British Journal of Obstetrics and Gynaecology March 1987, Vol. 94, pp. 193-195

COMMENTARY

The value of CA 125 serum assay in the management of ovarian cancer A specific tumour marker has not yet been found for epithelial ovarian carcinoma. The search continues for markers such as P-human chorionic gonadotrophin (fi-hCG) and a-fetoprotein (AFP) for germ cell tumours and choriocarcinoma which have revolutionized the treatment of these rare malignancies. In the past, many tumour markers have been detected in the sera of patients with ovarian epithelial tumours; for example CEA, OCA, OCAA (Van Nagell 1983) but none has been sufficiently specific or active to be of use in monitoring more than a very few patients.

Kohler Br Milstein (1975) reported the immor- talisation of specific antibody forming cells by somatic cell hybridization. Later mutant myeloma cells, deficient in an enzyme hypox- anthine guanine phosphoribose transferase (HGPRT) needed for RNA synthesis, were developed which did not secrete a myeloma pro- tein. These cells allowed the secretion of anti- body after fusion, separate from infused but fast growing myeloma cells. Each hybrid cell pro- duces antibody of a single specificity i.e. mono- clonal antibody, and once derived unlimited quantitites of antibody can be made.

Following this breakthrough, several mono- clonal antibodies have been made which have been useful in clinical oncology. In vitro, they have proved an important advance in diagnostic histopathology and cytology for characterizing human neoplasms (Gatler et al. 1984). In vivo, radiolabelled monoclonal antibodies have been used to localize and even to treat ovarian tumours (Epenetos et al. 1982; Report from the Hammersmith Oncology Group 1984). These antibodies to tumour antigens which include HMFG 1 and HMFG 2 , AUA 1; and H17E2 against placental alkaline phosphatase (PLAP) have been found to be useful in a broad spectrum of neoplasms of epithelial origin including car- cinoma of the ovary, but because they also react, albeit weakly, with normal tissue they must all be

considered to be tumour-associated antibodies rather than tumour-specific.

An important advance was made by Bast et al. (1983) who used a radioimmunoassay to monitor the course of epithelial ovarian carcinoma. This was based on the murine monoclonal antibody OC 125 which reacts with an antigen CA 125 present in most of wch tumours. The assay detected elevated serum levels of CA 125 (>35 Uiml) in only 1% of 888 apparently healthy people, in 6% of 143 patients with non-malig- nant disease and in 82% of 101 patients with epithelial ovarian carcinoma. Bast et al. (1983) also found that rising or falling levels of CA 125 correlated with progression or regression of disease in 42 of 45 patients (93%), suggesting that CA 125 was of use in monitoring ovarian cancer. Canney et al. (1984) confirmed the importance of the CA 125 assay by finding ele- vated levels in 48 of 58 patients (83%) with established ovarian cancer. They also found a positive correlation between the frequency and the serum level of CA 125 and the quantity of tumour. The use of CA 125 in monitoring ovarian tumour was substantiated by Dodd et al. (1985) and by Brioschi et al. (this issue p. 196) who found elevated CA 125 levels before initial laparotomy, the level fell substantially after suc- cessful debulking only to rise again with recur- rent disease. As a result of these and similar studies it has been established that CA 125 can be of value in the serial monitoring of epithelial ovarian cancer in those patients ( c 85%) in whom this antigen is released.

The question arises, however, as to the useful- ness of CA 125 serum assay in the diagnosis and management of epithelial ovarian carcinoma. We need a specific tumour marker easily detect- able in serum to screen asymptomatic women in order to detect ovarian carcinoma in the early and curable stage. CA 125 is not specific as was shown by Bast et al. (1983) who found raised levels in some normal patients and also in

