The role of CA 125 in epithelial ovarian carcinoma

Transcription

1 Journal of BUON 7: 13-17, Zerbinis Medical Publications. Printed in Greece REVIEW ARTICLE The role of CA 125 in epithelial ovarian carcinoma H. Mandeville, G. J. S. Rustin Department of Medical Oncology, Mount Vernon Hospital, Northwood, Middlesex, UK Summary CA 125 remains the only tumour marker to have any significant impact on the clinical management of epithelial ovarian carcinoma. Its role has developed over the past two decades by validating CA 125 criteria in large numbers of patients against established methods of disease assessment. CA125 has a role in the work-up of a patient with a pelvic mass. Its role in prognosis and screening remains uncertain. It is of value in the assessment of response to chemotherapy and to identify disease progression. When compared with previous methods of determining the onset of disease recurrence the use of CA 125 has been shown to be more sensitive and to be able to detect it at an earlier stage. However, it remains unknown as to whether the earlier introduction of chemotherapy actually improves survival. Until the results of an MRC / EORTC trial are available regular CA 125 monitoring during follow-up cannot be recommended. Once recurrence is suspected precise criteria based on CA125 can reliably confirm this. With this developing role it is likely that CA 125 will be of even more importance to the management of epithelial ovarian carcinoma in the future. Key words: CA 125, ovarian carcinoma, response, tumour marker Introduction Received ; Accepted Author and address for correspondence: Professor G. J. S. Rustin Mount Vernon Hospital Northwood, Middlesex, HA6 2RN United Kingdom Tel: Fax: rustin@mtvern.co.uk As the search for new and more refined tumour markers continues CA125 remains the only tumour marker to have a clinical impact in the management of epithelial ovarian carcinoma [1]. The use of CA 125 has been developed over the past two decades and is now an integral part of the management of ovarian carcinoma. This role has yet to be fully defined and its potential continues to be explored in ongoing clinical trials. The sensitivity and specificity of a tumour marker are essential to its use in the clinical setting. CA 125 is produced by derivatives of the coelomic epithelium but is not detectable in the normal ovary. In 99% of the population the serum CA 125 level is less than 35 IU/ml and is less than 65 IU/ml in 99.7%[2]. Raised levels can be found in a number of benign and malignant conditions. These include the first trimester of pregnancy, endometriosis and cirrhosis, especially in the presence of ascites [3,4]. Forty percent of those with any intra abdominal malignancy will have a raised CA 125 level. In non mucinous epithelial ovarian carcinoma CA 125 is raised in over 90% of patients with advanced disease and in approximately 50% of those with early stage disease [2,5]. Since the initial discovery of the CA 125 antigen through its reactivity to the murine monoclonal antibody, OC 125, the detection methods have been further improved allowing increasingly accurate measurement [2]. The current CA 125 II assays use M11 as a capture antibody whilst retaining the original OC125 as a tracer antibody and have improved sensitivity with some laboratories reducing the upper limit of normal to 22 U/ml [6]. Standardisation and improvements in accuracy have been important in establishing the widespread use of CA 125. Currently the uses of CA 125 extend from assisting diagnosis to monitoring response in the treatment in ovarian carcinoma [2,5]. This is of particular benefit

2 14 when assessing for either response or progression during treatment with chemotherapy as it can limit the need for further imaging or other investigations [7]. Its role is less well defined in post treatment follow-up and as a screening tool. These areas are where most of the ongoing research is focusing on, in order that the full limits of CA 125 as a tumour marker for epithelial ovarian carcinoma can be explored. Screening and Diagnosis Over 80% of those confirmed to have epithelial ovarian carcinoma have a raised level of CA 125 [8]. This has led to the exploration of using it as both a diagnostic and a screening tool. Unfortunately, when used as a single screening test it has a low sensitivity for detecting stage 1 ovarian tumours [9]. Despite detecting the majority of those with advanced disease, CA 125 measurement is not sensitive enough to be used in isolation as a screening test as almost half of those with potentially curable early disease would have normal CA 125 levels. It is useless for screening pre-menopausal women as levels fluctuate with menstruation and the prevalence is low in this group. Trials are investigating the use of serial changes in CA 125 with ultrasound of all those with elevated or rising levels. Although a pilot study has shown this approach to be capable of detecting early potentially curable cancers, we must await the results of a large randomised screening trial to determine if this translates into improved survival through screening [10]. Until that is available, screening should be discouraged except for women with a high familial