help button home button The Oncologist
HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Markman, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Markman, M.
The Oncologist, Vol. 2, No. 1, 6-9, February 1997
© 1997 AlphaMed Press

The Role of CA-125 in the Management of Ovarian Cancer

Maurie Markman

The Cleveland Clinic Cancer Center, Department of Hematology/Medical Oncology The Cleveland Clinic Foundation, Cleveland, Ohio, USA

Correspondence: Maurie Markman, M.D., Department of Hematology/Medical Oncology, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA. Telephone: 216-445-6888; Fax: 216-444-9464.


   ABSTRACT
Top
 Abstract
Introduction
 Clinical Settings Where the...
 Potential Uses of CA-125
 Potential "Overuse" of CA-125
 Potential Misuse of CA-125
 Conclusion
 References
 
Over more than a decade of clinical use, CA-125 has proven itself to be one of the most useful tumor markers in cancer medicine. The major clinical utility of this serum marker is in following the clinical course of women with known ovarian cancer. Other potential uses of CA-125 include the evaluation of the effectiveness of new antineoplastic agents in this malignancy, and in the modification of treatment strategies in individuals whose CA-125 levels fail to decline at an acceptable rate following the institution of therapy. At the present time, the use of CA-125 as a method to screen for ovarian cancer should be considered investigational.

Key Words. Ovarian cancer • CA-125 • Serum tumor markers • Ovarian cancer screening • Anti-neoplastic therapy • Second-look laparotomy


   INTRODUCTION
Top
 Abstract
 Introduction
Clinical Settings Where the...
 Potential Uses of CA-125
 Potential "Overuse" of CA-125
 Potential Misuse of CA-125
 Conclusion
 References
 
The serum level of CA-125, a mucin-like glycoprotein of molecular weight >200,000 [1], has been demonstrated in multiple clinical trials and standard oncologic practice to be one of the most useful tumor markers in cancer medicine [2, 3]. In this review the established and potential uses of CA-125 in the management of ovarian cancer will be discussed, along with concerns for the overuse, or actual misuse, of this valuable clinical test.


   CLINICAL SETTINGS WHERE THE CLINICAL UTILITY OF CA-125 HAS BEEN ESTABLISHED
Top
 Abstract
 Introduction
 Clinical Settings Where the...
Potential Uses of CA-125
 Potential "Overuse" of CA-125
 Potential Misuse of CA-125
 Conclusion
 References
 
The most common use of CA-125 is in following the clinical course of patients with documented ovarian cancer where the disease is not easily measurable or evaluable by other means. Following standard surgical debulking, a significant percentage of patients with ovarian cancer will persist with having only small-volume or microscopic residual intra-abdominal disease. Even with larger tumor volumes remaining after surgery, symptoms may be absent and physical findings or radiographic evaluation may not be helpful in documenting a response of the cancer to cytotoxic chemotherapy.

In addition, symptomatic patients or those with measurable or evaluable disease (e.g., ascites) who respond to treatment may eventually become "non-evaluable" for further evidence of a response. In each of these clinical settings, the serum level of CA-125 can provide helpful information regarding the initial response or continued response to later courses of chemotherapy. The percentage decrease in CA-125 which should be considered a "response" to therapy is a matter of some discussion in the oncologic literature. In a recent editorial, this author has proposed two "CA-125 response criteria" which could be employed in examining new antineoplastic drugs or strategies in ovarian cancer [4]. The proposed "criteria" are a >=50% or >=90% decrease in the CA-125 antigen level, compared to baseline (i.e., value obtained just prior to the initiation of the specific therapeutic program). Rustin et al. examined a large retrospective database of ovarian cancer patients to develop a model whereby the percentage decrease in CA-125 could closely coincide with the objective response rate as predicted by "response of measurable disease" [5]. This analysis led to the proposal that either a 50% decrease after two samples (compared to baseline), confirmed by an additional sample, or a 75% decline observed over three samples, be accepted as a responding patient. Individuals’ samples are to be separated in time by a minimum of 28 days.

For patients being treated on a clinical trial, specific criteria for "response" are generally built into the study design, along with indications to continue or stop treatment. However, for the majority of ovarian cancer patients who are not entered into investigative studies, is there a specific percentage decrease in CA-125 antigen level which should be considered a "response" to treatment?

In the absence of specific data from clinical trials, it is difficult to provide a definitive answer to this question. However, in the opinion of this author, if a patient has an elevated CA-125 level at the initiation of chemotherapy which, at that point in time, is at least double the upper range of normal (i.e., >60 U/ml), it is reasonable to consider a 50% decrease from baseline (in the absence of any indications of clinical tumor progression) to indicate an anti-tumor effect. Larger percentage decreases and more rapid falls in the antigen level indicate greater tumor cell kill.

