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Journal of Clinical Oncology, Vol 25, No 24 (August 20), 2007: pp. 3570-3571 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.11.9735
Ovarian Cancer, CA-125 Addiction, and Informed Confusion: Much Ado About LessClinical Research Branch, National Institute on Aging, National Institutes of Health and Greenebaum Cancer Center, University of Maryland, Baltimore, MD
Harry and Jeanette Weinberg Cancer Institute at Franklin Square Hospital and University of Maryland School of Medicine, Baltimore, MD Biomarkers can be useful in risk stratification of a disease or as a surrogate end point in determining the effectiveness of treatment. CA-125 has been proposed as a surrogate for response in ovarian cancer,1 and in most clinical trials, clinical complete response is defined as radiographic disappearance of all disease, resolution of all disease-related symptoms, and normalization of the CA-125 if it was elevated at therapy initiation. Less well accepted is assignment of complete response in a patient whose only evidence of disease is an elevated tumor marker that subsequently normalizes on therapy. It is possible that this type of serologic definition of complete response is as good as or better than conventional radiographic imaging in patients with advanced ovarian cancer. CA-125 has also been shown to be an accurate marker to define progression of ovarian cancer, and becomes elevated on an average of 3 to 4 months (range, 1 to 15 months) before clinically assessable (symptomatic, palpable, or visible by imaging) disease in 70% of patients.2,3 Furthermore, an increasing CA-125 serum level alone is sometimes being used to initiate cytotoxic systemic therapy for recurrence in the absence of clinically demonstrable disease, despite the lack of evidence demonstrating a survival advantage for this approach. Many investigators have attempted to codify what degree of CA-125 elevation can predict progression of ovarian cancer with acceptable specificity and sensitivity. Although this serologic approach to assess disease progression may eventually prove useful in the conduct of clinical trials, it may not demand routine treatment initiation, given that there is wide variability in lead time between biochemical and clinical progression. Furthermore, there is significant variation among investigators in terms of when to initiate treatment for recurrent disease based on personal bias and patient preference.
The Gynecologic Cancer Intergroup (GCIG) defines progressive disease after a complete response to primary therapy based on CA-125 criteria4: the date of first elevation of CA-125 to two-fold the upper limit of normal (documented on two occasions at least a week apart). For those with persistently elevated CA-125 levels, progression of disease is defined as the first date of CA-125 A number of ongoing and planned clinical trials incorporated these existing GCIG criteria in conjunction with the standard Response Evaluation Criteria in Solid Tumors Group (RECIST) classifications in an attempt to validate the use of serum CA-125 levels as surrogate markers for defining disease progression in ovarian cancer. Recently, the GCIG criteria of progression were validated using data from an Intergroup trial that randomly assigned patients to frontline combination chemotherapy with cisplatin and paclitaxel compared with cisplatin and cyclophosphamide.5 The analysis using GCIC criteria showed that the magnitude of therapeutic benefit was similar using either CA-125 or RECIST criteria. From an economic point of view, use of a biomarker seems preferable to more expensive radiographic testing that is often used to determine response and progression in the context of clinical trials. However, outside of a clinical trial, what should one do when the marker signals progression but the patient's review of systems is negative and the imaging study of choice is within normal limits? In such a situation the false-positive rate of the marker signal becomes paramount because this type of information could lead to inappropriate treatment. In addition, even if clinical recurrence is predicted by the marker signal, there are no data demonstrating a survival or quality-of-life benefit for the patient treated before clinical progression. In the validation trial by Rustin et al,5 the false-positive rate was 2%. The only two clinical trials addressing immediate versus delayed therapy at the time of biochemical progression are the Medical Research Council (MRC) 05 study combined with the European Organization for the Research and Treatment of Cancer (EORTC) study 55955, and Gynecologic Oncology Group (GOG) trial 198. The first trial simply randomly assigns notification or lack thereof of the patient when there is biochemical evidence of recurrence. Therapy is not controlled. In GOG 198, patients with biochemical recurrence are randomly assigned to receive either tamoxifen or thalidomide until clinical progression, with progression-free survival (PFS) as the end point. What might this new and potentially more sensitive indicator of recurrence do? First, it will shorten the PFS of the prior therapy. Second, it may alter the definition of platinum resistance, given that currently, platinum-free intervals are based largely on intervals between discontinuation of primary therapy and presentation with clinical recurrence. Third, it will lead to inappropriate therapy in those patients with false-positive results and possibly also in those patients where there is a long lead time between biochemical and clinical progression. These changes in definitions are largely surmountable because clinical trials typically are randomized eliminating the first two biases. The final risk that needs to be discussed with the patient who elects to start therapy based solely on marker signal of progression in the absence of symptoms or abnormal image studies is the 2% chance that this therapy is unnecessary.
