Correlation between CA-125 serum level and response by RECIST in a phase III recurrent ovarian cancer study☆
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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Phase II trial of albumin-bound paclitaxel and granulocyte macrophage colony-stimulating factor as an immune modulator in recurrent platinum resistant ovarian cancer
2017, Gynecologic OncologyCitation Excerpt :Finally, while biochemical response criteria in ovarian cancer clinical trials using CA-125 are well defined, immune therapies could act through mechanisms that may demand re-evaluation these definitions [33–35]. The use of CA-125 response criteria may also have been a factor in the observed completion rates since these levels were checked monthly, allowing earlier opportunities to detect progression, since CA-125 changes have been shown to precede RECIST responses [36]. Inflammatory conditions unrelated to malignancy are known to elevate CA-125 levels.
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
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Ovarian cancer
2014, The LancetCitation Excerpt :Thus, the global standard of care for the past 20 years has remained carboplatin and paclitaxel. Although response to this treatment is traditionally followed radiologically, the serum CA-125 concentration is also useful.65–67 Findings of five positive randomised trials55–57,68,69 have started to affect the options for first-line treatment (table).
Ovarian cancer clinical trial endpoints: Society of Gynecologic Oncology white paper
2014, Gynecologic OncologyCitation Excerpt :Deviations from the pre-specified schedule for disease assessments can artificially increase or decrease the measured progression-free interval. However, there are procedures that can ameliorate the effects of assessment-time bias in non-blinded studies that use PFS as a primary endpoint [31]. To be feasible, a study endpoint must obtain a reasonable balance between patient burden and study resources.
Evaluating the prognostic significance of preoperative thrombocytosis in epithelial ovarian cancer
2013, Gynecologic OncologyCitation Excerpt :Approximately 95% of ovarian cancers are of epithelial origin and in 2012, there were 22,280 estimated new diagnoses of ovarian cancer and 15,500 deaths from the disease [1]. Serologic measurements including cancer antigen 125 (CA-125), albumin, hemoglobin, and platelet levels, have emerged as potential preoperative predictors of outcome [2–7]. The rate of preoperative thrombocytosis in primary epithelial ovarian cancer (EOC) has been reported to range from 31–42% [2,3].
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Supported by Johnson and Johnson Pharmaceutical Research and Development, Raritan, NJ, and PharmaMar, Madrid, Spain.