Department of Medical Oncology, Mount Vernon Centre for Cancer Treatment, Northwood, Middlesex, United Kingdom

The Oncologist CA125 Response: Can it Replace the Traditional Response Criteria in Ovarian Cancer? A.E. GUPPY, G.J.S. RUSTIN Department of Medical Oncology, Mount Vernon Centre for Cancer Treatment, Northwood, Middlesex, United Kingdom Key Words. CA125 Ovarian cancer Response criteria LEARNING OBJECTIVES After completing this course, the reader will be able to: 1. Determine in what situations measuring CA125 levels could alter patient management. 2. Discuss with patients the pros and cons of measuring CA125 during follow-up of ovarian cancer. 3. Define response or progression of ovarian cancer. 4. Incorporate CA125 use into clinical trial design. CME ABSTRACT Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com CA125 is well established as an accurate and reliable means of monitoring response to treatment and confirming relapse in ovarian cancer patients. Its role in follow-up after initial treatment is less certain and the subject of a current clinical trial. Measuring response with computerized tomography scans is futile in the majority of patients, as disease is often nonmeasurable at presentation, e.g., ascites or peritoneal deposits, or all measurable disease has been removed at the time of surgery. Serial changes in CA125 can be used as a reliable indicator of disease response or progression so that patients can be classified as responding or progressing according to either standard or CA125 criteria. These precise definitions are currently being prospectively validated in conjunction with the new response evaluation criteria in solid tumor response guidelines and are being incorporated into all future clinical trials. The Oncologist 2002;7:437-443 INTRODUCTION Cytotoxic chemotherapy in conjunction with debulking surgery remains the treatment of choice for patients with epithelial ovarian carcinoma. To determine whether patients have a sustained response to treatment throughout chemotherapy regimes, continual disease assessment is required. Traditionally, this is sought by serial radiological imaging and the measurement of evaluable tumor lesions. Using this method alone, however, is problematic in ovarian cancer, as often patients have no macroscopic disease after initial surgery or patients present with widespread diffuse peritoneal disease that is difficult to quantify on computerized tomography (CT) scans. The tumor marker, CA125, has also been validated as an effective means of monitoring treatment response Correspondence: G.J.S. Rustin, M.D., Department of Medical Oncology, Mount Vernon Centre for Cancer Treatment, Rickmansworth Road, Northwood, Middlesex HA6 2RN, United Kingdom. Telephone: 01923-844700; Fax: 01923-844840; e-mail: rustin@mtvern.co.uk Received April 4, 2002; accepted for publication August 10, 2002. AlphaMed Press 1083-7159/2002/$5.00/0 The Oncologist 2002;7:437-443 www.theoncologist.com

438 Ovarian Cancer and CA125 Response and is now firmly established in the management of epithelial ovarian cancer. This paper reviews the evidence supporting the role of CA125 in disease assessment, describes its optimal use and limitations in both individual patient and clinical trial settings, and explains how, in certain circumstances, CA125 can replace standard response assessment. It does not, however, discuss the role of CA125 in screening, diagnosis, or prognosis. CA125 The ovarian cancer mucin, CA125, was first identified by the monoclonal antibody, OC125, in 1981 [1, 2], but its genetic structure has been determined only recently [3, 4]. The CA125 molecule is composed of a short cytoplasmic tail, a transmembrane domain, and an exceptionally large glycosylated extracellular domain dominated by in excess of 60, 156-amino-acid repeat units known to bind the antibodies OC125 and M11. This large glycosylated mucin molecule is present within normal ovarian tissue and on the epithelium of endometrium, endocervix, and fallopian tubes, however, its precise cellular function is yet unknown. Studies have shown CA125 to be elevated in over 90% of women with advanced ovarian cancer [5] and 40% of patients with any primary cancer with extensive intraabdominal disease. CA125 is also associated with the inflammatory cells of the pleura, pericardium, and peritoneum and, therefore, is often elevated in the context of benign conditions, such as peritonitis, endometriosis, and liver cirrhosis causing ascites. CA125 levels also fluctuate during the menstrual cycle in a small population of women and become elevated in pregnancy, making it an unreliable marker in premenopausal women. INDIVIDUAL PATIENT MANAGEMENT Initial Treatment Patients with ovarian cancer typically present first to the oncologist after initial debulking surgery or with widespread inoperable disease. Both groups are usually offered a standard five to eight courses of chemotherapy, with treatment only being discontinued or altered if there is clear-cut evidence of disease progression. Without signs or symptoms suggestive of progression, however, the clinician will only change patient management if he/she can rely upon further evidence. Outside clinical trials, patients rarely have serial CT scans but do have serial CA125 measurements. However, if CA125 is to be relied upon as an indicator of relapse in the absence