CA125 in ovarian cancer: European Group on ... - Wiley Online Library

Int J Gynecol Cancer 2005, 15, 679–691

SPECIAL ARTICLE

CA125 in ovarian cancer: European Group on Tumor Markers guidelines for clinical use M.J. DUFFY*y, J.M. BONFRERz, J. KULPA§, G.J.S. RUSTINk, G. SOLETORMOS{, G.C. TORRE#, M.K. TUXEN* & M. ZWIRNERyy *Department of Nuclear Medicine, St Vincent’s University Hospital, Dublin, Ireland; yDepartment of Surgery, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland; zNetherlands Cancer Institute, Antoni van Leeuwenhoek Huis, Amsterdam, The Netherlands; §Department of Clinical Biochemistry, Oncological Center, Cracow Branch, Krakow, Poland; kMount Vernon Centre for Cancer Treatment, Middlesex, United Kingdom; {Department of Clinical Biochemistry, Hillerod Hospital, University of Copenhagen, Copenhagen, Denmark; #Bogliasco, Italy; **Department of Oncology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark; and yyDepartment of Obstetrics and Gynecology, University of Tubingen, Tubingen, Germany

Abstract.

Duffy MJ, Bonfrer JM, Kulpa J, Rustin GJS, Soletormos G, Torre GC, Tuxen MK, Zwirner M. CA125 in ovarian cancer: European Group on Tumor Markers guidelines for clinical use. Int J Gynecol Cancer 2005;15:679–691.

CA125 is currently the most widely used tumor marker for ovarian epithelial cancer. The aim of this article is to provide guidelines for the routine clinical use of CA125 in patients with ovarian cancer. Due to lack of sensitivity for stage I disease and lack of specificity, CA125 is of little value in the detection of early ovarian cancer. At present, therefore, CA125, either alone or in combination with other modalities, cannot be recommended for screening for ovarian cancer in asymptomatic women outside the context of a randomized controlled trial. Preoperative levels in postmenopausal women, however, may aid the differentiation of benign and malignant pelvic masses. Serial levels during chemotherapy for ovarian cancer are useful for assessing response to treatment. Although serial monitoring following initial chemotherapy can lead to the early detection of recurrent disease, the clinical value of this leadtime is unclear. CA125 is the ovarian cancer marker against which new markers for this malignancy should be judged. KEYWORDS:

CA125, European Group on Tumor Markers (EGTM), guidelines, ovarian cancer.

Ovarian cancer is the fourth most common cause of tumor-related death in women and the most lethal gynecological malignancy(1,2). Although frequently viewed as a single disease, ovarian cancer represents a group of related but distinct tumor types including epithelial tumors, germ cell tumors, sex-cord stromal Address correspondence and reprint requests to: Professor M.J. Duffy, Nuclear Medicine Department, St Vincent’s University Hospital, Elm Park, Dublin 4, Ireland. Email: [email protected] #

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tumors, and metastatic tumors(2). Of these different types, cancers of epithelial origin are the most common, comprising 90% of all ovarian malignancies. Epithelial cancers can in turn be divided into multiple histologic subtypes, such as serous, mucinous, endometrioid, clear cell, undifferentiated, squamous cell, and transitional(3). In recent years, the tumor marker CA125 has played an increasing role in the detection and management of patients with ovarian cancer. The aim of this article is

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to present the European Group on Tumor Markers (EGTM) guidelines for the routine use of this marker in patients with epithelial ovarian carcinoma. The EGTM* is an ad hoc group of scientists and physicians from universities and the diagnostic industry with an interest in tumor markers(4). The group was founded in 1997, one of its aims being to publish guidelines for the clinical use of tumor markers. We wish to emphasize that adherence to these guidelines is voluntary and that the ultimate decision regarding marker use should be made by the treating clinician.

Structure of CA125 CA125 was originally identified as an antigenic determinant found on a high–molecular weight glycoprotein and recognized by the OC125 monoclonal antibody(5). This antibody was produced by immunizing mice with a cell line designated OVCA433 and which was derived from a human serous cystadenocarcinoma. Early data suggested that CA125 was a high-molecular glycoprotein with estimates of molecular weight ranging from 200 to 2000 kd(6). Recently, following molecular cloning(7,8), CA125 was reported to have a number of features characteristic of a mucin. These included an N-terminal region containing multiple partially conserved tandem repeats containing a high content of serine, threonine, and proline and a C-terminal region containing both a transmembrane region and a cytoplasmic tail. Because of these features, CA125 was regarded to be a mucin and was designated MUC16(7).

