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Journal of Clinical Oncology, Vol 23, No 36 (December 20), 2005: pp. 9338-9343 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.02.2582 Risk of Epithelial Ovarian Cancer Recurrence in Patients With Rising Serum CA-125 Levels Within the Normal RangeFrom the Kelly Gynecology Oncology Service, Johns Hopkins Medical Institutions, Baltimore, MD Address reprint requests to Antonio Santillan, MD, 600 N Wolfe St, Phipps 281, Baltimore, MD 21287-1281; e-mail: asantil1{at}jhmi.edu
PURPOSE: To evaluate the risk of epithelial ovarian cancer (EOC) recurrence in patients with rising serum cancer antigen 125 (CA-125) levels that remain below the upper limit of normal (< 35 U/mL). PATIENTS AND METHODS: All patients treated for EOC between September 1997 and March 2003 were identified and screened retrospectively for the following: (1) elevated serum CA-125 at time of diagnosis, (2) complete clinical and radiographic response (CR) to initial treatment with normalization of serum CA-125, (3) at least three serial serum CA-125 determinations that remained within the normal range, and (4) clinical and/or radiographic determination of disease status at the time of last follow-up or recurrence. For statistical analyses, univariate regression models were used to compare absolute and relative changes in CA-125 levels among patients with recurrent disease and those without EOC recurrence. RESULTS: A total of 39 patients satisfied study inclusion criteria; 22 patients manifested EOC recurrence at a median interval from complete response of 11 months. The median follow-up time from complete response to last contact was 32 months for the 17 patients in the no recurrence group. A relative increase in CA-125 of 100% (odds ratio [OR] = 23.7; 95% CI, 2.9 to 192.5; P = .003) was significantly predictive of recurrence. From baseline CA-125 nadir levels, an absolute increase in CA-125 of 5 U/mL (OR = 8.4; 95% CI, 2.2 to 32.6; P = .002) and 10 U/mL (OR = 71.2; 95% CI, 4.8 to > 999.9; P = .002) were also significantly associated with the likelihood of concurrent disease recurrence. CONCLUSION: Among patients with EOC in complete clinical remission, a progressive low-level increase in serum CA-125 levels is strongly predictive of disease recurrence.
Epithelial ovarian cancer (EOC) accounts for the majority of ovarian malignancies. Currently, the serum tumor marker, cancer antigen 125 (CA-125), is the most accurate tumor marker used for monitoring therapeutic response, and in surveillance, for recurrent disease. Specific guidelines for monitoring disease status after primary surgical cytoreduction and adjuvant chemotherapy remain controversial. Serial pelvic examinations and CA-125 serum measurements, augmented by radiographical exams on an individualized basis, have been incorporated into most contemporary surveillance programs. Commonly accepted definitions of disease recurrence based on serum CA-125 levels alone specify a doubling of this tumor marker level, either from the upper limit of normal (35 U/mL) in patients with normalization of this marker after primary treatment or from the nadir levels in patients with an elevated serum marker value that never normalizes after primary treatment.1,2 The objective of this study was to evaluate the risk of EOC recurrence in patients with rising serum CA-125 levels that remain below the upper limit of normal (< 35 U/mL).