of disease evaluable by standard criteria, it must be sufficiently sensitive to reliably confirm clinically suspected relapse or demonstrate progressive disease on treatment. Furthermore, it should be highly specific in order that effective therapy is not stopped prematurely because of a false-positive result. A serial fall in CA125 levels has been shown to be associated with response to treatment, and a serial rise with tumor progression [2, 6]. Clinicians are, therefore, reassured of response to treatment if a patient with no clinically measurable disease has a sustained decrease in CA125 and will continue current treatment. Conversely, if a patient develops worrying symptoms or signs suggestive of disease recurrence on treatment, a serial increase in CA125 levels can confirm disease progression and help the clinician change therapy. Studies have shown that a serial rise in CA125 of 25% over three samples is almost 100% specific for disease progression [7]. In order to use CA125 to monitor therapy, the value prior to starting chemotherapy should be twice the upper limit of normal (ULN) and rising after initial surgery. Debulking surgery or a paracentesis can, however, cause a temporary rise in CA125 levels [8]. Furthermore, the half-life for CA125 is approximately 6 days, and it is, therefore, important to appreciate that after initial surgery or, indeed, after ascitic drainage when large volumes of disease have been removed, the CA125 level, after an initial rise, will continue to fall for 3-6 weeks. This is the usual time of starting chemotherapy and, therefore, initial responses in CA125 should be regarded as resulting from a combination of surgery and chemotherapy. Routine Follow-Up A rising CA125 has been shown to predate clinical relapse by a median of 4 months in approximately 70% of patients [6, 9] and, therefore, may be an early indicator of disease relapse. In addition, tumor volume, performance status, and number of tumor lesions at relapse have also been shown to be independent prognostic factors for response and diseasefree and overall survivals [10]. Therefore, one might speculate that early detection and treatment of relapsed disease, as indicated by a rising CA125, would be beneficial to overall survival. In addition, multiple admissions for symptoms of large volume disease, e.g., ascitic drainage, intestinal obstruction, and pain, may also be avoided. However, there is currently no evidence that early treatment based on a raised CA125 in asymptomatic patients improves either survival or symptom control. Many patients and clinicians are reassured by a normal CA125, however, this can be falsely reassuring, as small volume ovarian cancer is often associated with a normal CA125. Disadvantages of routine CA125 measurements in follow-up include the anxiety generated by the regular blood tests required of patients which results in their loss of sleep prior to the next clinic visit. Such anxiety may even induce what some doctors call CA125 psychosis. Treatment for

Guppy, Rustin 439 relapsed ovarian cancer is aimed at palliation of symptoms and prolongation of survival but is almost never curative. Therefore, treating early, when patients are symptom free, will result in more chemotherapy in the patient s remaining life, and with this, more treatment-related toxicity. However, novel agents such as the new tyrosine kinase inhibitors may have potential for use as cytostatic therapy for the asymptomatic patient with a rising CA125. These uncertainties are currently being addressed in a multicenter Medical Research Council/European Organization for Research and Treatment of Cancer (MRC/EORTC) trial in which patients in remission from initial treatment have regular CA125 blood tests as part of their routine follow-up. These CA125 values are analyzed at accredited central laboratories, and both the patient and clinician are blinded from the result. Once the CA125 doubles from the ULN (precise values will differ slightly according to variation in assays), the patient is then randomized to receive either immediate treatment according to local standard practice, or treatment on clinical relapse (Fig. 1). The primary end point for this study is overall survival, with quality of life and health economics designated as secondary end points. Quality of life (QL) is measured every 3 months by the widely used quality-of-life questionnaire, EORTC QLQ-C30 [11]. This is a 30-item general self-reporting questionnaire that incorporates five functional scales, a global QL scale, three symptom scales, and a number of single-item measures relating to ovarian cancer symptoms. This study has already accrued over 750 patients, but to obtain adequate statistical power will be continuing for some years. Until the results of this trial are available, the survival benefit of the routine use of CA125 measurements in the follow-up of ovarian cancer patients remains unknown. In several large European centers, the majority of patients agree to enter the CA125 follow-up trial; however, for those patients not willing to enter, our default position is to suggest only doing CA125 measurements when there are symptoms or signs that might indicate disease progression. Patients are, therefore, given CA125 pathology request forms and advised only to use them if they have concerns. Many patients, particularly in the U.S., demand