It must be remembered that this tumor marker (like all other tumor markers) should not be employed in isolation, or independent of the specific clinical setting. For example, if the CA-125 antigen level decreases but the patient has clinical evidence of disease progression (e.g., development of ascites, increased mass on pelvic examination), the marker value has little importance.

As with all laboratory tests it is also possible that the test value returned to the physician is actually that of another patient, that there may have been a technical problem within the laboratory causing an error, or that there may have been a transcription mistake when the test results were recorded. Thus, in general, decisions regarding patient management should not be based on the results of a single CA-125 test unless there are supporting data (e.g., physical findings, symptoms) for the serum antigen level.

Just as a CA-125 value is a reasonable indicator of response, a rising level can be employed as one indication of the failure of a particular therapy [6]. Again, one must be careful when using this tumor marker to indicate the lack of benefit from treatment, particularly with initial chemotherapy, in view of the important prognostic implications of this conclusion.

However, when it is confirmed that the CA-125 level is rising, despite therapy, it is appropriate to question the value of subjecting a patient to the toxicity of a treatment program in the absence of clinical benefit.

The percentage increase in CA-125 levels which should be accepted as evidence of disease progression has not been agreed upon in the oncologic literature. However, in clinical practice it would appear reasonable to accept a confirmed (at least two samples) doubling of the CA-125 from a baseline value (with a minimum baseline at the upper limit of normal for the laboratory, usually 35 U/ml) as an indication of disease progression. Lesser degrees of change in the CA-125 value may indicate lack of response (so-called "stable disease") but should probably not be considered as actual disease progression in the absence of supporting data (e.g., new ascites, presence of a new mass on physical examination).

The CA-125 antigen level has also proven to be useful in demonstrating the persistence of disease following the completion of a standard chemotherapy regimen (e.g., 6 cycles of cisplatin/paclitaxel). If the CA-125 level remains abnormal, there is a >95% certainty that residual disease is present [7]. Even if a second-look surgery were performed and failed to confirm persistence of disease, it is likely that the elevated value reflects the presence of either microscopic cancer undetected within the peritoneal cavity or extra-peritoneal disease.

Unfortunately, it is well-established that the opposite situation is not true. That is, a normal CA-125 value at the completion of chemotherapy does not indicate the absence of disease. Several studies have reported that approximately 50% of patients with advanced ovarian cancer whose CA-125 levels return into the normal range will have persistent microscopic or macroscopic disease at second-look surgery [8-10].

Finally, a rising CA-125 level in patients with ovarian cancer whose CA-125 level had previously entered the normal range usually indicates disease progression [11]. However, as previously noted, a single elevation of the CA-125 in the absence of confirmatory data (e.g., new symptoms, physical findings) should not be accepted as definitive evidence of disease recurrence. While other causes of an elevated CA-125 are always possible (e.g., intra-abdominal infection, liver dysfunction, the development of a new primary cancer) [12], in the vast majority of cases a confirmed rise (at least two values) indicates return of the disease.


   POTENTIAL USES OF CA-125
Top
 Abstract
 Introduction
 Clinical Settings Where the...
 Potential Uses of CA-125
Potential "Overuse" of CA-125
 Potential Misuse of CA-125
 Conclusion
 References
 
As previously noted, a CA-125 response can be potentially utilized in trials of new anticancer agents [4]. Currently, patients without "measurable disease" are excluded from most phase II clinical trials of investigational drugs or strategies. This state of affairs often denies such patients access to new agents.

In addition, treating patients with only measurable disease imposes a particularly difficult task on these experimental drugs, as patients with measurable disease usually have considerably more tumor bulk than patients who do not have measurable masses. By employing CA-125 as a marker for disease response or progression, new drugs may be more rapidly screened for antitumor activity, and their effectiveness against small tumor volumes may be evaluated.

However, the clinical validity of this hypothesis must be directly tested in trials employing CA-125 as a surrogate marker for decrease in measurable tumor masses before it can be routinely considered as an acceptable marker in studies in ovarian cancer.

The initial level of CA-125 [13, 14] and the rate of decline following the institution of chemotherapy [15-20] have been suggested to be of important prognostic significance in ovarian cancer. In general, patients with extremely elevated values have greater tumor bulk than individuals with lower abnormal levels. Similarly, it is reasonable to state that patients whose CA-125 values fall rapidly following the initiation of chemotherapy are likely to be experiencing greater degrees of tumor cell kill and have cancers more sensitive to the cytotoxic agents employed compared with individuals exhibiting slow rates of decline in this marker level.