Between September 1, 1997, and March 31, 2003, all patients treated for EOC at the Johns Hopkins Medical Institutions (JHMI) were identified from the tumor registry database and screened retrospectively for their initial serum CA-125 level, age at diagnosis, tumor histology and grade, International Federation of Gynecology and Obstetrics (FIGO) stage of disease, the availability of serial serum CA-125 level determinations, and timing of recurrence and/or disease status at last follow-up. All patients underwent complete surgical staging and cytoreduction followed by adjuvant platinum and taxane-based therapy. The pathology for all patients had been previously reviewed by a JHMI gynecologic pathologist and presented at the multidisciplinary gynecologic oncology treatment planning conference. During the study period, the general clinical practice for surveillance of ovarian cancer patients achieving a complete clinical and radiographic response (CR) at JHMI was to perform a complete physical examination and serum CA-125 level at 3-month intervals and computed tomography (CT) scanning of the abdomen and pelvis at 6 month intervals (or as indicated based on symptomatology) for the initial 24 months after CR. Thereafter, clinical examinations and serum CA-125 levels were obtained at 6 month intervals and CT scans at 12-month intervals for an additional 36 months. Serum CA-125 levels were determined using a commercially available assay through the Johns Hopkins laboratories. During the study interval the clinical laboratory at JHMI utilized two different serum CA-125 immunoassay systems: Centocor CA-125 II (Centocor Inc,) and the automated AIA-Pack CA-125 (Tosoh Bioscience Inc, Japan), both technologies are second-generation heterologous, double-determinant assays. Following initial eligibility screening, the following inclusion criteria were applied to determine the final study population: (1) an elevated serum CA-125 at time of diagnosis (> 35 U/mL); (2) complete clinical and radiographic response (CR) to initial treatment with normalization of serum CA-125 (< 35 U/mL); (3) at least three serial serum CA-125 level determinations (at intervals ranging from 1 to 6 months following CR) that remained within the normal range (< 35 U/mL); and (4) clinical and/or radiographic determination of disease status at the time of last follow-up or recurrence. Definitive diagnosis of recurrence was taken as the histologic presence of cancer at the time of secondary cytoreductive surgery and/or the appearance of new lesions by CT scan or by positron emission tomography (PET) scan imaging. For statistical analyses, standard univariate logistic regression models were used to compare absolute and percentage changes (predictor variables) in serum CA-125 levels among patients with recurrent disease and those without ovarian cancer recurrence (outcome variables). Absolute changes were calculated by subtracting the CA-125 baseline nadir (CA-125 within the normal range value at the time of completion of primary chemotherapy and radiographic documentation of CR) from either the CA-125 level at the time of radiographic documentation of recurrence or the CA-125 level at time of last contact (last CA-125 level-nadir level). Relative changes were calculated as a percentage of the last CA-125 level and the baseline CA-125 nadir level at the time of complete response ([last CA-125 level/CA-125 nadir level] x 100.) For simplicity, a doubling of serum CA-125 from the baseline nadir (100% relative increase) was graphically represented as a two-fold change. The patient characteristics (age, FIGO stage, histology and grade) of the recurrent and nonrecurrent groups were compared with the use of the Fisher's exact test for discrete variables and the student t test for continuous variables. Multivariate logistic regression analysis model adjusted for stage of disease was not performed secondary to the high correlation of variables and the small sample size between groups.
Patient Characteristics A total of 39 patients satisfied all study inclusion criteria. The clinical characteristics of the study population are shown in Table 1 and Table 2. Twenty-two patients manifested ovarian cancer recurrence (group A) at some point during the surveillance interval. The majority (91%) of these patients had FIGO stage III/IV disease and serous tumor histology (86%) at initial diagnosis. For group A patients, the median serum CA-125 level at the time of diagnosis was 275 U/mL (range, 45 U/mL to 5,523 U/mL) and the median CA-125 nadir level at the time of CR was 6 U/mL (range, 3 U/mL to 16 U/mL). The median interval from time of CR to time of recurrence was 11 months (range, 5 months to 81 months). The median number of serial CA-125 assays performed in this group a patients from their baseline CA-125 nadir level to the CA-125 level at the time of documentation of recurrence was 5 (range, 3 to 10). The median interval from the time of last serum CA-125 level that remained within the normal range to the time of radiographic documentation of disease recurrence was 2.5 days (range, 0 days to 95 days; mean, 14.9 days). Fourteen patients from group A underwent secondary cytoreductive surgery after diagnosis of recurrence by imaging studies, all of which had pathologic confirmation of disease. All fourteen patients had optimal cytoreduction with no visible disease at the end of the procedure. The eight remaining patients in group A had documented recurrent ovarian cancer based on the appearance of new lesions by CT or by PET scan.