risk, as unnecessary surgical intervention will occur in some women with falsely elevated CA 125 levels. An elevated CA 125 level in a patient with a pelvic mass should alert one to the probability of malignancy. This should lead to more urgent investigations and consideration that any surgery should be performed by a gynaecological oncologist. To improve the diagnostic accuracy work has been done on creating a risk of malignancy index combining CA 125 measurement with other factors such as menopausal status and pelvic ultrasound for women presenting with a pelvic mass [11]. It should be remembered that a number of intra abdominal pathologies can potentially cause a raised level, both benign such as endometriosis and a variety of malignancies. Likewise a normal CA 125 does not exclude an ovarian malignancy. Prognosis There have been many publications that have demonstrated how CA 125 can be used as a powerful prognostic indicator [5, 12-16]. Grossly elevated levels prior to the initial surgery have been found to be associated with a worse prognosis. A persistently raised post-operative level in cases of confirmed ovarian carcinoma is strong evidence of residual tumour. Those who are found to have a very high CA 125 level, greater than 250 u/ml prior to commencing chemotherapy, have been shown to have a worse prognosis compared with those with lower levels [14]. However, post surgical levels can lead to some confusion and it is important that levels are measured at least two weeks after the initial operation. This is because postoperative peritoneal irritation can cause a falsely raised CA 125 level, that can remain elevated for several weeks [13]. A long half-life of CA 125 after the initiation of treatment with chemotherapy is another indicator of poor prognosis [15]. In cases where a greater than seven fold fall in the level after the initiation of chemotherapy is seen this has been shown to indicate better prognosis when compared to those where there is a lesser fall [16]. The CA 125 level prior to the third course of chemotherapy appeared as the best of all prognostic factors in multivariate analysis. However, almost 20% of cases who were predicted by CA 125 to have a poor prognosis had no disease progression by 12 months [12]. This lack of accuracy indicates that prognostic factors currently have no value in patient management decisions but can still be used as stratification factors in clinical trials. Response to Treatment In assessing response of ovarian carcinoma to chemotherapy the lack of measurable lesions using conventional imaging techniques previously made this process difficult. The half-life of CA 125 is around six days and therefore will continue to drop for some weeks after initial surgery even without the introduction of chemotherapy. In some cases there can be a transient rise in CA 125 level in those responding to treatment as a result of tumour lysis prior to the level falling [8]. However, a falling level of CA 125 after the initiation of chemotherapy is likely to be indicative of response and the use of serial CA 125 measurements has been validated as an accurate method for assessing this [2, 6, 17]. Through the monitoring of response with CA 125 levels the need for further imaging or second look operations can be dramatically reduced. This has both clinical and cost-saving implications in the management of ovarian carcinoma [7]. To ensure an accurate and reproducible definition for response, formal criteria have been developed, which are being increasingly used in clinical trials. The only criteria that have been validated prospectively are based on either a 50% fall of CA 125 over 4 samples or a 75% fall over 3 samples [17, 18]. To reduce the chance of falsely

3 15 predicting a response, the 50% CA 125 response definition requires 4 CA 125 levels, 2 initial elevated samples and the sample showing a 50% decrease requires confirmation by a fourth sample. The 75% CA 125 response definition requires only 3 CA 125 levels, with a serial decrease of at least 75%. In both 50% and 75% response definitions, the final sample has to be at least 28 days after the previous sample [17]. The clinical application of these criteria has been of particular importance in research, as it has enabled the inclusion of patients with ovarian carcinoma in clinical trials who would have previously been excluded due to inability to accurately assess response[19]. Progression The early identification of disease progression in those undergoing chemotherapy is of paramount importance to allow the swift modification of treatment regimes or even the withdrawal of treatment [20]. Progression occurs in less than 20% of those with ovarian carcinoma during initial chemotherapy, but still accounts for a significant number of patients [19]. In these patients identifying progression can reduce the length of time an ineffective regime is used for, and, in doing so, limiting any associated toxicity and side-effects. Through the serial measurement of CA 125 during the administration of chemotherapy it is possible to show progression on average 4 to 5 months in advance of the onset of clinical symptoms or radiologically detectable changes [21,22]. Although a serial rise