Journal of Clinical Oncology, Vol 19, Issue 20
(October), 2001: 4054-4057
© 2001 American Society for Clinical Oncology
Use of CA-125 to Define Progression of Ovarian Cancer in Patients With Persistently Elevated Levels
By Gordon J.S. Rustin,
Maria Marples,
Ann E. Nelstrop,
Mohamed Mahmoudi,
Tim Meyer
From the Department of Medical Oncology, Mount Vernon Hospital, Northwood, Middlesex, United Kingdom.
Address reprint to Gordon J.S. Rustin, MD, Department of Medical Oncology, Mount Vernon Hospital, Rickmansworth Rd, Northwood, Middlesex HA6 2RN, United Kingdom; email: rustin{at}mtvern.co.uk
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ABSTRACT
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PURPOSE: To determine an accurate definition for progression of ovarian cancer in patients with a persistently elevated serum CA-125.
PATIENTS AND METHODS: A retrospective analysis was performed on 300 patients with epithelial ovarian carcinoma with at least one measurement of CA-125. The date of progression according to clinical or radiologic criteria was ascertained in the 88 patients with persistently elevated CA-125 levels (> 23 U/mL). This was compared with the date of progression according to CA-125, defined as the date on which the CA-125 level first increased to  twice its nadir level, confirmed by a second sample also twice the nadir.
RESULTS: Eighty of the 88 patients had evidence of progression by both standard and CA-125 criteria, giving a sensitivity of 94%. In six of these patients, no sample was taken to confirm CA-125 doubling. In 13 patients, CA-125 doubling occurred after the date of clinical progression. Only one patient had a false-positive prediction of progression according to CA-125; the patient died as a result of a myocardial infarct before evidence of clinical progression.
CONCLUSION: In patients whose CA-125 level decreases to normal after chemotherapy, a doubling from the upper limit of normal has been shown to predict progression. In those with persistently elevated levels, doubling of CA-125 from its nadir level has now been shown to accurately define progression. If confirmed, these CA-125 criteria should be used as additional end points in clinical trials.
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INTRODUCTION
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PROGRESSION-FREE survival is an important end point in cancer clinical trials. The currently used definitions for progression rely on clinical signs, scans, or x-rays.1 Progression can be predicted in many patients by an increase in CA-125 levels.2-4 An increasing number of patients start the next line of therapy purely because they have an elevated CA-125 level. It has hitherto not been possible to obtain an accurate date of progression for these patients, as there is no elevated CA-125 value that has been agreed as a surrogate marker for progression. Comparison of the date of progression between studies is thus impossible. Incorporation of CA-125 into a new definition for progression-free survival would enable this end point to remain useful.
In patients whose CA-125 levels fell to within the normal range, a doubling of CA-125 from the upper limit of normal has been shown to predict tumor progression accurately.5 However, definitions based on CA-125 must also take account of the many patients who have persistently elevated levels of CA-125. It was proposed at a meeting of the Gynaecological Cancer Intergroup (GCIG) that definitions of progression be produced for this group of patients. We had previously produced definitions for progression based on a serial increase of 25% over four samples, 50% over three samples, or levels persistently elevated over 100 U/mL, which required a computer program to maintain accuracy.6 It was suggested that a simpler definition based on the doubling of CA-125 from the nadir level be investigated. We have now examined our database of ovarian cancer patients to determine what proportion had CA-125 levels that never fell to the normal range. We then determined the accuracy of a new definition for progression in this group of patients.
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PATIENTS AND METHODS
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The case records were analyzed of all patients treated with first-line chemotherapy for epithelial carcinoma of the ovary at Mount Vernon Hospital between 1981 and 1999 under the care of G.J.S.R. or in trials coordinated by G.J.S.R. The date of clinical progression was defined as the date of development of new clinical signs indicative of ovarian cancer. If there was uncertainty about a new clinical sign, the date of progression was considered to be the date on which a new tumor mass or development of ascites or pleural effusion was first confirmed on scan or x-ray.
Five different CA-125 assay kits were used consecutively during the period. To prevent a change of assay kit affecting serial measurements, at the time of transition, patients had samples analyzed by both assays for at least 6 months. We selected for analysis the results from the kit with the greatest number of samples assayed at the critical time when CA-125 levels were changing. The kits used were the one-step solid-phase enzyme immunoassay of Abbott (Maidenhead, United Kingdom), the CIS immunoradiometric assay (CIS Bio International, Gif-sur-Yvette, France), the Roche Cobas core enzyme-linked immunosorbent assay (Welwyn Garden City, United Kingdom), the CA-125 2 assay (Mannheim, Germany), and the Bayer Immuno1 assay (Bayer, Newbury, Berks, United Kingdom). The upper limit of normal was defined as 23 U/mL.
There were 300 patients, all of whom had at least one measurement of serum CA-125. We selected for further analysis the 88 patients whose CA-125 levels were persistently elevated above the upper limit of normal. These patients form the basis of this study.
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RESULTS
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Eighty-eight patients of the 300 analyzed had CA-125 levels that always remained above the upper limit of normal. These 88 patients all had at least four serial CA-125 measurements. The CA-125 nadir was between 24 and 99 U/mL in 51 patients and 100 U/mL in 37 patients (Fig 1). Clinical and/or radiologic progression has been documented in 85 of these patients. Although CA-125 levels were available for these patients, they were not used to define progression. The date of progression was only based on increasing CA-125 levels in one additional patient. This patient, who also had symptoms suggestive of recurrent disease and an unchanged palpable abdominal mass, had clinical progression confirmed 3 weeks later. Deaths have occurred in 81 patients, four from causes other than ovarian cancer, three before and one after evidence of progression. Seven patients are still alive, all with clinical progression. The median survival of the 81 patients from the date of doubling of their CA-125 level was 13 months (Fig 2).