Seventeen patients that met study inclusion criteria remained without evidence of detectable disease recurrence (group B) with a median follow-up time between CR to last contact of 32 months (range, 3 to 95 months). Again, the majority (59%) of patients had advanced stage disease and serous tumor histology (76%) at initial diagnosis (Table 1). For group B patients, the median serum CA-125 level at the time of diagnosis was 75 U/mL (range, 43 U/mL to 4,435 U/mL) and the median CA-125 nadir level was 11 U/mL at the time of CR (range, 4 U/mL to 17 U/mL). The median lowest CA-125 value achieved during follow-up interval was 6 U/mL (range, 2 U/mL to 17 U/mL). The number of serial CA-125 assays performed in this group a patients from their baseline nadir value to the CA-125 value at last follow-up was six assays (range, 3 to 17 assays).
Analyses of Changes in CA-125 Within the Normal Range Statistical analysis of the entire study population (N = 39) revealed that a relative increase in serum CA-125 from baseline nadir levels of 100% (OR = 23.7; 95% CI, 2.9 to 192.5; P = .003) was a highly statistically significant predictor of ovarian cancer recurrence. Similarly, an absolute increase in serum CA-125 level of 5 U/mL (OR = 8.4; 95% CI, 2.2 to 32.6; P = .002) and 10 U/mL (OR = 71.2; 95% CI, 4.8 to > 999.9; P = .002) compared with baseline CA-125 nadir values were also statistically significantly associated with an increased likelihood of disease recurrence (Table 3).
The association between both absolute and relative increases in the serum CA-125 level and the likelihood of ovarian cancer recurrence are graphically depicted in Figure 1. Of group B patients with no clinically detectable recurrence, only 5.8% (1 of 17) manifested an absolute increase of more than 5 U/mL and/or a more than two-fold increase in surveillance CA-125 levels during the study period. Conversely, all (22 of 22) group A patients with documented recurrent disease had either an absolute increase of more than 5 U/mL and/or a more than two-fold elevation in surveillance CA-125 levels relative to their baseline nadir.
Since the discovery of CA-125 in 1981, numerous studies have documented its role as a diagnostic and surveillance tool in patients with EOC.3 Immunohistochemistry analyses have shown that 80% of serous ovarian cancers will express CA-125, while fewer than 30% of mucinous, clear-cell, and endometrioid ovarian cancers are positive for this surface antigen.4 Current serum CA-125 assays utilizing heterologous antibodies have been shown to correlate well with each other and are clinically reliable with an accepted value of 35 U/mL as the upper limit of normal.5,6 Overall, approximately 85% of patients with EOC have serum CA-125 levels greater than 35 U/mL at the time of diagnosis.3 Although serum CA-125 is commonly used in an attempt to distinguish malignant from benign adnexal masses, it lacks sufficient sensitivity and specificity to be used exclusively as a reliable triage tool in premenopausal woman.7-9 More recently, ultrasound scanning, serum CA-125 and menopausal status have been combined in a risk of malignancy index for the differential diagnosis of adnexal masses.10,11 This approach has greater accuracy than either individual tests or clinical assessment and can assist with adequate preoperative referral. In addition, serum CA-125 elevation in asymptomatic postmenopausal woman has been associated with a 36-fold increase in risk of ovarian cancer.12,13 The principle role of the serum CA-125 assay in the management of ovarian cancer is its clinical utility in monitoring the response to treatment. In patients with elevated levels preoperatively, serum CA-125 correlates closely with regression or progression of disease.14 CA-125 is the most widely utilized tumor marker for disease surveillance once clinical remission has been achieved, with marker elevations often preceding the appearance of clinically detectable recurrence by 3 to 6 months.1,15 Two studies have indicated that the slope of longitudinal serum marker values predicts ovarian cancer recurrence more accurately than one or two isolated values.16,17 In the absence of clinically or radiographically demonstrable recurrence, the significance of a rising serum CA-125 level has yet to be precisely determined. Some clinicians have defined ovarian cancer recurrence as a serial increase in levels over time or any value greater than 100 U/mL. Recent studies have shown that in patients whose CA-125 levels normalize after treatment, a rise of serum CA-125 levels to more than twice the upper limit of normal is predictive of tumor relapse with a sensitivity of 84%.1 Among patients with persistently abnormal CA-125 levels following primary treatment, a doubling of the CA-125 level from its nadir can predict tumor progression with a sensitivity of 94%.2 A particularly challenging subgroup of patients are those with an elevated CA-125 level at the time of ovarian cancer diagnosis who achieve a complete clinical, radiographic, and serological (normal CA-125) response and then present with a minimal increase in their serum CA-125 level. The purpose of this study, therefore, was to evaluate the risk of EOC recurrence in patients with rising serum CA-125 levels that remain below the upper limit of normal (< 35 U/mL).