regular CA125 measurements either for reassurance or because they and their oncologist believe that earlier treatment of relapse is beneficial. They should, however, be counseled about the potential disadvantages. Confirming Disease Progression with CA125 In the presence of concerning symptoms or signs, CA125 has been shown to accurately diagnose disease progression. Several definitions of progression according to CA125 have been proposed. A rise of 50%, 100%, or just to above normal Patient in complete remission after first-line chemotherapy with therapy-free interval < 3 years and a normal* CA125 Clinician informed and patient treated immediately (within 4 weeks) Register with trials office CA125 > 2 upper limit of normal (monitored by Trials Office only) Randomize Clinician NOT informed and normal monitoring continues. *The upper limit of normal for CA125 values will differ between each centralized accredited laboratory. Figure 1. MRC/EORTC CA125 follow-up trial design. range have all been shown to be predictive of relapse [1, 2, 6, 12], but only one definition has been extensively validated. Rustin et al. [13] showed that, in a study of 255 patients in routine follow-up from initial chemotherapy, a confirmed doubling of CA125 from its ULN predicted progression with a sensitivity of 82% and a specificity of 98%. This translates to less than 2% of patients receiving unnecessary second-line treatment, and if patients also had symptoms suggestive of recurrence, it is unlikely that any patients would be treated unnecessarily. CT scans are often used in clinical practice to confirm progression suggested by symptoms and CA125 rise. However, CT scans are unable to detect disease less than 1 cm in size and, therefore, will miss the widespread miliary peritoneal disease so often seen in these patients at relapse. In addition, a rising CA125 has a median lead time of 63 days prior to the date of relapse as identified by standard criteria [13]. van der Burg et al. also demonstrated that CA125 together with routine general and pelvic examinations predicted relapse in 92% of patients, with routine radiological investigations only contributing to 8% [6]. With such a small false-positive rate, it is our recommendation that doubling of the CA125 from the ULN or nadir is sufficient to diagnose disease progression (see later text) without the need for confirmatory imaging. Before acting upon the CA125 level, it is important to confirm its

440 Ovarian Cancer and CA125 Response Table 1. CA125 definition of response Response according to CA125 has occurred if either of the following criteria are fulfilled: 50% response definition If there is a 50% decrease in serum CA125 level from two initially elevated samples, then a 50% response has occurred. The sample showing a 50% fall must be confirmed by a fourth sample (i.e., four samples required). 75% response definition If there has been a serial decrease in CA125 level of more than 75% over three samples, then a 75% response has occurred (i.e., three samples required). In both 50% and 75% response definitions, the final sample needs to be analyzed at least 28 days after the previous sample. elevation with a second sample. However, CA125 levels can rise in patients with abdominal pain from adhesions following intraperitoneal therapy or in coexisting conditions, such as endometriosis. Clearly, in this group of patients, a CT scan is warranted to exclude disease relapse before instigating potentially unnecessary chemotherapy. CLINICAL TRIALS Role of CA125 in Clinical Trials Therasse et al. [14] have recently published the new response evaluation criteria in solid tumors (RECIST) guidelines that are the result of a large international collaboration among the EORTC, the National Cancer Institute (NCI) of the U.S., and the National Cancer Institute of Canada (NCIC) Clinical Trials Group. These guidelines supercede the previously used World Health Organization standard criteria [15, 16] and use unidimensional measurements of target lesions to calculate response instead of the previous bidimensional approach. These guidelines are now being incorporated into the end points of all new clinical trials. Many patients with advanced ovarian cancer, however, present with nonevaluable disease according to the above criteria. The advantage, then, of defining response according to CA125 and introducing this criteria into clinical trials is that more women who were previously ineligible under standard response criteria are now eligible for entry into new drug trials. Definition of CA125 Response Many definitions of CA125 response have been proposed [17-19], but only one, by Rustin et al., has been retrospectively validated [13]. The initial CA125 response criteria were derived from 277 patients within the North Thames Ovary trial comparing maintenance radiotherapy with carboplatin. For each patient, CA125 percentage falls were examined by a computer program and, to reduce false-positive prediction of response to <2%, it was decided to classify patients according to CA125 by either a 50% fall over four samples or a 75% fall over three samples. In both definitions, the final confirmatory sample has to be analyzed at least 28 days after the previous sample, and the initial CA125 value must be 40 units/ml (Table 1). Once these 50% and 75% CA125 response criteria had been established, they