CA125 Validity a Concern for Assessing Ovarian Cancer Responses to Molecularly Targeted Therapies
Abstract & Commentary
By William B. Ershler, MD, Editor
Synopsis: In a pilot study of ovarian cancer patients treated with sorafenib and bevacizumab, CA125 concentrations were shown to not correspond with imaging analyses in the assessment of treatment response. Thus, caution is raised about using this tumor marker alone in the assessment of treatment outcomes for patients treated with newer, molecularly-targeted therapies.
Source: Azad NS, et al. Cancer. 2008;112:1726-1732.
CA125 has become an accepted indicator of epithelial ovarian cancer and is widely-used to monitor patients treated with cytotoxic chemotherapy. However, it remains uncertain how CA125 levels would be affected by molecularly targeted drugs. In this pilot study from Azad and colleagues at the National Cancer Institute in Bethesda, MD, the reliability of CA125 to predict clinical outcomes for patients treated with sorafenib, a Raf-kinase/VEGFR2 inhibitor, and bevacizumab, an anti-VEGF monoclonal antibody was addressed.
For this, 15 ovarian cancer patients with relapsed or refractory disease were enrolled on a phase I dose escalation study and received sorafenib 200 mg orally twice daily and bevacizumab 5 (dose level 1) or 10 (dose level 2) mg/kg intravenously every two weeks. Additional patients were treated on related protocols, the main purpose of which was to determine the appropriate dose and schedule of both drugs when used together. Computed tomography (CT) scans were performed every 2 cycles for restaging, and CA125 was measured monthly. CA125 concentrations were retrospectively analyzed in the context of clinical parameters and imaging results.
Fourteen of 15 patients had abnormal CA125 concentrations at study entry (median 1056 U/mL; range, 67 U/mL to 9813 U/mL). Seven (47%) patients had partial response by imaging criteria. Five of these 7 patients had partial response by CA125 criteria (71% sensitivity). Eight (53%) patients would have had partial responses if CA125 criteria were used; only 5 were confirmed by CT (63 % specificity). Imaging and CA125 criteria combined yielded a higher total response rate of 10 of 15 (67%). Three patients with objective partial response by imaging lasting >20, >22, and >24 cycles would have terminated treatment prematurely if CA125 had been used.
Commentary
Much has been written about the value of CA-125 as a useful marker of ovarian cancer as it has become a very useful clinical tool for predicting response to therapy and early recurrence.1,2 Just a few months ago in these pages we reviewed a retrospective analysis of maintenance chemotherapy conducted by the Southwest Oncology Group (SWOG) and the Gynecologic Oncology Group (GOG), in which the baseline CA-125 level just prior to the initiation of maintenance chemotherapy was found to strongly predict the risk of recurrence. Those with CA125 levels <10u/mL were found to have a superior progression free survival (PFS) compared with higher CA125 levels within the normal range.3 Subsequently, Riedinger and colleagues in France4 demonstrated from a retrospective analysis that the rapidity and magnitude of the CA125 response to the first and second cycles of chemotherapy could be used to define subgroups with varying chances of achieving pathological complete remission (pCR) and prolonged overall survival. It had been proposed that factors such as the rate of decline in CA125 during the first two cycles of initial chemotherapy and the absolute level just prior to the initiation of maintenance therapy could be used to distinguish those who should receive more intensive and prolonged maintenance treatment from those who might do well with lesser treatment.
The current report raises some concern about the value of CA125 in the setting of advanced disease, particularly when targeted therapy is undertaken. It is noted that the established CA125 criteria for response was formulated and validated in an era of cytotoxic chemotherapy and might not be generally applicable to molecularly-targeted approaches. Certainly, the discordance between imaging studies and CA125 levels observed in this pilot analysis is worthy of attention and highlights the important need for a complete reassessment of the effects of these targeted therapies on tumor markers and imaging results. Short of this, clinicians should be aware that traditional markers may not be as reliable in the setting of novel, targeted therapies and therapeutic decisions should be based upon a composite of clinical parameters including imaging studies, tumor markers and other available data.
References
1. Gard GB, Houghton CR. An assessment of the value of serum CA 125 measurements in the management of epithelial ovarian carcinoma. Gynecol Oncol. 1994;53(3):283-289.
2. Makar AP, et al. Prognostic value of pre- and postoperative serum CA 125 levels in ovarian cancer: new aspects and multivariate analysis. Obstet Gynecol. 1992;79(6):1002-1010.
3. Markman M, et al. Pretreatment CA-125 and risk of relapse in advanced ovarian cancer. J Clin Oncol. 2006;24(9):1454-1458.
4. Riedinger JM, et al. Change in CA 125 levels after the first cycle of induction chemotherapy is an independent predictor of epithelial ovarian tumour outcome. Ann Oncol. 2007;18(5):881-885.
In a pilot study of ovarian cancer patients treated with sorafenib and bevacizumab, CA125 concentrations were shown to not correspond with imaging analyses in the assessment of treatment response. Thus, caution is raised about using this tumor marker alone in the assessment of treatment outcomes for patients treated with newer, molecularly-targeted therapies.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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