of CA 125 levels indicates progression during therapy or relapse during follow-up, if one is going to alter management on just the basis of CA 125 its prediction must be accurate. Definitions have been produced that are based on CA 125 and accurately predict tumour progression [19, 22-24]. They are cost-effective through a reduction in radiological investigations undertaken and by limiting the expense of administering ineffective chemotherapy agents [7]. A definition based on either a doubling of CA 125 from the upper limit of normal or in those whose CA 125 levels never fell to the normal range, a doubling from the nadir is shown in Table 1. They have been shown to falsely predict progression in <2% of patients and if the rise is confirmed by a second elevated sample are sufficiently accurate to suggest a change in management. Follow-up This remains a controversial area in the role of CA 125 and current opinions vary as to its usefulness. It has Table 1. Definitions of progression of ovarian cancer based on either clinical or CA 125 criteria (modified from Vergote et al. [23]) Clinical definition of progression Measurable/Evaluable disease CA 125 definition of progression Group A Group B Group C Compared to baseline (or lowest sum while on study if less than baseline), a 20% increase in sum of longest diameters (RECIST definition) OR Any NEW lesions (measurable or non-measurable) Date PD : date of documentation of increase or new lesions Patient groups according to CA 125 behaviour during 1st line therapy: A. Patients with elevated CA 125 pretreatment and normalisation of CA 125 (~60% of all new patients) B. Patients with elevated CA 125 pretreatment which never normalises (~30% of all new patients) C. Patients with CA 125 in normal range pretreatment Group A Group B Group C CA 125 > 2 ULN documented on TWO occasions* CA 125 > 2 nadir value on TWO occasions* As for group A Date PD: first date of the CA 125 elevation to > 2 ULN Date PD: first date of the CA 125 elevation to > 2 nadir value Definitions for progression in the three groups A, B and C are as follows: A patient may be declared to have PD on the basis of EITHER the objective disease OR the CA 125 criteria. The date of PD will be the date of the EARLIER of the two events if both are documented. progressive disease; upper limit of normal; *repeat CA 125 any time, but normally not less than 1 week after the first elevated CA 125 level. CA 125 levels sampled after administration of mouse antibodies or within 4 weeks after surgery or paracentesis should not be taken into account.

4 16 been shown that CA 125 levels can predict relapse prior to the onset of clinical symptoms or detectable radiological changes [21, 22]. Even in cases where CA 125 was not raised with the initial presentation of ovarian carcinoma, a raised level can be the first indication of disease relapse especially in cases where there is peritoneal spread and/ or ascites. Over 90% of patients with advanced epithelial ovarian carcinoma will have an elevated CA 125 at presentation, and a similar proportion have elevated levels at relapse. The definitions for relapse based on a doubling of CA 125 from the upper limit of normal or from the nadir, as shown in Table 1, are now being recognised internationally. They are of increasing importance as many patients are being given second line chemotherapy just based on a rise in CA 125 levels. If they are in a clinical trial it is essential that further therapy is not started until patients have progression defined either by standard criteria or by the CA 125 criteria in Table 1. Otherwise it is impossible to determine the date of progression, and progression-free survival curves become unreliable. It should be appreciated that time to progression will be shortened if CA 125 criteria are compared with the use of just clinical or radiological criteria. The advantages of follow-up with CA125 is that, hopefully through the early confirmation of disease relapse, treatment can be instigated with the aim of reducing the associated morbidity and mortality. The main reason for measuring CA 125 levels during follow-up is probably reassurance. However, a considerable proportion of patients with small-volume disease or mucinous histology will not have a raised CA 125 level. There are major disadvantages to the use of CA 125 in follow-up. Some patients undergoing regular CA 125 measurement will experience anxiety associated with sleeplessness prior to finding out their most recent level and has led to some physicians calling this CA 125 psychosis [19]. It is as yet unknown if this early identification provides any survival benefit and the Medical Research Council and EORTC are currently undertaking a large randomised trial to determine the optimal role of CA 125 in follow-up. There is the possibility that the early introduction of chemotherapy causes additional toxicity without altering significantly the overall survival. Until the results of this trial are known there is no place for the widespread use of serial CA 125 measurements in the follow-up of ovarian carcinoma [19]. Discussion Since the discovery of CA 125 in the early 1980s, it has gained widespread use in the investigation and management