Predictive value of serum CA-125 levels in patients with persistent or recurrent epithelial ovarian cancer or peritoneal cancer treated with bevacizumab on a Gynecologic Oncology Group phase II trial☆,☆☆,★
Highlights
► CA125-defined response and progression were assessed for women with recurrent ovarian cancer. ► CA125 and RECIST-defined response and progression correlated in most cases, but CA125 progression significantly preceded RECIST in 8 cases. ► CA125-defined response to bevacizumab was associated with a statistically significant correlation with overall survival.
Introduction
In clinical trials for solid tumors, National Cancer Institute Response Evaluation Criteria in Solid Tumors (RECIST) represent the gold standard for response determination [1]. Although epithelial ovarian and peritoneal cancers are often assessed radiographically according to RECIST, clinical management is often guided by the less invasive and more cost-effective serum CA-125 level as a surrogate to RECIST. Gynecologic Cancer Intergroup (GCIG) CA-125 criteria have demonstrated a reasonable association with RECIST-defined response and progression in retrospective studies of patients treated with cytotoxic therapies [2], [3], [4], [5], [6]. Therefore, over the last decade, CA-125 has been incorporated into the assessment of disease in some clinical trials examining cytotoxic agents. It is unclear whether newer biologic targeted therapies, such as anti-angiogenic agents, could have an impact on CA-125 levels independent of tumor burden. If so, the accuracy of CA-125 in disease assessment could be compromised. Incorrect assessment of disease status by surrogate measures such as CA-125 might lead to premature discontinuation of, or rejection of, active therapy.
Gynecologic Oncology Group (GOG) Protocol 170-D was a phase II evaluation of single-agent bevacizumab in patients with persistent or recurrent ovarian or peritoneal carcinoma with primary endpoints of progression-free survival (PFS) at 6 months and response as determined by RECIST [7]. CA-125 measurements were collected, but these values were only required to confirm RECIST-defined complete responses.
The primary objective of this study was to assess the interactive and independent values of serum CA-125 and RECIST as measures of disease response or determinants of progression in the context of treatment with anti-angiogenic agent, bevacizumab, whose mechanism of action is unlike traditional cytotoxic agents. The secondary objective was to explore the prognostic significance of CA-125 and RECIST-defined responses and progressions.
Section snippets
Patients and methods
This is a retrospective analysis of serum CA-125 measurements recorded in patients enrolled on GOG Protocol 170-D. Details regarding the design and results of this study have been previously published [7], but in summary, GOG 170-D was a multi-center phase II evaluation of single-agent bevacizumab at 15 mg/kg intravenously every 21 days in patients with histologically-confirmed recurrent or persistent ovarian or peritoneal carcinoma. The original study received local Institutional Review Board
Results
Sixty-two patients were eligible and evaluable on clinical protocol [7]. Serum CA-125 levels over time were highly variable, and in several patients, CA-125 levels fluctuated in an oscillating pattern [Appendix A]. Determination of progression was limited by lack of CA-125 data following RECIST-defined progression, but progressions that were defined by death alone falsely prolonged PFS time. Therefore, a less-biased progression-free interval (PFI) was employed, defining progression by CA-125
Discussion
Assessment of disease progression by CA-125 has been advocated by the GCIG, especially in phase II trials in recurrent disease, citing advantages that include earlier determination of treatment failure, increased frequency of endpoint events, cost-savings over imaging assessments, and inclusion of patients without measurable disease [3], [4], [5], [6]. This argument was presented to the U.S. Food and Drug Administration (FDA) in a public workshop addressing endpoints in ovarian cancer clinical
Conflict of interest
Dr. Robert Burger served as a consultant for Genentech/Roche, but has not been compensated for this activity. All other co-authors have no conflict of interest to declare.
Acknowledgment
The authors would like to thank Sandra Dascomb for expeditious data extraction and transcription and Kim Blaser for publication assistance.
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Cited by (14)
Pazopanib based oral metronomic therapy for platinum resistant/refractory epithelial ovarian cancer: A phase II, open label, randomized, controlled trial
2021, Gynecologic OncologyCitation Excerpt :We have used the GCIG criteria [16] for response and progression. These criteria have been validated in earlier similar studies as well [27,28]. In EOC patients who are in poor general condition and not fit for intravenous therapy, offering an oral regimen with low toxicity and better QoL might be prudent.
Poor concordance between CA-125 and RECIST at the time of disease progression in patients with platinum-resistant ovarian cancer: Analysis of the AURELIA trial
2016, Annals of OncologyCitation Excerpt :It therefore remains uncertain whether CA-125 can be utilized in the platinum-resistant setting. In addition, in patients receiving bevacizumab, there is particular concern about the reliability of CA-125 measurements for assessing PD, as bevacizumab might influence CA-125 levels by altering mucin MUC16 levels [11]. Two single-arm bevacizumab studies demonstrated poor concordance between RECIST- and CA-125-defined PD [11, 12].
Recurrence patterns after extended treatment with bevacizumab for ovarian, fallopian tube, and primary peritoneal cancers
2013, Gynecologic OncologyCitation Excerpt :Our findings regarding the limitations of CA-125 are consistent with a prior study of 15 recurrent ovarian cancer patients treated with sorafenib and BEV, in which the authors reported that CA-125 changes did not agree with objective imaging (67% concordance) in predicting disease behavior [28]. In retrospective analysis of 62 patients with persistent or recurrent ovarian or peritoneal cancer treated with BEV (Gynecologic Oncology Group protocol 170-D), Randall and colleagues observed that CA-125 and RECIST-defined progression correlated in most cases (31% and 21%, respectively), but 12.9% of those with CA-125 defined progression remained progression-free according to RECIST criteria for at least 5.7 months [29]. These findings further support our conclusion that radiologic imaging may be more reliable than CA-125 to detect disease progression in patients treated with BEV.
Antiangiogenic agents as a maintenance strategy for advanced epithelial ovarian cancer
2013, Critical Reviews in Oncology/HematologyCitation Excerpt :Whereas the sorafenib Study 12007 requires that patients be in CT-confirmed or MRI-confirmed complete remission prior to commencing maintenance therapy, the AGO-OVAR16 trial of pazopanib permits the enrollment of patients with PR or even SD following first-line platinum/taxane. One recent study showed that CA-125 levels can increase in response to bevacizumab treatment prior to radiographic evidence of disease progression [85]. Therefore, recurrence should be confirmed by CT or MRI in order to limit premature discontinuation of therapy.
Outcomes and endpoints of relevance in gynecologic cancer clinical trials
2023, International Journal of Gynecological Cancer
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This research was supported by National Cancer Institute grants to the Gynecologic Oncology Group Administrative Office (CA 27469), the Gynecologic Oncology Group Statistical and Data Center (CA 37517) and to Dr. Randall and the Chao Family Comprehensive Cancer Center (ARRA supplement to CA 62203).
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These results were presented at the 2009 Joint Annual Meetings of the Western Association of Gynecologic Oncologists and the Society of Gynecologic Oncology of Canada, June 2009.
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The following institutions participated in this study: University of Alabama at Birmingham, Walter Reed Army Medical Center, University of California at Los Angeles, University of Washington, University of Iowa Hospitals and Clinics, University of California Medical Center at Irvine, Washington University School of Medicine, Columbus Cancer Council, North Shore University Hospital and Community Clinical Oncology Program.