Distribution of CA125 in normal tissues Early studies using immunohistochemistry with the OC125 antibody showed that CA125 was present in a number of normal adult tissues derived from the coelomic epithelium such as endometrium, endocervix, and fallopian tube. CA125 was also found to be present in cells of mesothelial origin such as pleural, pericardial, and peritoneal cells(9). Later, CA125 was detected in epithelia of kidney, lung, stomach, gall bladder, pancreas, and colon (for review, see Jacobs and Bast(10), Tuxen et al.(11), and Tuxen(12)). Although early studies failed to find CA125 in either fetal or adult ovary, more recent work showed that it was expressed in normal adult ovary(13). Clearly, CA125 has a widespread distribution in human tissues and lacks organ specificity. *All the authors of this article apart from G.R. and M.T. are members of the Gynecology Cancer Focus Group of the EGTM. G.R. and M.T. were guest contributors. #

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Serum CA125 levels in healthy subjects Using OC125 as both capture and labeled antibody, Bast et al.(14) developed an immunoradiometric assay for the quantitation of CA125 levels in serum. With this assay, 1% of 888 apparently healthy subjects (537 males and 351 females) were found to have serum levels of the marker .35 kU/L. Based on this initial report, a value of 35 kU/L has been widely adopted as the cutoff point for CA125. Recently, the CA125 assay was modified, ie, a new antibody known as M11 replaced OC125 as the capture antibody. This modified assay, which became known as CA125 II, is now universally used for measuring CA125. As originally reported by Bast et al.(14), basal or low levels of CA125 are found in serum from apparently healthy males and females. A number of factors are known to influence serum CA125 levels in apparently healthy women. These include the following. Age Multiple studies have shown that healthy premenopausal women have higher serum CA125 levels than postmenopausal women(15,16). In a study involving 1026 apparently healthy women, Bon et al.(15) reported that mean levels were 18 kU/L (range, 2–98) and 12 kU/L (range, 2–37) in the pre- and postmenopausal groups, respectively. In another study (N ¼ 652), Bonfrer et al.(16) found using an immunoradiometric assay for CA125 (Centocor, Malvern, PA) that the 95th percentile value was 36 kU/L for those aged 40–44 years, 30 kU/L for those aged 45–55 years, and 25 kU/L for women over 55 years. Using an automated luminescence assay (LIA, Byk-Sangtec, Dietzenbach, Germany) on the same population, the corresponding 95th percentiles were 31, 29, and 21 kU/L, respectively. In the group of women older than 55 years of age, none had a CA125 level greater than 35 kU/L. Menstrual cycle With some women, serum levels of CA125 fluctuate throughout the menstrual cycle. Grover et al.(17) measured CA125 levels in 1478 apparently healthy women and found elevated levels (.35 U/L) in 77 (5.2%). Forty of the women with high levels had weekly determinations carried out. In 29 of these, higher values were found at the time of menstruation than at other stages of the cycle. In another study, Lehtovirta et al.(18) found that CA125 was increased during menstruation in 16 women with ovulatory and in 12 women with anovulatory cycles. In women with

Guidelines for use of CA125 in ovarian cancer

anovulatory cycles, CA125 levels were also increased in the premenstrual phase. In this study, a negative correlation was found between CA125 and progesterone levels in the premenstrual phase of the cycle. Pregnancy CA125 levels can also increase during pregnancy, especially during the first trimester. Gocze et al.(19) measured CA125 levels in sera from 20 apparently healthy first trimester women and found four cases of increased CA125 ranging from 65 to .500 kU/L. The increased level of CA125 during the first trimester of pregnancy is likely to be derived from the decidualized endometrium(10). Race Pauler et al.(20) investigated the effect of race on serum CA125 levels using 18,748 postmenopausal women who participated in an ovarian cancer-screening program but were not diagnosed with ovarian malignancy during the 12-year follow-up period. Significantly higher levels were found in Caucasian women (median value, 14.2 kU/L) compared to either Asian (median value, 13 kU/L) or African women (median value, 9.0 kU/L). Other factors that may affect CA125 levels Some(20) but not all(21,22) reports showed that smoking decreased CA125 levels. Caffeine consumption has been reported to decrease CA125 levels(20). Parity, hormone replacement therapy, use of oral contraceptives, and unilateral oophorectomy, however, do not appear to affect CA125 levels(20). In contrast to unilateral oophorectomy, hysterectomy significantly decreased CA125 levels(20). Other factors that may alter serum CA125 levels include recent surgery, administration of mouse antibodies (eg, radiolabeled antibodies against CA125)(23), and the presence of endogenously produced antibodies(24).

Serum CA125 levels in patients with benign diseases Multiple benign diseases both gynecological and nongynecological can give rise to elevated serum levels of CA125. Benign gynecological disorders that may be associated with increased levels include endometriosis, fibromas, uterine myomas, acute salpingitis and chronic salpingitis, pelvic inflammatory disease,

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and Meig’s syndrome (for review, see Jacobs and Bast(10), Tuxen et al.(11), and Tuxen(12)). Nongynecological benign diseases shown to increase CA125 levels include liver cirrhosis, chronic active hepatitis, acute and chronic pancreatitis, and lung and pleural disease(10–12). Serum CA125 levels may also be elevated by ascites of benign origin or by any disorder that inflames the peritoneum, pericardium, or pleura(11,12).

Serum CA125 levels in nonovarian cancer Although the OC125 antibody was produced against a cell line derived from an ovarian carcinoma, elevated levels of CA125 can occur in most types of adenocarcinoma, especially if distant metastases are present. Advanced adenocarcinomas shown to give rise to elevated levels include those derived from breast, colorectum, pancreas, lung, endometrium, cervix, and fallopian tube(10–12).