of epithelial ovarian carcinoma. Many attempts have been made to improve the sensitivity for tumour detection by combining CA 125 with other tumour markers such as polymorphic epithelial mucins, LASA, D-dimer and TPA. Unfortunately this results in both a loss of specificity and increased cost and complexity. Research continues into finding new markers for ovarian cancer. Circulating tumour cells, naked DNA and soluble oncogene products have been detected by sensitive techniques such as reverse transcriptase and polymerase chain reaction (RT-PCR). Currently only CA 125 can be recommended for managing patients. The role of CA 125 in the monitoring of response to treatment and the early identification of disease progression has been clearly defined. Precise definitions based on CA 125 have been produced and should be used in future clinical trials. This will lead to improved accrual to trials as more patients are evaluable according to CA 125 than according to standard criteria. It will also lead to cost savings through avoidance of unnecessary scans. CA 125 is of value in the work-up of patients with a pelvic mass. Its use in screening and in follow-up should be discouraged until the results of further trials are available. References 1. Bast RC, Hunter V, Knapp RC. Pros and cons of gynecologic tumor markers. Cancer 1987; 60: Bast RC, Klug TL, John ES. A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. N Engl J Med 1983; 309: Barbieri RL, Niloff JM, Bast RC, Scaetzl E, Kistner RW, Knapp RC. Elevated serum concentrations of CA 125 in patients with advanced endometriosis. Fertility Sterility 1986; 45: Bergmann JF, Beaugrand M, Labadie H, Bidart JM, Bohuon C. CA 125 (ovarian tumour-associated antigen) in ascitic liver diseases. Clin Chim Acta 1986; 155: Tuxen MK, Soletormos G, Dombernowsky P. Tumor markers in the management of patients with ovarian cancer. Cancer Treat Rev 1995; 21: Clement M, Bischof P, Gruffat C et al. Clinical validation of the new ESA-CA 125 II assay: report of a European multicentre evaluation. Int J Cancer 1995; 60: Rustin GJ, Nelstrop A, Stilwell J, Lambert HE. Savings obtained by CA-125 measurements during therapy for ovarian carcinoma. The North Thames Ovary Group. Eur J Cancer 1992; 28: Canney PA, Moore M, Wilkinson PM, James RD. Ovarian cancer antigen CA 125: a prospective clinical assessment of its role as a tumour marker. Br J Cancer 1984; 50: Jacobs I, Davies AP, Bridges A et al. Prevalence screening for ovarian cancer in postmenopausal women by CA 125 measurement and ultrasonography. BMJ 1993; 306: Jacobs IJ, Skates SJ, MacDonald N et al. Screening for ovarian cancer: a pilot randomised controlled trial. Lancet 1999; 353: Jacobs I, Oram D, Fairbanks J, Turner J, Frost C, Grudzinskas JG. A risk of malignancy index incorporating CA 125,

5 17 ultrasound and menopausal status for the accurate preoperative diagnosis of ovarian cancer. Br J Obstet Gynaecol 1990; 97: Fayers PM, Rustin G, Wood R et al. The prognostic value of serum CA 125 in patients with advanced ovarian carcinoma: an analysis of 573 patients by the Medical Research Council Working Party on Gynaecological Cancer. Int J Gynecol Cancer 1993; 3: Talbot RW, Jacobsen DJ, Nagorney DM, Malkasian GD, Ritts RE. Temporary elevation of CA 125 after abdominal surgical treatment for benign disease and cancer. Surg Gynecol Obstet 1989; 168: Parker D, Patel K, Alred EJ, Harnden-Mayor P, Naylor B. CA 125 and survival in ovarian cancer: preliminary communication. J Roy Soc Medicine 1988; 81: van der Burg MEL, Lammes FB, van Putten WL, Stoter G. Ovarian cancer: the prognostic value of the serum half-life of CA 125 during induction chemotherapy. Gynecol Oncol 1988; 30: Rustin GJ, Gennings JN, Nelstrop AE, Covarrubias H, Lambert HE, Bagshawe KD. Use of CA-125 to predict survival of patients with ovarian carcinoma. North Thames Cooperative Group. J Clin Oncol 1989; 7: Rustin GJ, Nelstrop AE, McClean P et al. Defining response of ovarian carcinoma to initial chemotherapy according to serum CA 125. J Clin Oncol 1996; 14: Piccart MJ, Rustin GJS, Gore ME et al. Docetaxel in platinum-pretreated patients on behalf of the EORTC Early Clinical Trials Group. In: Sharp F, Blackett T, Leake R, Berek J (eds): Ovarian Cancer. Chapman & Hall Medical, 1996; pp Rustin GJ, Nelstrop AE, Tuxen MK, Lambert HE. Defining progression of ovarian carcinoma during follow-up according to CA 125: a North Thames Ovary Group Study. Ann Oncol 7; 1996: Krebs HB, Goplerud DR, Kilpatrick SJ et al. The role of CA 125 as a tumour marker in ovarian cancer. Obstet Gynecol 1986; 67: van der Burg MEL, Lammes FB, Verweij J. The role of CA 125 in the early diagnosis of progressive disease in ovarian cancer. Ann Oncol 1990; 1: Rustin GJS, Nelstrop AE, Bentzen SM, Piccart MJ, Bertelsen K. Use of tumour markers in monitoring the course of ovarian cancer. Ann Oncol 1999; 10: S21-S Vergote I, Rustin GJS, Eisenhauer EA et al. New Guidelines to Evaluate the Response to Treatment in Solid Tumours (Ovarian Cancer). J Natl Cancer Inst 2000; 92: Rustin GJS, Marples M, Nelstrop AE, Mahmoudi M, Meyer T. Use of CA 125 to define progression of ovarian cancer in patients with persistently elevated levels. J Clin Oncol 2001, In Press.