huge confusion around the world, as some doctors have considered these patients platinum-resistant, but most oncologists have waited until patients have signs or symptoms of recurrence before restarting chemotherapy (i.e., 4 or 5 months later when considered platinum-sensitive). If Morris and Monk had looked at Figure 3, they would have realized that there was no difference in lack of benefit from early treatment, whether less than 6 months, 6 to 11 months, 12 to 24 months, or more than 24 months from last treatment to randomization," Dr. Rustin said.
Drs. Morris and Monk also suggested that lack of access to contemporary therapies, such as bevacizumab and pegylated liposomal doxorubicin plus carboplatin, for many patients enrolled in this trial might have influenced the outcomes.
But Dr. Rustin replied that "this was another poorly considered point, as no new treatments have yet shown any survival advantage, and many patients did actually get pegylated liposomal doxorubicin.
"Our study stands until new agents actually prolong survival," Dr. Rustin stated, adding that "the 1.7 (ICON 7 results) or 3.8 month (GOG218 results) improvement in [progression-free survival] after bevacizumab almost certainly will not result in improved survival."
Drs. Morris and Monk further point out that "45% of the randomized patients had a treatment-free interval exceeding 12 months and were therefore potential surgical candidates, but only 7% received surgical intervention."
According to Dr. Rustin, the OV05/EORTC investigators were not convinced of the benefit from surgery for relapsed disease.
"Two clinical trials are investigating this and it will be fascinating to see if they do show any benefit. I personally consider surgery routinely for my relapsed ovarian cancer patients, but only offer it to less than 10% of them who have just 1 or 2 solitary metastatic sites, as it seems pointless to offer it to patients with widespread disease, which most patients have," Dr. Rustin said.
Like other provocative studies, [it] begs more questions than it answers.
Drs. Morris and Monk write: "This clinical trial should be appreciated for its bold challenge to the assumption that early treatment of relapsed disease must be better than delayed treatment. Indeed, the article provides some evidence that early retreatment might be detrimental. Rustin and colleagues should be commended for this endeavor, which, like other provocative studies, begs more questions than it answers. From their study, principles that we have considered fundamental are deservedly brought into question."
The data have resulted in changes at the study institutions. Dr. van der Burg said: "I was the most surprised by the fact that the quality of life in the early treatment group was significantly worse than in the delayed group. I was not aware that the psychological burden for the patient of knowing that you have a recurrence would be so great."
"We have implemented this treatment policy in our hospital and stopped regular measurement of CA125 in follow-up," Dr. van der Burg said, "but we continue with regular general and gynecological examinations with ultrasound."
"We explain the results of this study to our patients and explain that if they feel fine without signs or symptoms, there is no indication for worry or treatment. We instruct them to call us and to make an early appointment at the outpatient clinic for further evaluation at the time they have signs or symptoms or are worried," she explained. Then, depending on the signs, localization of the tumor, and extent of disease, "we decide together with the patient to start second-line treatment."
Dr. Rustin and van der Burg have disclosed no relevant financial relationships. Dr. Monk reports receiving honoraria for speaking from GlaxoSmithKline, Lilly, and Orthobiotech; receiving research support from Lilly and Sanofi-Aventis; receiving consultancy fees from VentiRx, Qiagen, and Roche; receiving payment for expert testimony from Johnson & Johnson; receiving research funding from GlaxoSmithKline, Pharma Mar, Sanofi-Aventis, Johnson & Johnson, and Merck; and receiving speaking fees from GlaxoSmithKline, Eli Lilly, Merck, Genzyme, and Roche.
Lancet. 2010: 2320-2322, 2355-2363.
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