As a result, it might be proposed that patients presenting with very high (e.g., >2,000 U/ml) CA-125 antigen levels or those exhibiting "slower" rates of decline be treated with alternative treatment approaches compared to "standard therapy" of ovarian cancer. Such a management strategy has been considered utilizing the level of B-HCG (beta human chorionic gonadotropin) in advanced testicular cancer [21].

Unfortunately, at the present time, there is no evidence in ovarian cancer that employing alternative initial chemotherapy regimens (e.g., high-dose chemotherapy with marrow or peripheral progenitor cell rescue) can improve the ultimate clinical outcome of the malignancy. Thus, while the use of CA-125 for this indication is attractive, it must be considered highly investigative at the present time.


   POTENTIAL "OVERUSE" OF CA-125
Top
 Abstract
 Introduction
 Clinical Settings Where the...
 Potential Uses of CA-125
 Potential "Overuse" of CA-125
Potential Misuse of CA-125
 Conclusion
 References
 
As noted, a rising CA-125 antigen level generally indicates disease recurrence in a patient who has previously normalized her level, even in the absence of signs or symptoms of disease. However, to date, there are no data available to demonstrate that this information is of any direct clinical relevance. Stated differently, there is no evidence that re-institution of therapy in an asymptomatic ovarian cancer patient with a rising CA-125 antigen level improves either survival or quality of life, compared with simply waiting until there are clinical signs or symptoms of disease progression.

In fact, it can be reasonably argued that restarting chemotherapy at an earlier time point may actually decrease the overall quality of life compared with treating only when symptoms develop [22]. The clinical utility of a strategy of "early re-institution" of chemotherapy must be evaluated in a well-designed controlled phase III randomized trial comparing this approach to treatment only after patients develop signs or symptoms of disease recurrence [23].

Concern can also be raised with the often "standard practice" of obtaining a CA-125 level to "reassure a patient" that her disease remains "in remission." As stated previously, a normal CA-125 value provides little if any reassurance regarding the absence of disease activity. Only prolonged (i.e., many years) follow-up can provide any assurance the ovarian cancer will not recur in patients initially presenting with advanced disease.


   POTENTIAL MISUSE OF CA-125
Top
 Abstract
 Introduction
 Clinical Settings Where the...
 Potential Uses of CA-125
 Potential "Overuse" of CA-125
 Potential Misuse of CA-125
Conclusion
 References
 
Data currently available indicate CA-125 is not a useful test for screening for ovarian cancer and that this laboratory test should not be used for this purpose outside carefully controlled clinical trials. Justification for this strong statement includes:

  1. At least 50% of patients with documented stage I ovarian cancer will not have an elevation in CA-125. Thus, this marker will never be of any benefit in 50% of patients with "early-stage disease."
  2. CA-125 is not a specific marker for ovarian cancer, as it is elevated in a number of other tumor types [12, 14-26], including cancer of the breast and gastrointestinal malignancies.
  3. CA-125 is not even specific for cancer, being abnormal in a variety of benign conditions affecting women [12, 27-29], including endometriosis, pelvic inflammatory disease, alcoholic cirrhosis, and infectious peritonitis.
  4. Finding an abnormal CA-125 level in the absence of other signs or symptoms of ovarian cancer (e.g., adnexal mass) frequently leads to extensive investigative efforts and unnecessary surgery (e.g., laparoscopy or laparotomy for benign conditions) with the potential for morbidity or even mortality. Further, the finding of an "abnormal CA-125 level" can lead to the development of considerable and prolonged anxiety for the individual, as well as for her family and physician.
  5. At the present time, there is no evidence that detecting ovarian cancer as a result of finding an isolated CA-125 elevation impacts favorably on ultimate survival. The few patients reported to have been "discovered" to have "early-stage disease" may simply reflect the long natural history of ovarian cancer in some patients, as currently >10% of all patients with ovarian cancer will be found at the time of surgical staging to have stage I disease without having undergone CA-125 screening.

In summary, screening for ovarian cancer with tumor markers (including CA-125) or other methods (e.g., vaginal ultrasound) remains an investigative strategy [30-35]. There is currently no evidence that such an approach should be employed routinely outside the clinical trials setting.

It is reasonable to suggest that individuals at particularly high risk for the development of ovarian cancer (e.g., strong family history, BRCA-1 positive) may experience some benefit from a screening program which might include the use of CA-125. However, as noted above, the clinical utility of such a strategy must be subjected to examination in well-designed clinical trials.