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194 Commentary

patients with non-malignant conditions. More- over, Cruickshank er al. (1987) reported ele- vated levels of C A 125 in patients with ovarian tumours, other than epithelial. It has been shown in patients with advanced disease that elevated and rising C A 125 levels appear to give more reliable information about the presence of tumour than when CA 125 levels.fal1 or become normal. In 15 patients with serum levels below the upper normal limit of 35 Uiml and in whom there was no clinical evidence of persistent disease, 11 (73%) were found to have persistent disease at laparoscopy or laparotomy with nod- ules up to lcm in diameter (Canney et al. 1984), i.e. the C A 125 serum assay failed to detect minimal residual disease. In addition, an analy- sis of the clinical significance of pre-operative serum C A 125 in epithelial ovarian carcinoma detailed by Cruickshank et a/. (1987) showed that while raised levels were present in advanced disease, disappointingly no patient with stage Ia (i) and only 2 of 5 with stage Ia (ii) showed a rise, again emphasizing that a critical tumour load is necessary for a positive (>35 Uiml) result, mak- ing this test unsuitable for screening purposes. This same problem of tumour load also affects the usefulness of C A 125 in monitoring response to treatment instead of second-look surgery to detect subclinical persistent disease. Berek eta/. (1986) examined the sera of 88 patients who were in clinical remission after chemotherapy and who subsequently underwent second-look operations. Raised levels ( 2 3 5 Uiml) were asso- ciated with finding persistent disease at surgery and no patient with a ‘negative’ second-look operation had an elevated C A 125 level. Unfor- tunately, a ‘negative’ C A 125 level (<35 Uiml) did not exclude the presence of disease in 44% of patients, all of whom had residual disease of <2 cm. Similar findings are detailed in this issue by Schilthuis et al. (p. 202).

The lack of specificity, combined with the need for a critical tumour mass, limits the useful- ness of C A 125 as a tumour marker in epithelial ovarian carcinoma. On the negative side it can- not be used to screen a population at risk and while raised levels are valuable as a predictor for persistent or recurrent disease in patients who appear to be in clinical remission, normal values d o not necessarily imply that the patient is free of disease thus limiting its value for assessing when to stop or change therapy. However, there is one positive gain. In patients in whom non-malig- nant causes have been excluded, a persistently

raised level of CA 125 is indicative of residual or recurrent tumour and is usually present 3 4 months before clinical confirmation (Canney ef al. 1984; Krebs et al. 1986). Such patients d o not require second-look laparoscopy or laparotomy before changes in therapy can be initiated. Whether this improves the prognosis for the patient is, however, questionable as second line therapy has seldom been successful in this disease but this may be related to tumour bulk as much as to developed drug resistance and the benefit of earlier institution of treatment needs to be assessed.

The search for a specific tumour marker must continue although the chances of finding one must be considered remote. In the meantime, we should consider the value of applying a com- bination of tumour markers. In this regard the work from the Hammersmith Hospital (Dhokia eta/ . 1986) is of interest. Monoclonal antibodies HMFG 1, HMFG 2 and H17E2, which alone are not particularly useful tumour markers for monitoring ovarian cancer, were examined together with CA 125 in 924 sera from 85 patients with advanced ovarian carcinoma. Raised levels of CA 125 were present in 85% of these sera but when the three markers were used in conjunction, 95% of sera were positive com- pared with 7 % in healthy subjects. No additional information was obtained from either CT or ultrasound scanning. Similarly Ward et al. (1987) using C A 125, HMFG 2 and placental alkaline phosphatase (PLAP) found elevated levels of at least one marker in all 26 patients with advanced disease, and in 7 of 11 with stage I or I1 ovarian cancer.

In conclusion CA 125 has a limited but useful role in monitoring patients with epithelial ovarian carcinoma, who are apparently in clini- cal remission, by detecting persistent or recur- rent tumour in the absence of clinical signs. It can thus avoid the necessity for more compli- cated examinations including ultrasound, CT scanning and second-look procedures in those patients with CA 125 levels that remain high or increase above normal. It can also lead to the earlier termination of unsuccessful chemo- therapy. However, normal values of CA 125 do not exclude the presence of active tumour, and not all patients with epithelial ovarian cancers release CA 125. Because of the need for a critical tumour load C A 125 has no place in screening asymptomatic women for epithelial ovarian car- cinoma. The value of using CA 125 together with

Commentary 195

The value of the monoclonal antibody (cancer anti- gen 125) in serial monitoring of ovarian cancer: a comparison with circulating immune complexes. Br J Obstet Gynaecol92, 1054-1060.