Fifty-seven patients had CA-125 progression before clinical progression, and in 23 patients, CA-125 levels were found to double either at the same time or after clinical progression (Table 1, Fig 3). These latter patients had a zero lead time, which gave an average lead time for all these 80 patients of 72 days. The date of CA-125 progression was up to 366 days before clinical progression. Of the 80 patients with both clinical progression and CA-125 doubling, 67 had CA-125 doubling before or  1 week after clinical progression, and 13 had CA-125 doubling more than 1 week after clinical progression (Fig 3). In six patients, the doubling was not confirmed by a second sample.
Accuracy of Defining Progression According to CA-125
The accuracy of the detection of progression comparing clinical and CA-125 methods is listed in Table 1. The sensitivity of the doubling definition is 79% if patients are counted as false-negative if they had just clinical progression and no CA-125 doubling at any time (five patients) or if they had doubling of CA-125 after date of clinical progression (13 patients). The sensitivity increases to 94% if the only patients to be counted as false-negative are those with no CA-125 doubling at any time.
There were only two patients who were true-negative for CA-125 predicted progression. They both died before their CA-125 levels doubled from its nadir and before there was evidence of clinical progression. There is only one patient who had a false-positive prediction of progression by CA-125. This patient died from a myocardial infarct less than 1 month after her CA-125 level doubled and before any evidence of clinical progression. The specificity is actually 67%, but this figure is obviously inaccurate because of such small numbers of true-negative and false-positive patients. The positive predictive value is 98.8%.
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DISCUSSION
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A definition of progression of ovarian cancer based on a confirmed doubling of CA-125 levels from the nadir level seems to predict tumor progression with a sensitivity of 94%. This is not surprising, as one would expect that patients with persistently elevated CA-125 levels have residual cancer and it is only a matter of time before tumor progression becomes apparent. The sensitivity is not 100%, as two patients died before there was evidence of progression and presumably the remaining three false-negative patients had tumors that did not express enough CA-125. Although the specificity is only recorded as 67%, the only patient with a false-positive prediction of progression according to CA-125 died from a myocardial infarct within 1 month of the doubling of her CA-125 level. It is far more likely that she had occult tumor progression than that the CA-125 level was increasing because of nontumor causes. In view of the small numbers of patients without progression, the positive predictive rate of 98.8% is a better guide to the accuracy of the CA-125 progression definition.
Progression was predicted earlier by CA-125 than by standard criteria, with an average lead time of 72 days. In this report, CA-125 was measured at widely differing intervals; had it been measured more frequently, the lead time would have been longer. In randomized trials, it is essential that the schedule of evaluations is the same in all arms. It has been proposed that CA-125 levels be obtained on day 1 of each chemotherapy cycle, 4 weeks after the last course, thereafter every 3 to 4 months for the first 3 years, every 6 months for the fourth and fifth years, and every year from 5 years after the primary diagnosis.7 Using CA-125 as a criterion for progression will also reduce progression-free survival, and this will have implications for comparing data with older trials.
The CA-125 definitions now being proposed rely on a doubling of CA-125, either from the upper limit of normal or from the nadir. The choice of using an upper limit of normal of 23 U/mL in this report (as opposed to 30 to 35 U/mL, as used in some laboratories) would therefore have no effect on the results. Tables 2 and 3 list the new definition of progression incorporating CA125 that has been proposed by the GCIG.7 The current study provides data that should increase confidence in that definition. Before it can be accepted into the Response Criteria in Solid Tumor (RECIST),1 it should be tested in a separate database.
Caution needs to be exercised in altering patient management based only on a tumor marker result, even if the accuracy of the definition is confirmed. There will always be patients with tumor progression missed by CA-125 because of insufficient expression of the antigen. A very small percentage of patients will have progression falsely predicted by CA-125. The overwhelming majority of this group will have tumor progression. However, it is crucial not to treat unnecessarily those patients with progression solely defined by CA-125. The Medical Research Council (OV05)/European Organization for Research and Treatment of Cancer (55955) trial comparing early treatment based on CA-125 versus delayed treatment based on clinical indicators will complete recruitment in October 2002. Until the results of this trial are available, there is no proven benefit of early treatment.
Many doctors already treat patients purely on the grounds of an increasing CA-125 level. Therapy for relapsed disease is purely palliative. The observation that the median survival from date of CA-125 progression was 13 months and the average lead time before clinical progression was 72 days indicates that, for many patients, there is no urgent need to restart chemotherapy. If they delay therapy at least until the CA-125 criteria for progression are satisfied, the end point of progression can be used in those patients. Once they have a confirmed CA-125 progression, such patients may be good candidates for trials of the new cytostatic agents being developed.
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ACKNOWLEDGMENTS
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We thank Søren M. Bentzen for statistical advice.
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REFERENCES
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Krebs HB, Goplerud DR, Kilpatrick SJ, et al: The role of CA 125 as a tumour marker in ovarian cancer. Obstet Gynecol 67: 473-477, 1986[Medline]
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Rustin GJ, Nelstrop A, Stilwell J, et al: Savings obtained by CA-125 measurements during therapy for ovarian carcinoma: The North Thames Ovary Group. Eur J Cancer 28: 79-82, 1992
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Submitted February 28, 2001;
accepted June 1, 2001.
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TOP
ABSTRACT
INTRODUCTION
