Elsevier

Gynecologic Oncology

Volume 122, Issue 2, August 2011, Pages 350-355
Gynecologic Oncology

Correlation between CA-125 serum level and response by RECIST in a phase III recurrent ovarian cancer study

https://doi.org/10.1016/j.ygyno.2011.04.005Get rights and content

Abstract

Objectives

To evaluate in a large phase III recurrent ovarian cancer trial (OVA-301): 1) the concordance between CA-125 level vs. best overall response (OR) and progression-free survival (PFS) determined by radiological assessment 2) the impact of early CA-125 changes over the subsequent radiological response, and 3) the prognostic value of CA-125 response and CA-125 PFS to predict radiological response and PFS.

Methods

Assessment of response in the entire randomized population was performed by the Response Evaluation Criteria in Solid Tumors 1.0 (RECIST) and modified Rustin criteria for CA-125 determination.

Results

Most CA-125 decreases were observed in RECIST responders (82% of patients treated with the combination and 74% in the PLD alone). CA-125 progression preceded RECIST progression in 35% of patients with a median lead time of 8.4 weeks. A high concordance rate between CA-125 PFS status at 4 months (PFS4) and CA-125 response as a predictor of PFS4 (87%) and radiological response (79%) was found in the combination, with high positive predictive value for radiological PFS4 (92%) and high negative predictive value for OR (90%). An early CA-125 decrease was predictive for the ultimate response since it was found in a high rate of RECIST responders.

Conclusion

Radiological response was preceded by a favorable predictive CA-125 decrease in a high proportion of patients, suggesting that CA-125 evaluation may be an appropriate tool for tumor assessment in patients with ovarian cancer.

Research highlights

►We evaluate the concordance, prognostic value and impact of early CA-125 changes vs. RECIST response in recurrent ovarian cancer. ►CA-125 monitoring is a useful surrogate marker of efficacy. ►CA-125 expression in recurrent ovarian cancer can be used as a decision tool to evaluate the utility of chemotherapy continuation.

Introduction

Ovarian cancer is the most common cause of death among gynecological cancers, with approximately 125,000 deaths annually worldwide [1]. Early-stage ovarian cancer is often asymptomatic with few non-specific pelvic or abdominal symptoms [2], [3]. This frequently leads to a delay in diagnosis causing approximately 75% of women to present an advanced stage of ovarian cancer at diagnosis, of which up to 70% will suffer from recurrent disease [4].

Objectively determining clinical response to therapy in patients is essential as cost and toxicity from chemotherapeutics are important considerations in assuring that the optimal therapy is utilized. Similarly, selecting the most efficient means of defining whether a regimen is working is also important. Radiographic studies are the standard for oncology clinical trial reporting where often only patients with measurable disease are enrolled, and they are required by regulatory agencies for drug approval [5], [6]. However, disease assessments by imaging are expensive and inconvenient for the patient and have a number of significant side effects including radiation exposure on a serial basis and potential dye reactions resulting in nephrotoxicity [7]. Furthermore, radiological studies are subjectively interpreted and significant interobserver error has been reported [8]. An objective test such as serum cancer antigen (CA)-125 would be an attractive alternative to serial radiography if the results correlated well with radiographic assessment and most importantly with patient outcome.

To test the hypothesis that CA-125 levels may be an acceptable surrogate to radiography in patients with recurrent ovarian cancer, the data from OVA-301, a large phase III trial, was analyzed to assess CA-125 changes in predicting objective responses and PFS. The trial compared trabectedin plus PLD (Doxil®) vs. PLD alone in second-line relapsed ovarian cancer. Trabectedin (formerly ecteinascidin 743, ET-743; Yondelis®) is a synthetic drug originally isolated from the Caribbean tunicate Ecteinascidia turbinata[9]. Trabectedin has a unique mechanism of action based on interaction with the minor groove of the DNA double helix, which triggers a cascade of events that interfere with several transcription factors, DNA binding proteins, and DNA repair pathways [10].

In OVA-301 the effectiveness of re-treatment in relapsed ovarian cancer was evaluated by CA-125 measurements according to Rustin criteria [11] at the same time as tumor assessments in accordance with the Response Evaluation Criteria in Solid Tumors 1.0 (RECIST) radiological response [12]. CA-125 remains the only well-defined and validated tumor marker to have any significant impact on the clinical management of ovarian carcinoma [13], [14]. More than 90% of patients with advanced ovarian cancer have elevated CA-125 values at the beginning of treatment [15]. Assessments of CA-125 levels in the monitoring of response or recurrence of ovarian cancer are easy to follow. A negative slope of serial determinations (CA-125 nadir) is considered as evidence of therapeutic efficacy. Simplified CA-125 criteria for definition of response has been recommended by the Gynecologic Cancer Intergroup (GCIG) [11].

The current evaluation of the data from OVA-301 investigated: 1) the concordance between overall response (OR) and progression-free survival (PFS) determined by CA-125 and the RECIST, 2) the impact of early CA-125 changes over the subsequent OR by the RECIST, and 3) the prognostic value of CA-125 response and CA-125 PFS to predict radiological response and PFS by the RECIST.

Section snippets

Study design

Full details of OVA-301 trial have been reported earlier [16]. Briefly, OVA-301 was an open-label, multicenter, randomized, phase III clinical trial designed to investigate the efficacy and safety of the combination of PLD 30 mg/m2 followed by trabectedin 1.1 mg/m2 every three weeks compared with PLD 50 mg/m2 every four weeks. Eligible patients were women ≥ 18 years old with histologically proven and measurable by the RECIST epithelial ovarian, fallopian tube, or primary peritoneal carcinoma in

Results

A total of 672 patients were randomly assigned to the PLD (n = 335) or trabectedin + PLD (337) arms, and 430 (64%) of them belonged to the platinum-sensitive population with a PFI  6 months (Supplementary material, Table S1, online only) [16].

Discussion

Ovarian cancer is a disease that often is more difficult objectively to assess for response, as the disease volume is often small and widely distributed. Identifying reliable radiographic target lesions of sufficient volume is frequently problematic. Previous radical cytoreductive procedures may lead to false positive imaging in areas of scar tissue. Conversely, postoperative anatomic changes may obscure small volume tumors that may then go clinically undetected. The costs and toxicity of

Conflict of interest statement

Dr. Thomas J. Herzog received honoraria from Johnson and Johnson and Dr. Jan B. Vermorken received honoraria from PharmaMar. Bradley Monk has research funding from Johnson and Johnson. Youn Choi Park and Trilok Parekh are Johnson and Johnson employees and stockholders, and Claudia Lebedinsky and Javier Gómez are PharmaMar employees and stockholders. All other co-authors have no conflict of interest to declare.

Acknowledgments

The authors would like to acknowledge Eliel Bayever, Alejandro Yovine, Antonio Nieto and Pedro Santabarbara for assistance in developing the protocol and data analysis and Adnan Tanović for providing writing assistance for the manuscript.

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    Supported by Johnson and Johnson Pharmaceutical Research and Development, Raritan, NJ, and PharmaMar, Madrid, Spain.

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