Department of Medical Oncology, Airedale General Hospital, Skipton Road, Steeton, Keighley BD20 6TD, UK
* Correspondence to: Dr S. M. Crawford, Department of Medical Oncology, Airedale General Hospital, Skipton Road, Steeton, Keighley BD20 6TD, UK. Tel: +44-1535-292947; Fax: +44-1535-292948; Email: michael.crawford{at}anhst.nhs.uk
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Abstract |
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Key words: CA125, carcinoma of the ovary, prognosis, response to chemotherapy, tumour markers
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Introduction |
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Commercially available automated assays for CA125 are widely available. The reference range quoted is usually 0 to 35 U/ml; values within this range are considered normal and their sustained attainment is regarded as a complete biochemical response to chemotherapy. Prompted by the impression that variations within the normal range had a bearing on patient outcome, a retrospective analysis has been conducted of patients treated for ovarian cancer who have attained a complete biochemical response.
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Patients and methods |
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All have been treated at one institution under the care of one physician.
The nadir value of CA125 was categorised into three arbitrary groups: group A, 10 U/ml, group B, 1120 U/ml, group C, 2130 U/ml. Patients were categorised into a particular group by having two consecutive samples within the stated range and the date of attainment of the nadir was defined as the date of the second sample. Biochemical progression was defined as the occurrence of a value greater than 60 U/ml that was confirmed by a subsequent value greater than 60 U/ml, the first date defining the date of progression [4
]. The time to biochemical progression (TBP) was defined as the interval between the nadir and progression, and overall survival was calculated from the date of the nadir.
Assays were conducted in the Airedale General Hospital Pathology Laboratory. An Abbott Laboratories IMX system was used before 1996. After that date, an Axsym analyser from the same manufacturer was used. The manufacturer's reagents were used with standard quality control procedures to ensure comparability. The upper limit of normal was 35 IU/ml.
The CA125 value at the time of the third cycle of treatment was recorded as a potential correlate of prognosis [3], as was the fact that a patient had received a taxane as part of her chemotherapy or not. Standard KaplanMeier methods were used to plot the survival of members of each of the nadir groups and to plot the survival of patients categorised by their CA125 value at the time of the third cycle of treatment. The statistical significance of differences between the curves was tested by the log rank method and the relative contribution of the different potential correlates of prognosis was assessed by the Cox proportional hazards method.
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Results |
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The TBP of the three groups can be seen in Figure 1 and the overall survival in Figure 2. The median TBP in group A was 2436 days, in group B 182 days and in group C 90 days, (2=39.52 38.20, df = 2, P < 0.001). The median survival was 2968 days in group A, 537 days in group B and 537 days in group C, (
2=21.76, df = 2, P < 0.001). The differences between the curves are statistically highly significant and the overall survival of patients in group A with very low values of CA125 is highly significantly greater than that of patients in groups B and C.
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Discussion |
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The attainment of a value less than 70 U/ml at the time of the third cycle of treatment has previously been proposed as the optimal prognostic indicator based on CA125 and this may very well be the case for the interim assessment of patients during treatment [3]. Confirmation of the findings of the present study would establish that a separate assessment of prognosis following the completion of treatment has an important value. This would add to the information available to plan management. It is recognised that when platinum-based treatment is used, which is accepted as the optimal standard for chemotherapy in ovarian cancer, progression of the disease within 6 months is evidence of resistance to these drugs. Platinum compounds are unlikely to be successful in second-line therapy in these patients. The nadir CA125 value appears from the present data to be an early indicator of this situation.
Drugs in the taxane group are accepted as important components in the chemotherapy for ovarian cancer [7]. Controversy exists over their use in first-line or subsequent chemotherapy. This study does not address whether or not taxanes induce low CA125 values in more patients than other platinum-based chemotherapy but it does suggest that once an optimal CA125 response has been attained, they do not add to the durability of that response.
Maintenance paclitaxel chemotherapy has been explored in ovarian cancer [8]. New developments may include biologically targeted treatments that are used chronically as maintenance therapy. The nadir CA125 value would seem to be an important way to stratify these patients according to their risk of progression in clinical trials evaluating such agents.
The early detection of ovarian cancer is also an important area given the problems of treating advanced disease. The concentration of substances in the serum may assist in the detection of tumours; CA125 has been used in screening studies, but its sensitivity and specificity are poor. This demonstration that values within the normal range convey information about ovarian cancer may be used to increase the sensitivity of this assessment, especially if lower values are used as the starting point for longitudinal measurements [9].
This study is based on a relatively small series of data. The three categories defined were adopted simply on the grounds of numerical convenience and are not derived specifically from the characteristics of this database, so they may well be robust but need to be validated against other databases. One such study has supported their use [10]. The difference in biochemical progression between groups B and C must in part reflect the fact that a smaller proportion of increase is required to define biochemical progression from values in group C than in Group B which therefore takes less time, in other words it is a lead-time effect. For the majority of patients in group A it seems that the low values imply biological difference rather than there being an artefact of the same rate of tumour growth.
The hypotheses generated by this study require confirmation in larger series. Analyses are in progress to validate the principle observations and to investigate whether there is an optimal cut-off value or values. This is being undertaken in a large clinical trial database that will enable the relationship of the CA125 nadir to both anatomical and biochemical definitions of disease progression.
The present data add to understanding of the value of CA125 in documenting the course of patients with ovarian cancer. They show that values within the normal range convey important information about the tumour in that patients with a value greater than 10 U/ml have a very high risk of progression within the first year of diagnosis but values less than 10 U/ml imply that the patient may have an excellent outcome.
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Acknowledgements |
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Received for publication August 27, 2003. Revision received August 12, 2004. Accepted for publication August 12, 2004.
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References |
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