   CONCLUSION
Top
 Abstract
 Introduction
 Clinical Settings Where the...
 Potential Uses of CA-125
 Potential "Overuse" of CA-125
 Potential Misuse of CA-125
 Conclusion
References
 
It has been >15 years since Bast and Knapp described the CA-125 antigen and proposed its potential use as a diagnostic tool in ovarian cancer [1, 2]. Since that time, CA-125 has proven itself to be a valuable addition to the oncologist’s armamentarium when managing women with this malignancy. Further investigative efforts are required to determine how this marker may be rationally and optimally employed in new drug development and treatment of patients with persistent or recurrent disease following initial cytotoxic chemotherapy.


   REFERENCES
Top
 Abstract
 Introduction
 Clinical Settings Where the...
 Potential Uses of CA-125
 Potential "Overuse" of CA-125
 Potential Misuse of CA-125
 Conclusion
 References
 

  1. Bast RC Jr, Feeney M, Lazarus H et al. Reactivity of a monoclonal antibody with human ovarian carcinoma. J Clin Invest 1981;68:1331–1337.
  2. Bast RC Jr, Klug TL, St. John E et al. A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. N Engl J Med 1983;309:883–887.[Abstract]
  3. Canney PA, Moore M, Wilkinson PM et al. Ovarian cancer antigen CA125: a prospective clinical assessment of its role as a tumour marker. Br J Cancer 1984;50:765–769.[Medline]
  4. Markman M. A proposal to use CA-125 to evaluate activity of new antineoplastic agents in ovarian cancer. Gynecol Oncol 1993;51:297–298.[Medline]
  5. Rustin GJS, Nelstrop AE, McClean P et al. Defining response of ovarian carcinoma to initial chemotherapy according to serum CA 125. J Clin Oncol 1996;14:1545–1551.[Abstract/Free Full Text]
  6. Rustin GJS, Nelstrop AE, Tuxen MK et al. Defining progression of ovarian carcinoma during follow-up according to CA 125: A North Thames Ovary Group study. Ann Oncol 1996;7:361–364.[Abstract/Free Full Text]
  7. Rubin SC, Hoskins WJ, Hakes TB et al. Serum CA-125 levels and surgical findings in patients undergoing secondary operations for epithelial ovarian cancer. Am J Obstet Gynecol 1989;160:667–671.[Medline]
  8. Atack DB, Nisker JA, Allen HH et al. CA 125 surveillance and second-look laparotomy in ovarian carcinoma. Am J Obstet Gynecol 1986;154:287–289.[Medline]
  9. Krebs H-B, Goplerud DR, Kilpatrick SJ et al. Role of CA 125 as tumor marker in ovarian carcinoma. Obstet Gynecol 1986;67:473–477.[Medline]
  10. Alvarez RD, To A, Boots LR et al. CA 125 as a serum marker for poor prognosis in ovarian malignancies. Gynecol Oncol 1987;26:284–289.[Medline]
  11. Quaranta M, Coviello M, Donadeo A et al. Measurement of the ovarian cancer-associated antigen CA 125 in monitoring tumor burden and response to chemotherapy. Tumori 1991;77:167–169.[Medline]
  12. Daoud E, Bodor G, Weaver C. CA-125 concentrations in malignant and nonmalignant disease (Washington University Case Conference). Clin Chem 1991;37:1968–1974.[Abstract/Free Full Text]
  13. Brand E, Lidor Y. The decline of CA 125 level after surgery reflects the size of residual ovarian cancer. Obstet Gynecol 1993;81:29–32.[Medline]
  14. Kivinen S, Kuoppala T, Leppilampi M et al. Tumor-associated antigen CA 125 before and during the treatment of ovarian carcinoma. Obstet Gynecol 1986;67:468–472.[Medline]
  15. Rustin GJS, Gennings JN, Nelstrop AE et al. Use of CA-125 to predict survival of patients with ovarian carcinoma. J Clin Oncol 1989;7:1667–1671.[Abstract]
  16. Gadducci A, Zola P, Landoni F et al. Serum half-life of CA 125 during early chemotherapy as an independence prognostic variable for patients with advanced epithelial ovarian cancer: results of a multicentric Italian study. Gynecol Oncol 1995;58:42–47.[Medline]
  17. Frasci G, Conforti S, Zullo F et al. A risk model for ovarian carcinoma patients using CA 125. Time to normalization renders second-look laparotomy redundant. Cancer 1996;77:1122–1130.[Medline]