were then tested in two other patient groups 254 patients in the North Thames Ovary five versus eight trial [20] and 458 patients in the Gynecologic Oncology Group (GOG) protocol 97, which both investigated dose-intense versus standard chemotherapy. Of all 620 patients assessable by CA125 criteria, only two patients (0.3%) showed a CA125 response with clinical progression. In the GOG trial, CA125 response rate was 66% in all 317 patients assessable by CA125 criteria and 67% in 221 patients nonmeasurable according to GOG standard criteria. This is comparable with the GOG-defined response rate of 62%. A recent retrospective analysis looked at how accurate the response rates obtained using the 50% and 75% response definitions were at predicting the activity of drugs in phase II trials for ovarian cancer compared with the response rates obtained by standard criteria [21]. In this analysis, data were obtained from 25 treatment groups within 19 phase II clinical trials looking at 14 different cytotoxic drugs for relapsed ovarian cancer (Table 2). Response rates were estimated in 1,457 assessable patients according to standard criteria and in 1,092 assessable patients according to CA125. Results showed that there was no statistically significant difference between response rates obtained by standard and CA125 criteria and, therefore, there was no difference in accurately predicting whether a phase II drug was active and worth pursuing in further clinical trials. A recent analysis by Guastalla et al., has also validated the CA125 response criteria [22] and has shown CA125 response to predict progression-free survival and correlate with RECIST response. In this study, 595 patients with recurrent ovarian cancer from six consecutive phase II trials were evaluated. Response rates were assessed independently according to RECIST criteria in 338 patients with measurable disease and according to the 50% CA125 definition in 490 patients evaluable by CA125.

Guppy, Rustin 441 Table 2. Details of phase II trials and response rates by standard and CA125 criteria [21] Standard criteria CA125 criteria Treatment Trial details Responders/ % response Responders/ % response evaluable evaluable Altretamine Complete remission after previous platinum regimen, 18/45 40 20/51 39 relapse defined as rising CA125 or measurable or assessable disease Docetaxel EORTC study stratified by disease-free interval after 11/37 30 17/42 41 platinum-based therapy. Group 2 Etoposide British Columbia Cancer Agency study of patients with 5/17 29 3/14 21 platinum-resistant disease Gemcitabine Eli Lilly trial 0026 of platinum-pretreated patients 7/36 19 5/18 28 Isotretinoin/Calcitriol Study of asymptomatic patients with rising CA125 0/17 0 0/16 0 levels after at least one standard chemotherapy regimen Oxaliplatin DEB 9502/EORTC 55951 randomized trial of paclitaxel 7/42 17 4/26 15 versus oxaliplatin in platinum-pretreated patients Paclitaxel EORTC/NCIC randomized trial OV09 of platinum- 54/259 21 44/209 21 pretreated patients Platinum based Vermorken et al. Amsterdam study 9/20 45 9/18 50 Raltitrexed Trial 1694IL/0002 of platinum-resistant disease, 2/28 7 2/14 14 or relapse within 12 months of previous platinum-based treatment Topotecan 034 European trial after failure of first-line cisplatin- 16/109 15 16/83 19 based regimen Concern has been raised by several authors that CA125 response may be altered by certain drugs, including paclitaxel [23, 24]. Bridgewater et al. [25], however, reanalyzed the data from four trials of paclitaxel as first- or second-line therapy using the 50% and 75% response criteria as stated above. In 144 patients treated, the response rates according to standard criteria and CA125 criteria were equivalent (30.7% versus 31.7%). Furthermore, the false-positive rate was 2.9% with paclitaxel and 2.2% with cisplatin, suggesting that precise CA125 response criteria behave similarly with the two drugs. In another study by Eisenhauer et al. [26], CA125 appeared to overestimate the response to paclitaxel; however, when these results were reanalyzed using precise CA125 response definitions, the response rates according to standard criteria and CA125 criteria were comparable. The disparity between this and previous studies is thought, in part, to be due to the large variability seen with weekly CA125 measurements, perhaps due to tumor lysis, and the difference between precise and more simple definitions. The above data therefore clearly identify CA125 as an accurate, reliable, and cheap means of assessing response. They also show how, in the majority of circumstances, it can replace the need for expensive and time-consuming radiological assessment. Definition of CA125 Progression In many clinical trials of first- and second-line treatment for ovarian cancer in which progression-free survival is often the primary end point, it is well known that many investigators will instigate second-line treatment according to a rise in serum CA125 levels before overt clinical signs of progression. This, then, causes great confusion when deciding the date of disease progression, with wide variability among different trial groups in what to do with the data. Some groups will include these patients in the progressive disease population, other groups will censor these patients, and others will ignore treatment before the documented date of clinical progression altogether. The Gynecologic Cancer Intergroup (GCIG), therefore, proposed that a precise CA125 definition of progression be used as a secondary end point in first-line therapy randomized trials [27]. The precise CA125 definition of progression they accepted was the definition previously validated by Rustin and colleagues [9] (Table 3). This was initially derived from patients receiving first-line treatments for ovarian cancer within the North Thames Ovary Group trials and is based on how the CA125 level behaves during first-line treatment. This definition accurately predicts progression in patients whose CA125 level initially falls to normal on first treatment and then doubles from the ULN. In patients whose baseline CA125 level after first-line treatment is not in the

