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Journal of Clinical Oncology, Vol 24, No 9 (March 20), 2006: pp. 1454-1458 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.7373 Pretreatment CA-125 and Risk of Relapse in Advanced Ovarian Cancer
From the M.D. Anderson Cancer Center, Houston, TX; Southwest Oncology Group Statistical Office, Seattle, WA; Vanderbilt University Medical Center, Nashville, TN; University of California, Irvine, Orange, CA; Gynecologic Oncology Group Statistical Center, Buffalo, NY; University of Arizona Cancer Center, Tucson, AZ Address reprint requests to Southwest Oncology Group (SWOG-9701/9326), Operations Office, 14980 Omicron Dr, San Antonio, TX 78245-3217. Address editorial correspondence to Maurie Markman, MD, M.D. Anderson Cancer Center (mail box #121), 1515 Holcombe Blvd, Houston, Texas 77030-4009; e-mail: mmarkman{at}mdanderson.org
PURPOSE: A previous report suggested the nadir serum CA-125 level within the group of patients with ovarian cancer who achieved normalization of CA-125 accurately defined the risk of relapse. Using similar CA-125 subgroups, we sought to determine if the baseline CA-125 level before initiation of maintenance chemotherapy in women achieving a clinically-defined complete response to primary chemotherapy would be of prognostic value.
PATIENTS AND METHODS: Patients included in this retrospective analysis had been treated on one of two previously reported trials of maintenance chemotherapy (three v 12-monthly cycles of paclitaxel; oral altretamine), with a baseline CA-125 level of
RESULTS: The distribution of premaintenance baseline CA-125 levels for the 384 patients was 58%, 34%, and 8% for values of (A)
CONCLUSION: The baseline CA-125 level before initiation of maintenance chemotherapy strongly predicts the risk of subsequent relapse. Patients with premaintenance baseline CA-125 values
Despite the high objective response rate of advanced ovarian cancer to platinum-taxane–based chemotherapy, the large majority of patients ultimately experience relapse of the malignancy.1-3 As a result, there has been considerable interest in the gynecologic cancer research community in developing a maintenance or consolidation treatment approach that would favorably impact survival, while maintaining an acceptable quality of life during the extended treatment program.4-8 In an effort to examine the potential clinical utility of a maintenance strategy, the Southwest Oncology Group (SWOG) conducted a feasibility trial of altretamine administered for 6 months in women in complete clinical remission, following front-line chemotherapy that demonstrated acceptable compliance and a 2-year survival rate from the time of registration of 75%.7,8 Subsequently, SWOG and the Gynecologic Oncology Group (GOG) conducted a randomized phase III trial, which demonstrated that 12-monthly treatments with single agent paclitaxel, following the attainment of a clinically-defined complete response in advanced ovarian cancer, reduced the risk of relapse by approximately 50% compared with a regimen of three additional monthly treatments.9 At the time of publication of this manuscript, data regarding the impact of this approach on overall survival were not available but will be subsequently reported with adequate follow-up of the treated patient populations.
A highly provocative report has suggested it may be possible to more adequately define the risk of ultimate relapse in patients with advanced ovarian cancer who achieve a major response to primary chemotherapy, including achieving normalization (
These data led us to retrospectively assess the impact of similar premaintenance therapy baseline CA-125 groupings ( The aim of this exercise was to determine if it would be possible to employ this factor to help better define the patient population who may benefit from a maintenance treatment strategy. We report here the results of this analysis.
Patient Populations The details of the two maintenance chemotherapy studies included in this assessment have previously been published,7-9 and are briefly outlined below.
The SWOG conducted a phase II trial of single-agent altretamine (260 mg/m2/d orally for 14 days every 28 days for six cycles) in women with stage III advanced ovarian cancer, who had achieved a clinically-defined complete response to primary chemotherapy, which included a premaintenance baseline serum CA-125 antigen level of
The SWOG and GOG subsequently conducted the previously noted randomized phase III trial comparing single agent paclitaxel (175 mg/m2 over 3 hours), administered for either 12-monthly or 3-monthly cycles (S9701/GOG178).9 Patients with both stages III and IV ovarian cancer, who achieved a clinically-defined complete response, were eligible for entry into this trial. A premaintenance therapy baseline serum CA-125 antigen level of
Disease progression in S9326 included standard clinical criteria (eg, development of new tumor masses, increase in the size of existing masses), but not changes in the serum CA-125 antigen level, while the definition of disease progression in S9701/GOG178 included both standard clinical criteria as well as an elevation in the serum CA-125 levels to
Statistical Methodology
To assess the potential differential effects of baseline CA-125 among the three treatment groups, a treatment versus CA-125 interaction analysis was also performed. To assess this interaction, the Cox model included the treatment group indicator variables instead of stratifying by study and treatment. In addition, CA-125 treatment versus CA-125 interaction terms, disease stage, and age were also included in the model. Because of the small number of patients with CA-125 greater than 20 u/mL (ie, a total of 31 among 384 patients), CA-125 was treated as a two-category variable ( All P values presented are two-sided.