Determining the clinical significance of a rising CA-125 level that remains within the normal range is complicated by the potential for analytic imprecision of the assay and normal intraindividual biologic variation. Tuxen et al18 have shown that the average intraindividual biologic variation of serum CA-125 (24%) is similar for healthy women and for ovarian cancer patients without clinically detectable disease. Recently, Wilder et al19 reported results of a study of 11 patients suggesting that a progressive increase in three consecutive serum CA-125 values within the normal range was highly predictive of tumor recurrence within 4 to 24 months (median, 14 months). The current study represents the largest reported series to date examining this specific patient population. Our results suggest that among ovarian cancer patients known to be marker positive, an absolute increase in serum CA-125 level of 5 U/mL and 10 U/mL are highly predictive of disease recurrence. Similarly, a relative increase of 100% compared to baseline nadir CA-125 levels is statistically, significantly associated with the likelihood of detectable tumor recurrence. The discriminating criteria of an absolute increase of more than 5 U/mL and or a relative increase of more than 100% in CA-125 levels compared to baseline nadir correctly identified all patients with recurrent disease and 94.2% of patients that remained disease free. Consequently, the false-positive prediction of relapse was 5.8% (one of 17), with a sensitivity of 100% and a specificity of 94% (95% CI, 71% to 99%). From the nonrecurrent group, only two patients had a variation increase The relatively short median interval time of 2.5 days from the time of last serum CA-125 level that remained within the normal range to the time of documented recurrent disease by imaging studies, can be explained by the institutional practice of performing imaging studies at an earlier interval, prompted by a doubling of CA-125 within the normal range. There are several limitations of the current study that must be considered in interpreting the results presented. First, the limited sample size and retrospective study design raise the possibility of selection bias that can only be controlled for by a larger and prospectively gathered database. Second, the heterogeneity of our study groups with respect to the histological subtype and FIGO stage may limit the comparability of patients in groups A and B. However, study inclusion criteria specifically required an abnormal CA-125 level before definitive treatment in an effort to include only those patients that were known to be marker positive. A third limitation of our methodology was the change in laboratory testing instrument for CA-125 that occurred during the study period. Assays for CA-125 have great clinical importance and have changed from the first generation immunometric assays, using the OC125 antibody both as solid phase antibody and as labeled antibody, into the second generation immunometric assays, in which the M11-like or OC125-like antibody is used as the capture antibody, replacing the OC125 antibody on the solid phase of the original CA-125 assay. Although not desirable, this alteration in clinical practice was a hospital-based decision that was beyond the authors' control. Nevertheless, both assays used in this study were second-generation heterologous, double-determinant assays. The day-to-day precision (interassay variation) for the Centocor CA-125 II assay has been reported to be 10% at 180 U/mL and 12% at 66 U/mL.20 Total precision (intra-assay plus interassay) of the Tosoh AIA-Pack CA-125 assay has been reported by the manufacture manual to be 5% at both 22 U/mL and 657 U/mL. This change in assay occurred during January 2000, in which the Centocor CA-125 II (Centocor Inc) was replaced by the automated AIA-Pack CA-125 (Tosoh Bioscience Inc) in January 2000. The majority of patients in the study (74%) had only the Tosoh AIA-Pack CA-125 assay for ovarian cancer recurrence surveillance. From the recurrent group (group A), six patients were initially monitored from their nadirs with the Centocor assay. Only five of these patients changed to the automated assay at some point during the study period. In this second group of patients, the median number of follow-up CA-125 assays performed was five assays (five to 12 assays) and the median number of follow-up CA-125 assays performed using only the initial Centocor assay was three (range, two to seven). From the nonrecurrent group (group B), five patients were initially monitored from their nadirs with the Centocor assay. All of these patients changed to the automated Tosoh AIA-Pack CA-125 assay. In this group of patients, the median number of follow-up CA-125 assays performed was 11 (seven to 17) and the median number of follow-up CA-125 assays performed using only the initial Centocor assay was three (two to 10). Since the majority of follow-up studies performed in both groups (group A and B) were done with the automated Tosoh AIA-Pack CA-125 assay, no difference in documented disease recurrence before or after the change in assays could be inferred. Perhaps the most important limitation of the current study, however, is that it does not directly address whether early detection and treatment of small-volume ovarian cancer recurrence has a direct and clinically significant impact on long-term survival outcome. Currently, there is a lack of consensus as to the optimal time to initiate second-line therapy for EOC recurrence. Management options include immediate intervention with surgery and/or chemotherapy, use of cytostatic agents, serial observation until serum tumor markers reach an arbitrary minimum level, or initiation of salvage therapy only on the manifestation of symptoms. An ongoing randomized clinical trial in Europe may help to clarify this dilemma by comparing the benefits of early administration of chemotherapy based on CA-125 levels alone versus delaying treatment until recurrent disease is apparent through conventional clinical indicators.21 Despite these limitations, the current study suggests that among patients with EOC in complete clinical remission, a progressive low-level increase in serum CA-125 levels is strongly predictive of disease recurrence. Although, increasing within the normal range serum CA-125 levels should not be use as the sole indicator for starting potentially toxic therapy. Diagnosis of recurrence should be always validated by a confirmatory sample of serum CA-125 level in conjunction with the appearance of new lesions by CT scan or by PET scan imaging. Appropriate management of such patients must be individualized and take into consideration both the available therapeutic options as well as the personal goals of the patient. For selected patients with localized ovarian cancer recurrence that may benefit from secondary cytoreductive surgery, a comprehensive radiographic imaging survey (PET-CT) at the time of minimal CA-125 elevation may facilitate early detection and successful surgical resection.
The authors indicated no potential conflicts of interest.