Serum CA125 levels in ovarian cancers In their original study, Bast et al.(14) found that CA125 was elevated (.35 kU/L) in 83 of 101 (82%) of patients with ovarian cancer. Subsequent studies, however, reported that both the proportion of patients with elevated levels and the extent of elevation depended primarily on disease stage and histology type (for review, see Jacobs and Bast(10), Tuxen et al.(11), and Tuxen(12)). Jacobs and Bast(10) combined the data from 15 different studies and showed that CA125 levels were increased in 49 of 96 (50%) patients with FIGO stage I disease, 55 of 61 (90%) in stage II, 199 of 216 (92%) with stage III, and 77 of 82 (94%) in stage IV disease. In 14 of 15 of these studies, the cutoff point used for CA125 was 35 kU/L, while in the remaining one it was 25 kU/L. Combining data from 12 separate studies(10), elevated levels (.35 kU/L) were detected in 254 of 317 (80%) patients with tumors of serous type, 35/51 (69%) with mucinous type, 39/52 (75%) with endometrioid type, 28/36 (78%) with clear cell type, and 56/ 64 (88%) with undifferentiated type. Some but not all studies found that serum CA125 levels were higher in patients with undifferentiated than differentiated ovarian cancers(11,12). In summary, although elevated levels occur in 80– 90% of all patients with ovarian cancer, the frequency of positivity is greater in patients with nonmucinous than mucinous tumors and in patients with high stage (FIGO II, III, or IV) than in those with stage I disease. #



CA125 as a marker for ovarian cancer Screening Because of lack of specific symptoms, 65–75% of ovarian cancers are diagnosed at an advanced stage. Although the overall 5-year survival rate is about 30%, the 5-year survival rate for stages III and IV combined is only about 10%. On the other hand, a 5-year survival rate of .90% can be achieved when disease is confined to the ovary. Unfortunately, only about 25% of ovarian cancers are detected at this early stage(25). This correlation between 5-year survival rates and stage at diagnosis suggests that early detection may improve outcome. Potential screening procedures for ovarian cancer include transabdominal ultrasound, transvaginal ultrasound, transvaginal ultrasound with color Doppler, and serum CA125. Of these modalities, assay of CA125 is attractive as it is largely noninvasive, relatively cheap, and widely available. Use of CA125 alone, however, has a number of serious limitations. Firstly, as stated above, it has a low sensitivity for early or stage I disease. Secondly, it lacks specificity especially in premenopausal women, see above. This lack of sensitivity and specificity when combined with the low prevalence of ovarian cancer in the general population means that CA125 alone has a low positive predictive value (PPV) in detecting ovarian cancer in an asymptomatic population. For example, with a sensitivity of 80%, a specificity of 99% (ie, in a general population) and a prevalence of ovarian cancer of 0.0003, CA125 would have a PPV of only 2.3%(26). In practice, this would mean that 50 women would need to undergo laparoscopy or laparotomy in order to detect one ovarian cancer. According to Jacobs and Bast(10), a screening test for ovarian cancer should have a PPV of at least 10% to be clinically useful. With a PPV of 10%, ten women would need to undergo surgery for each case of ovarian cancer detected. In order to enhance the clinical utility of CA125 as a screening test, a variety of strategies have been attempted. These include the assay of other markers in addition to CA125, sequential assays of CA125, and a combination of CA125 with ultrasound (ie, multimodal screening). It is the latter approach that has been used most frequently in the screening studies reported to date (for review, see Rosenthal and Jacobs(27) and Bast et al.(28)). In multimodal screening, CA125 is usually assayed first and ultrasound only carried out if elevated marker levels are found. The advantage of this strategy is that only a minority of women need to have #


ultrasound, which reduces costs and the need for a clinical examination. In a systematic review of the literature, Bell et al.(29) identified four prospective but nonrandomized studies that have used multimodal screening for ovarian cancer in the general population. In total, over 27,000 women were screened and 14 ovarian cancers were detected of which 7 were stage I disease. In the largest study (N ¼ 22,000), the PPV of CA125 followed by ultrasound for the detection of ovarian cancer was 26%(30). Recently, the combination of CA125 and ultrasound in screening for ovarian cancer was evaluated in a pilot randomized trial(31). In this study, postmenopausal women aged 45 years or older were randomized to either a control group (N ¼ 10,977) or a screened group (n ¼ 10,958). Women in the screened group were offered three annual screens, ie, CA125, pelvic ultrasound if CA125 value was greater than 30 kU/L, and referral for gynecological investigation if ovarian volume was 8.8 mL or greater. Of the women allocated to screening, 29 underwent surgical investigation and 6 cancers were detected, ie, a PPV of 20.7%. During 7 years of follow-up after the screening, 10 further cases of ovarian cancer were detected in the screened group and 20 in the control group. In the women who developed cancer, survival was longer in those who underwent screening than in the control group (73 months versus 42 months, P ¼ 0.011). Nine deaths occurred in the screened group compared to 18 in the control group but this difference was not statistically significant. The study, however, had insufficient numbers of subjects to show a possible difference in mortality. It nevertheless demonstrated for the first time that a multimodal approach to ovarian cancer screening in a randomized trial was feasible. Another promising approach being evaluated for ovarian cancer screening involves an algorithm incorporating subject’s age, rate of change in CA125 level, and absolute level of CA125(32). This algorithm was based on the observation that while women with ovarian malignancy generally have rising levels of CA125, women with other diseases tend to have constant or declining levels(32). The algorithm calculates the slope (change in levels over time) and intercept (initial value) of the best-fit line drawn between sequential CA125 values. The greater the slope or intercept, the higher was the risk of ovarian cancer. In a study of over 5000 subjects, this approach yielded a sensitivity of 83%, a specificity of 99.7%, and a PPV of 16% in predicting ovarian cancer in the year following the last screening(32). In a more recent and larger study, Skates et al.(33) found that use of a risk calculation based on serial