442 Ovarian Cancer and CA125 Response Table 3. Definition of CA125 progression Progression according to CA125 has occurred if any of the following criteria are fulfilled: Patients A Patients B Patients C CA125 2 ULN documented on two occasions. CA125 2 nadir value on two occasions. As for patients A Date of disease progression: First date of CA125 Date of disease progression: First date of the CA125 elevation to 2 ULN. elevation to 2 nadir value. Patients A: Patients with elevated pretreatment CA125 levels that normalize on first-line chemotherapy. Patients B: Patients with elevated pretreatment CA125 levels that do not normalize on first-line chemotherapy. Patients C: Patients with normal pretreatment CA125 levels. Adapted from Vergote et al. [27]. normal range, a doubling from the nadir value is also an accurate predictor of progression, with a false-positive of <2% [28]. The date of progression is defined as either the date of the first doubling of CA125 or the date of progression according to RECIST criteria. If both criteria are met, the first of the two dates is documented as the date of progression. The above CA125 progression definition is currently being validated in the data obtained from the European- Canadian Intergroup trial (OV10), which compared paclitaxel and cisplatin chemotherapy with cyclophosphamide and cisplatin chemotherapy as first-line treatment for advanced epithelial ovarian cancer [29]. The Use of CA125 Criteria in Future Clinical Trials In the guidelines outlining the new RECIST criteria, Therasse et al. discussed the role of combining standardized tumor marker response definitions with the RECIST response criteria in future clinical trials. In the case of ovarian cancer trials, this has the advantage of evaluating more patients according to CA125 or RECIST or by both criteria. However, the CA125 response and progression criteria were derived from known data sets and have been retrospectively validated. Therefore, at present, in order to use CA125 response criteria as a secondary end point in clinical trial design, it should be discussed with the regulatory authorities before incorporating in a trial protocol. Examples of the use of the CA125 response and progression definitions in recently published data include the phase II trials for oral altretamine in relapsed ovarian carcinoma [30] and the use of weekly cisplatin and oral etoposide in relapsed ovarian cancer [31]. The initial aim of any phase II trial is to determine whether the activity of a drug is sufficient to justify further investigation. If response rates according to CA125 are lower than a predetermined threshold efficacy, the drug should be rejected and further studies are not necessary. However, if response rates according to CA125 are satisfactory, the patient numbers within the trial should be expanded allowing sufficient patients to be evaluated by both CA125 and RECIST criteria. Having decided to incorporate CA125 criteria into future trials, a standardized CA125 definition must be used. The GCIG has recently proposed a simplified CA125 definition that just uses the 50% response criteria. This requires two pretreatment CA125 levels greater than or equal to twice the ULN, with samples taken at least 1 week and not more than 3 months apart, with one of the two samples being taken within 1 week of starting treatment. The GCIG is very keen that this new 50% CA125 response definition be tested in a wide variety of new phase II trials to facilitate prospective validation and general acceptance. Details on the complete definition and method of analyzing data can be obtained by contacting Gordon Rustin (see contact details) or Monica Bacon (mbacon@ctg.queensu.ca). CONCLUSION This review outlines the research that has proven CA125 to be an accurate, cheap, and readily available means of predicting response to therapy in both routine patient management and clinical trials. The data also show that, in most cases, CA125 can replace standard response assessment and, therefore, absolve the need for time-consuming and expensive radiological imaging. Prospective validation of the CA125 response definitions is currently in progress and, in conjunction with RECIST, should form the basis of response criteria in all future phase II trials of new cytotoxic drugs. REFERENCES 1 Bast Jr RC, Feeney M, Lazarus H et al. Reactivity of a monoclonal antibody with human ovarian carcinoma. J Clin Invest 1981;68:1331-1337. 2 Bast Jr RC, 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.

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