Characteristics of the patient population included in this analysis, and distribution of premaintenance therapy baseline CA-125 levels are outlined in Tables 1 and 2, respectively. Figures 1 and 2 demonstrate the PFS for patients treated on S9701/GOG178 (paclitaxel), and S9326 (altretamine), respectively, with the number of PFS events for each protocol outlined in Table 3.
Figures 3 to 6 show the PFS, on the basis of the entry CA-125 levels of all patients and those treated with three cycles of paclitaxel, 12 cycles of paclitaxel, and six cycles of altretamine, respectively.
The Cox model, stratified by study and treatment, revealed a statistically significant impact on PFS for both the amount of residual tumor at the start of primary chemotherapy and the baseline CA-125 level obtained before initiation of the maintenance regimen (Table 4). Median PFS was 24 months (95% CI, 19 to 31 months), 17 months (95% CI, 13 to 18 months), and 7 months (95% CI, 5 to 22 months) in patients with baseline CA-125 values of  10 u/mL, 11 to 20 u/mL, and 21 to 35 u/mL, respectively.
The premaintenance baseline CA-125 level was highly statistically significant either as a categoric variable (  2 P < .0001 with 2 df), or as a continuous variable (P < .0001). The results were similar when tumor histology and grade were added to the Cox regression model. Further, the treatment versus CA-125 interaction analysis showed no indication of inconsistency in the predictive ability of baseline CA-125 across the three treatment regimens investigated (P = .70).
In an exploratory analysis, the CA-125 levels of
In S9701/GOG178, the observed differences in median PFS between the 12-monthly cycle and 3-monthly cycle paclitaxel regimens were 9 months (26 months v 17 months), 4 months (16 months v 12 months), and 0 months (7 months in both groups) in patients with premaintenance therapy baseline CA-125 levels of
Crawford et al11 observed that survival for one series of ovarian cancer patients receiving chemotherapy varied between groups that attained nadir CA-125 10 u/mL (best) v 11 to 20 u/mL v 21 to 30 u/mL (worst). In their subsequent examination of patients (n = 556) treated with front-line chemotherapy consisting of either carboplatin/paclitaxel or carboplatin/docetaxel (SCOTROC trial), the authors validated this observation and found that women responding to treatment and whose nadir serum CA-125 antigen level was 10 u/mL experienced a median PFS of 17 months compared with 13 months if the nadir CA-125 was 11 to 20 u/mL and only 8 months with a nadir CA-125 of > 20 u/mL.10
In the current analysis, using similar serum CA-125 groups as employed in the Crawford study, we have shown that the baseline antigen level obtained at the time of initiation of maintenance chemotherapy in women with advanced ovarian cancer, who attained a clinically-defined complete response (which included a CA-125 level What are the potential clinical implications of these findings? First, the similar results found in patients treated with three different maintenance chemotherapy programs (3-monthly and 12-monthly cycles of single-agent paclitaxel; six cycles of altretamine) and after the attainment of a major clinical response to carboplatin plus either paclitaxel or docetaxel (with normalization of the serum CA-125 level) suggest that the observation is not unique to a particular treatment program. However, a definitive statement regarding this point is not possible because of relatively small numbers in each individual patient subgroup. Second, the data suggest that future trials of maintenance therapy in this clinical setting should consider this factor to be certain that randomized treatment assignments are balanced within each subgroup (as was the case in S9701/GOG178).