levels of CA125 was superior to that of fixed cutoff points for the preclinical detection of ovarian cancer in postmenopausal women. According to Skates et al.(33), these results justify the incorporation of the risk calculation in a prospective randomized controlled trial. The third approach aimed at enhancing the efficiency of CA125 in screening for ovarian cancer involves the additional assay of complementary markers. Although CA125 is presently the best available marker for ovarian cancer, it lacks sensitivity in two subgroups, ie, those with stage I disease and those with mucinoustype tumors. Markers that complement CA125, especially in these subgroups, are therefore urgently needed. Woolas et al.(34) measured CA125, OVX1, and macrophage colony stimulating factor (M-CSF) in 46 patients with stage I ovarian cancer, 237 patients with benign pelvic masses, and 204 apparently healthy controls. In the cancer group, CA125 was elevated in 67%, CA125 or OVX1 in 87%, and M-CSF or CA125 in 91%. The sensitivity of the three markers together was 98%, which was significantly superior to CA125 alone. One of the three markers was elevated in 11% of the controls and 51% of those with benign pelvic masses. Clearly, combining the different markers led to enhanced sensitivity but resulted in decreased specificity. In a more recent report, one of these three markers was elevated in 76% of 58 patients with stage I disease(35). Markers that have been shown to complement CA125 in mucinous cancers include tumor-associated trypsin inhibitor, CA19-9, CA72.4(36), and inhibin(37). Other markers that may complement CA125 in the detection of ovarian cancer are listed in Table 1. Rather than using specific markers, Petricoin et al.(46) recently described the use of proteomics for the diagnosis of ovarian cancer. Using sera from 50 women with ovarian cancer and 50 controls, mass spectroscopy was

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used to generate proteomic spectra. The spectra were analyzed by an iterative searching algorithm, which defined a proteomic pattern that completely differentiated patients with cancer from controls. The discovered pattern was then used to examine 116 masked sera samples (50 from women with ovarian cancer and 66 apparently healthy controls. The pattern identified all samples from women with cancer including all 18 with stage I disease. Of the 66 samples from the control group, 63 were identified as not having malignancy. Overall, this methodology yielded a sensitivity of 100%, specificity of 95%, and a PPV of 94%. For comparison, the PPV for CA125 in the same masked patient group was 34%. It is important to point out that in this study, the population was artificially constructed to have a prevalence of ovarian cancer close to 50%. In a further study on proteomics, Zhang et al.(47) identified three markers that were altered in ovarian cancer and for which an immunoassay was available. The markers were apolipoprotein A1 (down-regulated), a truncated form of transthyretin (down-regulated), and a cleavage fragment of inter-alpha-trypsin inhibitor chain H4 (up-regulated). In an independent validation study aimed at differentiating early-stage invasive epithelial ovarian cancer from healthy controls, the sensitivity of the three markers combined with CA125 was 74% versus 65% for CA125 alone at a matched specificity of 97%. When compared at a fixed sensitivity of 83%, the specificity of the three markers plus CA125 (94%) was significantly better than that of CA125 alone. Although these results with proteomics are promising, it should be pointed out that the results to date are preliminary. Before clinical use, this technology must be made more robust, standardized (eg, with respect to sample handling and storage) and evaluated in external quality assessment schemes. Furthermore,

Table 1. Markers that may complement CA125 in ovarian cancer Marker

Type of molecule

Reference

OVX1 M-CSF TATI CA19-9 Inhibin HMFG1 and HMFG2 CASA TPS Lysophosphatidic acid Prostasin Osteopontin Kallikrein 6 and 10

Mucin Growth factor Protease inhibitor Mucin Glycoprotein Milk globulin Mucin Cytokeratin 18 Lipid Serine protease Glycophosphoprotein Serine protease

Woolas et al.(34) and van Haaften-Day et al.(35) Woolas et al.(34) and van Haaften-Day et al.(35) Stenman et al.(36) Stenman et al.(36) Robertson et al.(37) Dhokia et al.(38) Devine et al.(39) Devine et al.(39) and van Dalen et al.(40) Xu et al.(41) Mok et al.(42) Kim et al.(43) Diamandis et al.(44) and Luo et al.(45)