In this issue of the Journal of Clinical Oncology, a more sensitive and less specific algorithm for CA-125 elevation to predict recurrence is put forth, compared with both RECIST and GCIG criteria. This new algorithm seems to compound the problems mentioned above. Markman et al have reported previously that maintenance paclitaxel after complete remission from primary therapy leads to a significant delay in recurrence at the risk of some increase in neurotoxicity, but without improvement in overall survival.6 More recently, these same investigators found that the longest survivals with maintenance therapy were observed in patients who achieved CA-125 levels The GCIG CA-125 criteria for progressive disease were based on a well-defined validation of the CA-125 data from two randomized trials. In one study (n = 255) with a confirmed increase in CA-125 to more than 2x the upper limit of normal during follow-up after the first-line chemotherapy, recurrence could be predicted, with a sensitivity of 84% and a false-positive rate of less than 2%.9 In another study with 88 patients, a confirmed doubling time of CA-125 from its nadir predicted progression with a sensitivity of 94% and specificity of 100%.10 Although specified intervals for serial monitoring of disease using EPD criteria would detect disease progression earlier than the GCIG criteria in some patients, one must ask several obvious questions. Apart from its possible role in the conduct of clinical trials, what is the clinical utility of earlier detection based on CA-125 criteria in the absence of symptoms? Is it acceptable to have a false-positive signal in 8%, even with the higher sensitivity of the proposed EPD definition? The clinical value of earlier detection of recurrence remains unclear. Given that recurrent ovarian cancer remains incurable, and the role of systemic therapy is palliation, one must question the ability to palliate when symptoms are not present. In addition, we should not assume that earlier treatment with its attendant toxicity equates to a survival advantage for the patient, unless this is proven in randomized clinical trials, such as those being conducted by MRC/EORTC in Europe and by the GOG in protocol 198 in the United States. If this proposed definition were accepted, it would increase the number of patients with biochemical-only recurrence, leading to treatment with potentially toxic therapies earlier than needed. In comparison to the GCIG criteria, the EPD criteria would lead to four-fold more patients being incorrectly labeled with recurrent disease (false positive rate increase). In addition, what should the physician tell the patient? Should the patient be told about the suspicion of recurrence, a suspicion about which the physician is now less certain and for which treatment has unclear benefit? Should patients worry on average 2 more months than they already do? The authors suggest that earlier knowledge of recurrence and subsequent initiation of second-line therapy may favorably influence patient outcome, but there are no data to support this statement. One could actually postulate that maintenance therapy as used in the protocol from which these data were derived, in a way, is a type of second-line therapy aimed to retard the rate of recurrence. To date, this has been the only study among several evaluating maintenance therapy to have any impact on patient outcome, and then only by extending PFS rather than symptom-free survival or overall survival. Others are trying to replicate these results, and we all await those data. If those studies do not verify an impact on outcome, and the MRC/EORTC and GOG studies of early compared with later treatment of recurrent disease using less stringent criteria for recurrence are all negative, then it becomes very difficult to understand any reason for adoption of the EPD criteria for recurrence, outside of a clinical trial setting. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Mohan K. Tummala, William P. McGuire Manuscript writing: Mohan K. Tummala, William P. McGuire Final approval of manuscript: William P. McGuire REFERENCES
1. Rustin GJ, Quinn M, Thigpen T, et al: Re: New guidelines to evaluate the response to treatment in solid tumors (ovarian cancer). J Natl Cancer Inst 96:487-488, 2004 2. van der Burg ME, Lammes FB, Verweij J: The role of CA 125 in the early diagnosis of progressive disease in ovarian cancer. Ann Oncol 1:301-302, 1990 3. Tuxen MK, Soletormos G, Dombernowsky P: Tumor markers in the management of patients with ovarian cancer. Cancer Treat Rev 21:215-245, 1995[CrossRef][Medline] 4. Vergote I, Rustin GJS, Eisenhauer EA, et al: Re: New guidelines to evaluate the response to treatment in solid tumors [ovarian cancer]: Gynecologic Cancer Intergroup. J Natl Cancer Inst 92:1534-1535, 2000 5. Rustin GJS, Timmers P, Nelstrop A, et al: Comparison of CA-125 and standard definitions of progression of ovarian cancer in the intergroup trial of cisplatin and paclitaxel versus cisplatin and cyclophosphamide. J Clin Oncol 24:45-51, 2006 6. Markman M, Liu PY, Wilczynski S, et al: Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: A Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol 21:2460-2465, 2003 7. Markman M, Liu PY, Rothenberg ML, et al: Pretreatment CA-125 and risk of relapse in advanced ovarian cancer. J Clin Oncol 24:1454-1458, 2006 8. Liu P-Y, Alberts DS, Monk BJ: An early signal of CA-125 progression for ovarian cancer patients receiving maintenance treatment after complete clinical response to primary therapy. J Clin Oncol 25:3615-3620, 2007 9. Rustin GJS, Nelstrop AE, Tuxen MK, et al: Defining progression of ovarian carcinoma during follow-up according to CA 125: A North Thames Ovary Group Study. Ann Oncol 7:361-364, 1996 10. Rustin GJS, Marples M, Nelstrop AE, et al: Use of CA-125 to define progression of ovarian cancer in patients with persistently elevated levels. J Clin Oncol 19:4054-4057, 2001
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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2x the nadir value documented on two occasions no less than a week apart. 
10 at the conclusion of primary therapy,