  18. Buller RE, Berman ML, Bloss JD et al. CA 125 regression: a model for epithelial ovarian cancer response. Am J Obstet Gynecol 1991;165:360–367.[Medline]
  19. Mogensen O. Prognostic value of CA 125 in advanced ovarian cancer. Gynecol Oncol 1992;44:207–212.[Medline]
  20. Makar APH, Kristensen GB, Bormer OP et al. Serum CA 125 level allows early identification of nonresponders during induction chemotherapy. Gynecol Oncol 1993;49:73–79.[Medline]
  21. Motzer RJ, Gulati SC, Crown J et al. High-dose carboplatin + etoposide with autologous bone marrow rescue in poor risk nonseminomatous germ cell tumor patients with slow serum tumor marker decline during induction with cyclophosphamide, bleomycin, actinomycin D, vinblastin, cisplatin. Proc Am Soc Clin Oncol 1991;10:164.
  22. Markman M. Follow-up of the asymptomatic patient with ovarian cancer. Gynecol Oncol 1994;55:S134–S137.[Medline]
  23. Makar APH, Kristensen GB, Bormer OP et al. Is serum CA 125 at the time of relapse a prognostic indicator for further survival prognosis in patients with ovarian cancer? Gynecol Oncol 1993;49:3–7.[Medline]
  24. Haga Y, Sakamoto K, Egami H et al. Clinical significance of serum CA125 values in patients with cancers of the digestive system. Am J Med Sci 1986;292:30–34.[Medline]
  25. Bergmann J-F, Bidart J-M, George M et al. Elevation of CA 125 in patients with benign and malignant ascites. Cancer 1987;59:213–217.[Medline]
  26. Diez M, Torres A, Pollan M et al. Prognostic significance of serum CA 125 antigen assay in patients with non-small cell lung cancer. Cancer 1994;73:1368–1376.[Medline]
  27. O’Connell GJ, Ryan E, Murphy J et al. Predictive value of CA 125 for ovarian carcinoma in patients presenting with pelvic masses. Obstet Gynecol 1987;70:930–932.[Medline]
  28. Haga Y, Sakamoto K, Egami H et al. Evaluation of serum CA125 values in healthy individuals and pregnant women. Am J Med Sci 1986;292:25–29.[Medline]
  29. Candocia SA, Locker GY. Elevated serum CA 125 secondary to tuberculous peritonitis. Cancer 1993;72:2016–2018.[Medline]
  30. Helzlsouer KJ, Bush TL, Alberg AJ et al. Prospective study of serum CA-125 levels as markers of ovarian cancer. JAMA 1993;269:1123–1126.[Abstract/Free Full Text]
  31. Grover S, Quinn MA, Weideman P et al. Screening for ovarian cancer using serum CA125 and vaginal examination: report on 2550 females. Int J Gynecol Cancer 1995;5:291–295.[Medline]
  32. Carlson KJ, Skates SJ, Singer DE. Screening for ovarian cancer. Ann Intern Med 1994;121:124–132.[Abstract/Free Full Text]
  33. Schapira MM, Matchar DB, Young MJ. The effectiveness of ovarian cancer screening. A decision analysis model. Ann Intern Med 1993;118:838–843.[Abstract/Free Full Text]
  34. Mackey SE, Creasman WT. Ovarian cancer screening. J Clin Oncol 1995;13:783–793.[Abstract/Free Full Text]
  35. Markman M. Screening for ovarian cancer: Is it appropriate? J Cancer Res Clin Oncol 1994;120:257–258.[Medline]
accepted for publication December 11, 1996.




This article has been cited by other articles:


Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
K. A. Lowe, C. Shah, E. Wallace, G. Anderson, P. Paley, M. McIntosh, M. R. Andersen, N. Scholler, L. Bergan, J. Thorpe, et al.
Effects of Personal Characteristics on Serum CA125, Mesothelin, and HE4 Levels in Healthy Postmenopausal Women at High-Risk for Ovarian Cancer
Cancer Epidemiol. Biomarkers Prev., September 1, 2008; 17(9): 2480 - 2487.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
I. Simon, S. Zhuo, L. Corral, E. P. Diamandis, M. J. Sarno, R. L. Wolfert, and N. W. Kim
B7-H4 Is a Novel Membrane-Bound Protein and a Candidate Serum and Tissue Biomarker for Ovarian Cancer
Cancer Res., February 1, 2006; 66(3): 1570 - 1575.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow eLetters: Submit a response to this article
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Markman, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Markman, M.

HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
THE ONCOLOGIST STEM CELLS CME ALPHAMED PRESS JOURNALS