M-CSF, macrophage colony stimulating factor; TATI, tumor-associated trypsin inhibitor; HMFG, human milk fat globulin; CASA, cancer-associated serum antigen; TPS, tissue polypeptide specific antigen. #



these preliminary results must be confirmed in a large prospective study or a meta-analysis/pooled analysis of smaller studies. While the use of complementary markers can increase sensitivity for disease detection, specificity may be impaired. This decreased specificity, however, might be counteracted by determining serial levels of the markers under study, use of multimodal screening as discussed above or the application of advanced statistics such as neural networks(48). Although screening with CA125 can detect ovarian cancer in some asymptomatic women, there is currently no evidence as to whether screening reduces mortality. The EGTM Panel therefore recommends that screening for ovarian cancer in asymptomatic women without a family history of the disease using either CA125 alone or in combination with other modalities should not be carried unless in the context of a clinical trial. In 1995, a National Institutes of Health (NIH) Consensus Conference(49) also concluded that there was no evidence that screening with CA125 and transvaginal ultrasound could reduce mortality from ovarian cancer and that its use would result in decreased rather than increased morbidity and mortality. Therefore, for subjects with either no or only one first-degree relative, screening was not recommended. On the other hand, for women with a hereditary ovarian cancer syndrome where the lifetime risk of ovarian cancer is approximately 40%, at least annual rectovaginal pelvic examination, transvaginal ultrasound, and CA125 assay were recommended(49). More recently, a joint National Academy of Biochemistry/EGTM Panel recommended that CA125 levels should be determined every 6 months, with transvaginal ultrasound performed annually in women with either a strong family history of breast or ovarian cancer, a demonstrated mutation in BRCA1, BRCA2, or a mismatch repair gene(50). There is, however, no evidence at present that screening these high-risk women reduces morbidity or mortality. In order to evaluate a potential role for CA125 in screening for ovarian cancer in asymptomatic populations, two major prospective randomized trials are currently in progress. One of these is being carried out in the United States as part of the Prostate, Lung, Colorectal and Ovarian (PLCO) trial(51). In this study, 74,000 women aged 54–74 years are being enrolled at ten different centers in the United States. Women in the screening arm undergo annual CA125 determination and transvaginal ultrasound for 3 years and CA125 alone for a further 2 years. The second randomized trial known as the United Kingdom Collaborative Trial of Ovarian Cancer #


Screening started to recruit patients (aged 54–74 years) in 2001(52). In total, 200,000 women will be randomized to either screening with ultrasound, screening with CA125 plus ultrasound, or no screening. As well as investigating a possible effect of screening on mortality, this trial will also address issues such as compliance, health economics, and morbidity. Differential diagnosis of pelvic masses For women presenting with a pelvic mass, it is desirable to know preoperatively whether the mass is likely to be benign or malignant. Both small-scale retrospective studies(53–55) and a multicenter prospective study(56) have shown that CA125 can aid this differentiation, especially in postmenopausal subjects. In the multicenter prospective trial, 228 postmenopausal women with pelvic masses were evaluated with CA125, transvaginal ultrasound, and pelvic examination(56). The accuracy of CA125 (cutoff level, 35 kU/L) in differentiating between benign and malignant lesions was 77%. This was almost identical to that achieved with pelvic examination (76%) and ultrasound (74%). Using logistic regression analysis, CA125 was a stronger predictor of disease diagnosis than ultrasound but was less strong than pelvic examination. Importantly, no malignancy was detected in women in whom all three tests were negative. Measurement of CA125 may thus contribute to the preoperative management of pelvic masses in postmenopausal women. If the CA125 is elevated, the patient should be promptly referred to a specialized Gynecological Oncology Unit. A number of nonrandomized studies have shown that those patients who undergo surgery for ovarian cancer in such specialized units have a better outcome than those operated on by general surgeons(57,58). Since knowledge of the preoperative level of CA125 may help differentiate between benign and malignant masses, the EGTM Panel recommends its measurements in postmenopausal women presenting with such masses. Patients with elevated levels (eg, .35 U/L) should be considered for referral to a surgeon who routinely performs thorough abdominal exploration, node sampling, omentectomy, and cytoreductive operations. For premenopausal women, the American College of Obstetricians and Gynecologists recently suggested that patients with a pelvic mass and a very elevated CA125 level (eg, .200 U/L) should be considered for referral or consultation with a gynecological oncologist(59). The EGTM supports this view but points out that multiple benign diseases can give rise to elevated CA125 levels in this age group (see above).


