Elsevier

Gynecologic Oncology

Volume 124, Issue 3, March 2012, Pages 563-568
Gynecologic Oncology

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,☆☆,

https://doi.org/10.1016/j.ygyno.2011.11.035Get rights and content

Abstract

Objective

To compare two methods of determining therapeutic response and disease progression — modified Gynecologic Cancer Intergroup (GCIG) criteria based on CA-125 and Radiographic Evaluation Criteria in Solid Tumors (RECIST), in a phase II trial of bevacizumab for patients with recurrent or persistent epithelial ovarian and peritoneal carcinoma.

Methods

Patients were treated with bevacizumab 15 mg/kg every 21 days. Modified GCIG definitions of progression and response were retrospectively applied and compared to RECIST-defined progression and response. The prognostic significance of CA-125- and RECIST-defined responses and progressions were explored.

Results

Sixty-two patients were evaluable by RECIST, 59 for progression by CA-125, and 45 for response by CA-125. Median progression-free survival (PFS) by RECIST and progression-free interval (PFI) by CA-125 were 4.7 and 5.2 months respectively. However, 12.9% of those with CA-125 defined progression remained progression-free according to RECIST for at least 8 months. Thirteen of 62 patients (21%) had response by RECIST and 14/45 (31%) by CA-125. Time dependent analyses indicated that progression by CA-125 was associated with a 5.2 fold increased risk of progression by RECIST, and response by CA-125 had a 5 fold decrease in risk of progression by RECIST. Landmark and time dependent analyses showed prognostic value of responses by CA-125 and RECIST.

Conclusions

In this study, disease assessment by RECIST and CA-125 appears to correlate in general. However, approximately 10% of patients might demonstrate progression earlier by CA-125.

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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    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).

    ☆☆

    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.

    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.

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