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Comparison of Standard and CA-125 Response Criteria in Patients With Epithelial Ovarian Cancer Treated With Platinum or Paclitaxel

From the Mount Vernon Centre for Cancer Treatment, Middlesex, United Kingdom; Department of Medicine, Royal Marsden Hospital, London, England; University of Mississippi School of Medicine, Jackson, Mississippi; and Memorial Sloan-Kettering Cancer Center, New York, New York.

Address reprint requests to Gordon J.S. Rustin, Mount Vernon Centre for Cancer Treatment, Rickmansworth Rd, Northwood, Middlesex HA6 2RN, United Kingdom; email rustin{at}mtvern.co.uk

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To assess CA-125 as a measure of response in patients treated with paclitaxel.

PATIENTS AND METHODS: One hundred forty-four patients treated with paclitaxel derived from four different trials and 625 patients treated with platinum from two trials were analyzed using precisely defined 50% and 75% reductions in CA-125. The standard and CA-125 response rates to paclitaxel and platinum were compared. In addition, we analyzed individual patient groups in which there was a difference in response according to the two response criteria.

RESULTS: Patients with stable disease as determined by standard criteria who were treated with platinum and responded according to CA-125 criteria have an improved median progression-free survival compared with patients with stable disease who did not respond according to CA-125 criteria (10.6 v 4.8 months; P < .001). Standard and CA-125 response rates for patients treated with platinum (58.93% v 61.31%, respectively) and paclitaxel (30.65% v 31.67%, respectively) were very similar, as were rates of false-positive prediction of response by CA-125 (platinum 2.2% and paclitaxel 2.9%). Responders to paclitaxel had a significantly improved progression-free survival compared with nonresponders by both standard criteria (median progression-free survival, 6.8 v 2.5 months; P < .001) and CA-125 criteria (median progression-free survival, 6.8 v 3.4 months; P < .001).

CONCLUSION: For assessing activity of therapy for ovarian cancer, these data show that precise 50% or 75% CA-125 response criteria are as sensitive as standard response criteria. We propose that they may be used as a measure of response in lieu of or in addition to standard response criteria in clinical trials involving epithelial ovarian cancer. Sensitivity is maintained whether patients are treated with platinum or paclitaxel.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
ELEVATED LEVELS of serum CA-125 are found in more than 90% of women with advanced epithelial ovarian cancer.¹ There is evidence that the serum CA-125 can substitute for conventional measures of tumor response as defined by the World Health Organization (WHO),² Eastern Cooperative Oncology Group (ECOG),³ or Gynecologic Oncology Group (GOG),⁴ in terms of defining response or progression and as a prognostic indicator.^5-17 If CA-125 criteria were shown to be as accurate as conventional measures, more patients would become assessable for response and would not require sequential computed tomography (CT) or ultrasound scans in everyday practice or for the assessment of overall response in clinical trials.

Doubt has been cast on the role of CA-125 in the evaluation of patients undergoing second-line treatment with taxanes, in particular paclitaxel.^18-20 Much of the controversy concerns the reliability of CA-125 in the management of individual patients, and some conclude that CA-125 cannot be used as a guide for determining response and individual patient management. Common criticisms include the following: (1) patients who respond as determined by standard criteria do not correlate with those who respond as determined by CA-125 criteria, and (2) patients who respond as determined by standard criteria have an improved progression-free survival when compared with nonresponders, but those who respond according to CA-125 criteria do not. A suggested explanation for a discrepancy between response as determined by standard criteria and as determined by CA-125 criteria is increased shedding of CA-125 antigen induced by paclitaxel, but this explanation has not been proved. Reports that question the use of CA-125 can be criticized for the small numbers of patients analyzed and insufficiently stringent definitions of CA-125 response.^18-20

Using precise definitions of CA-125 response determined by 50% and 75% reductions,⁵ we have studied patients with epithelial ovarian cancer treated with paclitaxel and compared them with patients treated with platinum. Data presented (1) compare whole patient populations as required in a clinical trial, and (2) examine specific patient groups in which there was a discrepancy between standard and CA-125–determined response to determine the reliability of CA-125 as an indicator of response in the assessment of clinical trials and in the management of individual patients.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
Patients treated with platinum were treated on one of two studies: the GOG study of dose-intense versus standard-dose cisplatin and cyclophosphamide (451 patients²¹) and the London Gynaecological Oncology Group study of high-dose versus standard-dose carboplatin (174 patients, Royal Marsden Hospital²²), providing a total of 625 patients. Patients treated with paclitaxel were treated on one of four studies at Charing Cross, Mount Vernon, and Royal Marsden Hospitals sponsored by Bristol Myers Squibb: 14 patients were treated on trial 675, 33 patients were treated on trial 68-93.005, 61 patients were treated on trial CA139-052, and 36 patients were treated on trial CA139-039,²³ providing a total of 144 patients. All patients treated with platinum and patients on the paclitaxel trial 139-039 were treated first-line, and the remainder (all paclitaxel patients) were treated second-line. Paclitaxel was used as a single agent in all trials.

Inclusion Criteria
For inclusion in the analysis, patients were required to have CA-125 measurements performed on at least three serum samples, with at least one sample having a level more than or equal to 40 U/mL at the start of treatment, taken between 9 days prior to and 35 days after the first course of chemotherapy. Only blood samples taken during the first 6 months after the initiation of chemotherapy were considered in this analysis as the maximum period during which a response might occur. CA-125 response was classified as "response" or "no response." To be eligible, patients had to have at least one bidimensionally measurable lesion as evidenced by CT or magnetic resonance imaging scan, ultrasound, or physical examination. Written informed consent was obtained from each patient before study entry. The study was conducted in accordance with "Good Clinical Practices" and the Declaration of Helsinki as amended in Hong Kong (1989).