Assessing prognosis Several small-scale retrospective studies have shown that either the rate of fall of CA125 levels following initial treatment or the absolute levels after one, two, or three courses of chemotherapy correlated with patient survival. In one of the first such studies, Canney et al.(60) measured CA125 levels in patients with residual tumor following surgery and receiving chemotherapy. In three patients with apparently stable disease, the CA125 levels declined with a mean half-life of 22.6 days, whereas in 12 patients with a response to chemotherapy, the mean half-life was 9.2 days. In a later study, van der Burg et al.(61) reported that patients with a CA125 half-life of 20 days or more had a 3.2 times progression rate and a significantly shorter time to progression than those with a half-life ,20 days. Although different methods have been used to calculate the rate of CA125 decline (eg, time to normalize level, slope of the exponential regression curve, and half-life), in general, these early results have been confirmed(62,63). Furthermore, in many of these studies, the prognostic information supplied by CA125 was independent of traditionally used parameters(61–63). Other reports have shown that either the absolute level of CA125 after one, two, or three courses of chemotherapy(64–66) or a less than sevenfold fall in CA125 levels over the first month of chemotherapy(67) could also be used to predict outcome. Although the abovementioned studies are consistent in showing that measurement of CA125 levels during initial chemotherapy can yield prognostic information, they have a number of limitations. These include use of small numbers of patients, retrospective design of most studies, employment of different cutoff points for CA125, and use of different end points, eg, progression of disease, survival, and relapse of patients in remission. These reports can thus be regarded as level 3 evidence studies or lower(68). In an attempt to obtain larger numbers of patients for validating the prognostic value for CA125 in ovarian cancer, the Gynaecology Working Party of the Medical Research Council in the United Kingdom combined the results from 11 British Institutions, giving a total of 573 patients(69). Following exclusion for different reasons, 248 patients were available for analysis. Three different models for assessing CA125 levels during primary chemotherapy were tested and compared for their impact on patient outcome. The models investigated were (a) half-life of CA125 decline measured between prechemotherapy value and level after one course of chemotherapy: cutoff, 20 days

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(b) absolute value after two courses of chemotherapy: cutoff point, 35 kU/L, and (c) sevenfold decline between prechemotherapy value and level after one course of chemotherapy. Other variables evaluated in this study included patient age, residual tumor bulk (, or .2 cm), tumor stage, and administration of chemotherapy. Analysis of the data showed that the absolute value of CA125 level after two courses of chemotherapy was the single most important factor for predicting progression at 12 months. This best predictor, however, gave a falsepositive rate of 19%. The authors concluded that the prognostic information supplied by CA125 alone was not accurate enough to be used in the management of individual patients. While the majority of studies have concluded that CA125 measurements during the early phases of firstline chemotherapy can provide prognostic information, conflicting data also exists. Thus, in a study of 1189 patients, Clark et al.(70) using multivariate analysis found no significant prognostic impact for CA125 using overall survival as endpoint. Factors found to be independent predictors of outcome in this study included age at diagnosis, FIGO stage, tumor grade, histology type, and presence or absence of ascites. In another study, the prognostic value of CA125 was found to be time dependent(63), ie, was only of value for the first year after surgery. Based on available data, the EGTM Panel concludes that the prognostic information supplied by CA125 up to the start of the third course of chemotherapy is not accurate enough to manage individual patients. CA125 measurements during the early phases of initial chemotherapy should therefore not be used to predict long-term outcome. Assessing response to therapy In 1999, a consensus statement issued by a group of specialists in ovarian cancer recommended that the standard treatment for patients with advanced ovarian cancer should be cytoreductive surgery followed by chemotherapy with a taxoid and a platinum compound(71). Assessing response to such treatment can be difficult as following surgical debulking, many patients have low-volume disease that may not be palpable or detectable by radiologic procedures such as computed tomography or ultrasound. CA125 is a potential marker for monitoring response as serum levels are elevated in over 80% of patients with advanced ovarian cancer, see above. Furthermore, multiple studies have shown that CA125 #



levels increase with tumor progression and decrease with regression (for review, see Tuxen et al.(11) and Tuxen(12)). One of the problems in using a tumor marker to monitor patients is how to define an alteration in marker levels that reliably correlates with a response. As Rustin et al. pointed out(72), a response based on CA125 alterations must be as accurate as that available from standard World Health Organization, European Organisation for Research and Treatment on Cancer, or Gynecologic Oncology Group. Although a number of CA125–response definitions have been used such as halving of marker level to indicate response and doubling to indicate progression(11,12), until recently none were validated. Based on a pilot study with subsequent testing in two further studies, Rustin et al.(72) proposed the following definitions for determining response of ovarian cancer to initial chemotherapy. Response according to CA125 occurred if there was either a 50% or a 75% reduction in CA125 levels (Table 2)(73). For the 50% response criteria, four separate samples are required, ie, two initial samples showing an elevation with two subsequent samples showing a 50% decrease. For the 75% response definition, only three samples are necessary, which must exhibit a serial decrease of at least 75%. In both definitions, the final sample must be taken at least 28 days after the previous sample. According to Rustin et al.(72), both definitions are necessary as some responses are detected by only one of the definitions. It should be pointed out that patients with initial concentrations of CA125 less than 40 U/L cannot be evaluated using these definitions. The above definitions were retrospectively tested in 19 phase 2 clinical trials investigating 14 different cytotoxic drugs for recurrent ovarian cancer(74,75). Overall, responses based on CA125 were similar to those Table 2. Original ‘‘Rustin’’ CA125 response criteria (Rustin(73), Reprinted with permission from the American Society of Clinical Oncology.) Response according to CA125 has occurred if either of the following criteria are fulfilled 50% response definitiona If there is a 50% decrease in serum CA125 levels, from two initially elevated samples, then a 50% response has occurred. The sample showing a 50% fall must be confirmed by a fourth sample (ie, four samples required) 75% response definitiona If there has been a serial decrease in CA125 levels of more than 75% over three samples, then a 75% response has occurred (ie, three samples required) a