Supported by The Elizabeth Frost Ovarian Cancer Research Fund. Presented at the Annual Meeting on Women's Cancer (Society of Gynecologic Oncologists) March 22, 2005, Miami, FL. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Rustin GJ, 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 7:361-364, 1996 2. Rustin GJ, Marples M, Nelstrop AE, et al: Use of CA-125 to define progression of ovarian cancer in patients with persistently elevated levels. J Clin Oncol 19:4054-4057, 2001 3. 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 309:883-887, 1983[Abstract] 4. Mainguene C, Aillet G, Kremer M, et al: Immunohistochemical study of ovarian tumors using the OC 125 monoclonal antibody as a basis for potential in vivo and in vitro applications. J Nucl Med Allied Sci 30:19-22, 1986[Medline] 5. Davelaar EM, van Kamp GJ, Verstraeten RA, et al: Comparison of seven immunoassays for the quantification of CA 125 antigen in serum. Clin Chem 44:1417-1422, 1998 6. With Molz P, Teuter C, Schelp C, Amann E: A new tumor marker assay for ovarian cancer on the OPUS immunoassay system. Anticancer Res 17:3051-3053, 1997[Medline] 7. Einhorn N, Bast RC Jr, Knapp RC, et al: Preoperative evaluation of serum CA 125 levels in patients with primary epithelial ovarian cancer. Obstet Gynecol 67:414-416, 1986[Medline] 8. Curtin JP: Management of the adnexal mass. Gynecol Oncol 55:S42-S46, 1994[CrossRef][Medline] 9. Jacobs I, Bast RC Jr: The CA 125 tumour-associated antigen: A review of the literature. Hum Reprod 4:1-12, 1989 10. Jacobs I, Oram D, Fairbanks J, et al: A risk of malignancy index incorporating CA125, ultrasound and menopausal status after the accurate pre-operative diagnosis of ovarian cancer. Br J Obstet Gynaecol 97:922-929, 1990[Medline] 11. Tingulstad S, Hagen B, Skjeldestad FE, et al: Evaluation of a risk of malignancy index based on serum CA125, ultrasound findings and menopausal status in the pre-operative diagnosis of pelvic masses. Br J Obstet Gynaecol 103:826-831, 1996[Medline] 12. Hogdall EV, Hogdall CK, Tingulstad S, et al: Predictive values of serum tumour markers tetranectin, OVX1, CASA and CA125 in patients with a pelvic mass. Int J Cancer 89(6):519-523, 2000[CrossRef][Medline] 13. Jacobs IJ, Skates S, Davies AP, et al: Risk of diagnosis of ovarian cancer after raised serum CA125 concentration: A prospective cohort study. BMJ 313:1355-1358, 1996 14. Hawkins RE, Roberts K, Wiltshaw E, et al: The clinical correlates of serum CA125 in 169 patients with epithelial ovarian carcinoma. Br J Cancer 60:634-637, 1989[Medline] 15. Cruickshank DJ, Terry PB, Fullerton WT: The potential value of CA125 as a tumour marker in small volume, non-evaluable epithelial ovarian cancer. Int J Biol Markers 6:247-252, 1991[Medline] 16. Skates SJ, Pauler DK, Jacobs IJ: Screening based on the risk of cancer calculation from Bayesian hierarchical change-point and mixture models of longitudinal markers. J Am Stat Assoc 96:429-439, 2001[CrossRef] 17. Meier W, Baumgartner L, Stieber P, et al: CA-125 based diagnosis and therapy in recurrent ovarian cancer. Anticancer Res 17:3019-3020, 1997[Medline] 18. Tuxen MK, Soletormos G, Rustin GJ, et al: Biological variation and analytical imprecision of CA 125 in patients with ovarian cancer. Scand J Clin Lab Invest 60:713-721, 2000[CrossRef][Medline] 19. Wilder JL, Pavlik E, Straughn JM, et al: Clinical implications of a rising serum CA-125 within the normal range in patients with epithelial ovarian cancer: A preliminary investigation. Gynecol Oncol 89:233-235, 2003[CrossRef][Medline] 20. Bonfrer JMG. Korse CM, Verstraeten RA, et al: Clinical evaluation of the Byk LIA-mat CA125 II assay: Discussion of a reference value. Clin Chem 43:491-497, 1997 21. Medical Research Council Clinical Trial Unit http://www.ctu.mrc.ac.uk/studies/OV05.asp Submitted April 6, 2005; accepted September 23, 2005.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
than 24%; one patient had a relative increase of 50% and the second had an increase of 175%, the median follow-up time of these patients from the baseline CA-125 nadir value were 17 and 3 months, respectively. Parenthetically, it is noteworthy that both of these patients had documented disease recurrence at follow-up times of 5 and 3 months, respectively, after completion of the study. None of the remaining of the patients in this nonrecurrent group had an increase of CA-125 level from the baseline nadir 