Epenetos, A. A . , Britton, K. E., Mather, S . et al. (1982) Targeting of iodine-123-labelled tumour- associated monoclonal antibodies to ovarian, breast and gastrointestional tumours. L.ancet ii,

Gatler, K. G., Falini, B. & Mason, D. Y. (1984) The use of monoclonal antibodies in histopathological diagnosis. In Recent Advances in Histopathology 12 (Anthony, P. P. & McSween, R. N., eds), Churchill Livingstone, Edinburgh.

Kohler. G. & Milstein. C. (1975) Continuous culture of fused cells secreting antibody of predefined specificity. Nature (London) 256, 465.

Krebs, H. B., Goplerud. D. R., Kilpatrick, S. J., Myers.M. B. &Hunt ,A. (1986jRoleofCA125as tumour marker in ovarian carcinoma. Obstet Gynecol67, 473-477.

Report from the Hammersmith Oncology Group and the Imperial Cancer Research Fund (1984) Anti- body-guided irradiation of malignant lesions: Three cases illustrating a new method of treat- ment. Lancet i, 1441-1443.

Schilthuis, M. S . , Aalders, J . G., Bouma, J., Kooi? H., Fleuren, G . J . , Willemse, P. H. B. & De Bruijn, H. W. A. (1987) Serum CA 125 levels in epithelial ovarian cancer: relation with findings at second- look operations and their role in the detection of tumour recurrence. Br J Obstet Gynaecol94,202- 207.

Van Nagell, J. R . (1983) Tumour markers in gynecologic malignancies. In Gynecologic Oncology (Grifhths, C. T. & Fuller, A. F., eds). Martinus Nijhoff Pubs, Boston. pp. 63-79.

Ward, B. G . , Cruickshank, D. J . , Tucker, D. F. & Love, S. (1987) Independent expression in serum of thrcc tumour associated antigens: CA 125, pla- ccntal alkaline phosphatase and HMFG? in ovarian carcinoma. Rr J Ohstpt Gwaecd 94, in press.

999-1004.

other tumour markers should continue to be assessed in view of the apparent increased sen- sitivity thus gained.

Joanna Lambert Consultant Radiotherapist and Oncologist

Hammersmith Hospital Du Cane Road

London W12 OHS

References

Bast, R. C., Klug; T. L., St John, E. et al. (1983) A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. N Engl J Med 309, 883-887.

Berek, J. S., Knapp, R. C., Malkasian, G. D. , Lavin, P. T., Whitney, C., Niloff, J . M. & Bast, R. C. (1986) CA 125 serum levels correlated with second-look operations among ovarian cancer patients. Obsret Gynecol67, 685-689.

Brioschi, P. .4., Irion. O., Bischof, P., Bader, M., Forni. M. & Krauer, F. (1987) Serum CA 125 in epithelial ovarian cancer. A longitudinal study. Br J Obstet Gynaecol94, 196-201.

Canney, P. A, , Moore, M., Wilkinson, P. M. &James, R. D. (1984) Ovarian cancer antigen CA 125: a prospective clinical assessment of its role as a tumour marker. Br J Cancer 50, 765-769.

Cruickshank, D. J.. Fullerton, W. T. & Klopper, A. (1987) The clinical significance of pre-operative serum CA 125 in ovarian cancer. Br J Obstet Gynaecol94, in press.

Dhokia, B., Canney, P.. Pectasides, D. et al. (1986) A new immunoassay using monoclonal antibodies HMFG 1 and HMFG 2 Logether with an existing marker CA 125 for the serological detection and management of epithelial ovarian cancer. tlr J Cancer 54, 891-895.

Dodd. J . Tyler, J . P. P., Crandon, A . J . et al. (1985)