In both 50% and 75% response definitions, the final sample needs to be analyzed at least 28 days after the previous sample.

#


based on standard criteria, leading Rustin et al.(74,75) to suggest that the 50% and 75% response criteria could substitute for standard responses in phase 2 clinical trials evaluating new treatments for ovarian cancer. As assessable disease is found in only a minority of patients with cancer of the ovary following debulking surgery, use of these definitions would increase the number of patients participating in clinical trials. A simpler CA125–based response definition was recently recommended by the Gynecologic Cancer Intergroup (GCIG)(76). According to this definition, a response according to CA125 has occurred if there is at least a 50% reduction in CA125 levels from a pretreatment sample. The response must be confirmed and maintained for at least 20 days. Patients can be evaluated according to CA125 only if they have a pretreatment sample that is twice the upper limit of normal and taken within 2 weeks prior to starting treatment. The GCIG recommend that this definition be used in evaluating therapies for relapsed ovarian cancer. For assessing response to initial therapy that includes surgery and chemotherapy, any CA125 response results from both treatments. In this situation, CA125 cannot differentiate between the effects of each therapy(76). Rather than using arbitrary alterations, Tuxen et al.(77,78) suggested that interpretation of changes in serial CA125 levels should be based on a statistical estimation adjusted to both the analytical variation of the assay used and the normal background intraindividual biologic variation of the marker. This approach has also been used to interpret changes in CA15-3, CA549, carcinoembryonic antigen (CEA), and tissue polypeptide antigen (TPA) in the follow-up of patients with breast cancer(79). The theoretical background for this statistical procedure has recently been reviewed in detail(80). According to Tuxen et al.(77), a change in marker concentrations is significant (P , 0.05) if the change exceeded the random fluctuations due to both analytical and biologic variation. This approach, however, requires validation before it can be recommended for routine use. Although no consensus currently exists as regards how best to define CA125–based response, a number of expert panels have recommended its use for monitoring chemotherapy in patients with ovarian cancer(50,71,76). The EGTM also recommends assay of CA125 for monitoring chemotherapy in patients with ovarian cancer. Levels or trends suggesting treatment failure should result in discontinuation of ineffective therapy, switch to an alternative therapy, or randomization in trials evaluating novel treatments. On the other hand, trends indicating response would help in the decision to continue with potentially toxic


chemotherapy. For evaluating response based on CA125, either the 50% and 75% response definitions as proposed by Rustin et al.(72) and Rustin(73) (Table 2) or the recent GCIG criteria(76) may be used. Follow-up after completion of initial therapy A common practice in recent years has been to followup patients, who had a diagnosed malignancy and are apparently cured, with serial levels of tumor markers. Thus, following primary treatment of ovarian cancer, many patients are regularly monitored with CA125. The aim of this longitudinal monitoring is to preclinically detect recurrent/metastatic disease, the assumption being that early administration of salvage chemotherapy enhances outcome. Following a review of the literature, Tuxen et al.(11) and Tuxen(12) showed that the lead-time between CA125 increase and clinical progression of disease varied from 1 to 15 months, the median lead-time being about 3–4 months. Again, multiple definitions of tumor progression according to CA125 levels have been described. These include increases of 50%, 100%, increases from below to above the reference range, and a confirmed doubling of its upper limit of normal level (reviewed in Tuxen et al.(11) and Tuxen(12)). This latter definition was based on two studies carried out by Rustin et al. In one of these involving 255 patients, a confirmed increase in CA125 to more than twice the upper limit of normal

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during follow-up after first-line chemotherapy was found to predict recurrence with a sensitivity of 84% and a false-positive rate of ,2%(82). In the other study (n ¼ 88), a confirmed doubling of CA125 from its nadir predicted progression with a sensitivity of 94% and specificity of almost 100%(83). Although these definitions require further validation, they have been adopted by the GCIG for defining progression following first-line chemotherapy (Table 3). In fact, this GCIG definition has now been accepted by all international Gynecological Trial Groups. Using a definition based on analytical variation and intraindividual biologic variation, Tuxen et al.(84) have also evaluated the diagnostic performance of CA125 monitoring during follow-up after first-line chemotherapy. In a study using 255 patients with stage IC–IV ovarian cancer, CA125 detected progression with a sensitivity of 76% and a false-positive rate of 1%. The median lead-time provided by CA125 was 100 days. Again, the validity of this approach requires confirmation in other patient populations. Although it is now clear that serial measurements of CA125 can provide a short lead-time for the early detection of relapsed ovarian cancer, the clinical value of this early warning is less clear. For example, it is well known that recurrent ovarian cancer is usually incurable with existing treatments. Thus, any potential advantage that might be derived from administration of palliative chemotherapy must be balanced against