Third, while the total number of patients in each premaintenance therapy baseline serum CA-125 antigen subgroup in the randomized trial comparing three v 12 cycles of monthly paclitaxel is limited and do not permit a definitive statement regarding the impact of this clinical factor on the outcome of maintenance therapy, it is of potential interest that the subgroup with the greatest difference in median PFS (9 months) was the group with patients with the lowest baseline CA-125 antigen levels ( Finally, perhaps the major difficulty faced by clinicians considering maintenance chemotherapy in patients with ovarian cancer, who have achieved a clinically-defined complete response to primary chemotherapy, is the determination of the therapeutic ratio of possible harm versus potential benefit for an individual patient. It will be important for future trials of maintenance treatment in ovarian cancer to carefully assess a role for the premaintenance therapy baseline CA-125 level as one method to help clinicians advise patients in this difficult clinical setting.
The authors indicated no potential conflicts of interest.
Conception and design: Maurie Markman, David S. Alberts Provision of study materials or patients: Mace L. Rothenberg, Bradley J. Monk, David S. Alberts Collection and assembly of data: P.Y. Liu Data analysis and interpretation: Maurie Markman, P.Y. Liu, Mace L. Rothenberg, David S. Alberts Manuscript writing: Maurie Markman, P.Y. Liu, Mace L. Rothenberg, Mark F. Brady, David S. Alberts Final approval of manuscript: Maurie Markman, Mace L. Rothenberg, Bradley J. Monk, Mark F. Brady, David S. Alberts
Supported in part by PHS Cooperative Agreement Grant Nos. CA38926, CA32102, CA105409, CA58723, CA13612 awarded by the National Cancer Institute, DHHS. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Ozols RF, Bundy BN, Greer BE, et al: Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: A Gynecologic Oncology Group study. J Clin Oncol 21:3194-3200, 2003 2. International Collaborative Ovarian Neoplasm (ICON) Group: Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: The ICON3 randomized trial. Lancet 360:505-515, 2002[CrossRef][Medline] 3. Covens A, Carey M, Bryson P, et al: Systemic review of first-line chemotherapy for newly diagnosed postoperative patients with stage II, III, or IV epithelial ovarian cancer. Gynecol Oncol 85:71-80, 2002[CrossRef][Medline] 4. Gershenson DM, Mitchell MF, Atkinson N, et al: The effect of prolonged cisplatin-based chemotherapy on progression-free survival in patients with optimal epithelial ovarian cancer: "Maintenance" therapy reconsidered. Gynecol Oncol 47:7-13, 1992[CrossRef][Medline] 5. Sorbe B (on behalf of the Swedish-Norwegian Ovarian Cancer Study Group): Consolidation treatment of advanced (FIGO stage III) ovarian carcinoma in complete surgical remission after induction chemotherapy: A randomized, controlled, clinical trial comparing whole abdominal radiotherapy, chemotherapy, and no further treatment. Int J Gynecol Cancer 13:278-286, 2003[CrossRef][Medline] 6. Markman M, Glass T, Smith HO, et al: Phase 2 trial of single agent carboplatin followed by dose intense paclitaxel, followed by maintenance paclitaxel therapy in stage IV ovarian, fallopian tube and peritoneal cancer: A Southwest Oncology Group trial. Gynecol Oncol 88:282-288, 2003[CrossRef][Medline] 7. Rothenberg ML, Liu PY, Wilczynski S, et al: Phase II trial of oral altretamine for consolidation of clinical complete remission in women with stage III epithelial ovarian cancer: A Southwest Oncology Group trial (SWOG-9326). Gynecol Oncol 82:317-322, 2001[CrossRef][Medline] 8. Alberts DS, Jiang C, Liu PY, et al: Long-term follow-up of a phase II trial of oral altretamine for consolidation of clinical complete remission in women with stage III epithelial ovarian cancer in the Southwest Oncology Group. Int J Gynecol Cancer 14:224-228, 2004[CrossRef][Medline] 9. Markman M, Liu PY, Wilcyznski S, et al: Phase 3 randomized trial of 12 versus 3 months of single agent paclitaxel in patients with advanced ovarian cancer who attained a clinically-defined complete response to platinum/paclitaxel-based chemotherapy: A Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol 21:2460-2465, 2003 10. Crawford SM, Paul J, Reed NS, et al: The prognostic significance of the CA-125 nadir in patients that achieve a CA-125 response. J Clin Oncol 23:448, 2004 (abstr 5001)[Medline] 11. Crawford SM, Peace J: Does the nadir CA-125 concentration predict a long-term outcome after chemotherapy for carcinoma of the ovary? Ann Oncol 16:47-50, 2005 Submitted November 3, 2005; accepted January 9, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
70 u/mL, measured on two occasions at least 1 week apart. 