Table 3. GCIG definition of progression of ovarian cancer according to both clinical and CA125 criteria (Rustin(73), Reprinted with permission from the American Society of Clinical Oncology.) Group Aa Measurable or assessable disease

CA125

Group Ba

Group Ca

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 nonmeasurable) Date PDb Date of documentation of increase or new lesions and/or CA125 2 3 ULN documented CA125 2 3 nadir value As for group A on two occasionsc on two occasionsc Date PD: first date of the Date PD: first date of the CA125 elevation to 2 3 ULN CA125 elevation to 2 3 nadir value

RECIST, response evaluation criteria in solid tumors group; PD, progressive disease; ULN, upper limit of normal; GCIG, gynecological cancer intergroup. a Patient groups according to CA125 behavior during first-line therapy: group A, patients with elevated CA125 pretreatment and normalization of CA125 (;60% of all new patients); group B, patients with elevated CA125 pretreatment, which never normalizes (;30% of all new patients); group C, patients with CA125 in normal range pretreatment. b Definitions for progression in the three groups A, B, and C are as follows: A patient may be declared to have PD (progressive disease) on the basis of either the objective disease or the CA125 criteria. The date of PD will be the date of the earlier of the two events if both are documented. c Repeat CA125 any time, but normally not less than 1 week after the first elevated CA125 level. CA125 levels sampled after administration of mouse antibodies or within 4 weeks after surgery or paracentesis should not be taken into account. #



the side effects and the subsequent decreased quality of life for the patient. On the other hand, it might be argued that if palliative chemotherapy is to have any real impact on advanced cancer, early administration might be more effective than late administration. Indeed, recent evidence from a multivariate analysis carried out on 704 platinum pretreated patients showed that tumor size and number of disease sites (as well as serosal histology) were independent predictors of response to subsequent chemotherapy(85). In order to directly address the issue and ascertain whether administering chemotherapy based on CA125 elevations enhances outcome compared to giving chemotherapy based on clinical evidence of recurrence, the Medical Research Council (UK) and the European Organisation for Research and Treatment on Cancer have established a randomized trial(85). Until the results of this trial are known, there is no established role for regularly monitoring with CA125 following the completion of primary therapy. Similarly, there is no evidence that initiating treatment in an asymptomatic patient based on a rising CA125 level improves outcome. The EGTM Panel therefore recommends that serial measurements of CA125 should not be routinely carried out at present on patients with a prior diagnosis of ovarian cancer and who are apparently well, unless part of clinical trials. However, should such a patient develop symptoms suggestive of relapse, a CA125 level should be determined both to help confirm recurrent disease and establish a baseline value for possible further therapy. We are aware, however, that some doctors as well as some patients may wish to have serial CA125 levels determined during follow-up after initial therapy. The ultimate decision whether or not to use CA125 in this situation must be taken in the best interest of the patient. For establishing progression based on CA125, either a confirmed doubling in levels as proposed by Rustin et al.(82) and adopted by GCIG(73) or the approach based on analytical and biologic variation as proposed by Tuxen et al.(77,84) may be used.

Conclusions At present, CA125 is the best available marker for epithelial cancer. As with most markers in clinical use, lack of sensitivity for stage I disease and lack of specificity limits its use for the early diagnosis of ovarian cancer. In postmenopausal women, however, measurement of CA125 may aid the differential diagnosis of benign and pelvic masses. Either absolute levels or its rate of decline during initial chemotherapy can provide independent prognostic information but this is of #


little value for management of individual patients. Measurement of CA125 during initial chemotherapy can be useful in predicting response. Trends in levels suggesting failure should lead to the cessation of treatment. On the other hand, trends indicating response should result in continuation of treatment. Although serial assay of CA125 in the follow-up of asymptomatic patients can lead to the early detection of recurrences, there is no evidence at present that the initiation of treatment based on rising CA125 levels results in either improved outcome or better quality of life. It is important to point out, however, that CA125 levels are not elevated in 10–20% of patients with advanced ovarian cancers. In these patients, other markers (Table 1) or radiologic imaging techniques are necessary.

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Appendix

d

Key points relating to the EGTM guidelines for the use of CA125 in ovarian cancer d

d

d

At present, CA125, either alone or in combination with other modalities, should not be used in screening asymptomatic subjects outside the context of a clinical trial. Preoperative CA125 levels in postmenopausal women may aid in the differentiating of benign and pelvic masses.

d

#

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Alterations in serial levels of CA125 during initial therapy, using defined criteria, can be used to assess disease response or progression. Although serial determinations of CA125 following initial chemotherapy can lead to the early detection of recurrent disease, the clinical value of this lead-time remains to be established. CA125 is the ovarian cancer marker against which new markers for this disease should be compared.