Assay Kits
Roche Cobascore kits (Roche, Welwyn Garden City, United Kingdom) were used in all United Kingdom trials. Several different kits were used in the GOG trials. Kits differ in their sensitivity and are therefore accurate to different lower limits of normal. A comparison of different kits is valid when levels are elevated, as the changes between elevated levels will be equivalent regardless of the kit.²⁴

Definitions of Response
The CA-125 response criteria have been precisely defined previously.⁵ Response according to CA-125 is considered to have occurred if either of the following criteria is applicable⁵: (1) A 50% response is considered to have occurred if there is a 50% decrease in serum CA-125 levels. There must be two initial elevated samples, and the sample showing a 50% decrease must be confirmed by a fourth sample, thus four CA-125 levels are required. (2) A 75% response is considered to have occurred if there has been a serial decrease in serum CA-125 levels of more than 75% over three samples, thus three CA-125 levels are required. In both 50% and 75% response definitions, the final sample must be analyzed at least 28 days after the previous sample. Response definitions take into account natural variations in CA-125 levels and missing samples. An upper limit of normal for CA-125 of 30 U/mL and a lower limit of accuracy of 15 U/mL are used. Precise definitions use mathematical logic and have been incorporated into a computer program used in the analysis of this study ("Tumor Marker Evaluation," written using Microsoft Visual FoxPro in Windows 95 [Microsoft, Redmond, WA]; contact GJS Rustin). These response criteria will be referred to in the text as CA-125 criteria.

Response as determined by standard criteria was classified as complete response and partial response, stable disease, progressive disease, not measurable, or ineligible or not assessable. The standard response criteria were determined according to WHO criteria.² These response criteria will be referred to in the text as standard criteria.

Statistical Methods
The difference between the observed and expected number of responses and variance was calculated for each study using standard methodology (overview program available from W Gregory, 2 The Towers, Lower Mortlake Road, Richmond, Surrey TW9 2JR, UK). The odds ratio (OR), defined as the ratio of the odds of response according to CA-125 compared with standard response, was compared for each trial. The individual variances and observed and expected differences were combined to obtain a pooled odds ratio (POR) with confidence intervals (CI). Odds ratio and POR more than 1.00 indicates a higher CA-125 response rate than standard response rate. The results were expressed graphically, indicating the OR, CI (horizontal bar), and statistical information content (square on each bar reflects sample size) of each study. The POR and CI of the overview were expressed as a diamond at the bottom. The large square in the corner represents the overall information content of all trials. The Mantel-Haenszel ² test was used to test for heterogeneity in response rates among studies. If this test is statistically significant, this would suggest that the studies cannot be assumed to be random samples subject to the same underlying effect.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
CA-125 Predicts for Progression-Free Survival Among Patients With Stable Disease
Patients with stable disease as determined by standard criteria who are treated with platinum and who respond according to CA-125 criteria have an improved median progression-free survival compared with patients with stable disease who did not respond according to CA-125 criteria (10.6 v 4.8 months; P < .001; Fig 1). The former group can be considered responders to treatment using CA-125 criteria despite the absence of standard response because of their favorable clinical course. The improved median progression-free survival of 10.6 months does not differ significantly from the median progression-free survival of those patients who respond by standard and CA-125 criteria (10.6 v 12.2 months [standard] and 14.1 months [CA-125]; P = .29). The number of patients treated with paclitaxel in this study was too small for reliable statistical analysis; however, there was a trend toward improved progression-free survival (7.7 v 4.6 months; NS).

View larger version (14K): [in this window] [in a new window]   Fig 1. Progression-free survival of CA-125 responders versus CA-125 nonresponders in all patients with stable disease as determined by standard criteria. Progression-free survival data are available on 14 of 18 CA-125 responders and 27 of 29 nonresponders.

Standard and CA-125 Response Rates for Patients Treated With Platinum or Paclitaxel Are Equivalent
CA-125 criteria give response rates that are very similar to the standard response rates, not only for patients treated with platinum⁵ but also for patients treated with paclitaxel (Table 1). Overall, the CA-125 response was not significantly higher than the standard response rate (7%, SD ± 14%), with no significant difference among any of the six studies individually (Fig 2). A greater proportion of patients with epithelial ovarian cancer treated with platinum as first-line are assessable by CA-125 criteria (68.6%; 429 of 625 patients) than by standard criteria (35.8%; 224 of 625 patients). In contrast, a similar number of paclitaxel-treated patients (mostly second-line) are assessable by CA-125 criteria (83.3%; 120 of 144 patients) as by standard criteria (86.1%; 124 of 144 patients). This reflects the requirement for assessable disease, according to WHO criteria, for entry into second-line paclitaxel trials from which the majority of these data are taken (vide supra patients).

View larger version (17K): [in this window] [in a new window]   Fig 2. Odds ratio comparison of CA-125 and standard responses for six studies.

Standard and CA-125 Responders Demonstrate Improved Progression-Free Survival Compared With Nonresponders
Standard and CA-125 responders demonstrate improved progression-free survival compared with nonresponders for patients treated with platinum and with paclitaxel (Fig 3, data not shown for platinum but previously described⁵). Responders to paclitaxel have improved progression-free survival compared with nonresponders whether they are assessed using standard criteria (median progression-free survival, 6.8 v 2.5 months; P < .001; Fig 3A) or CA-125 criteria (median progression-free survival, 6.8 v 3.4 months, P < .001; Fig 3B). Sensitivity, specificity, and positive predictive value for response are equivalent for patients treated with platinum and paclitaxel (Table 2). These statistical rates are based on patients with stable disease as determined by standard criteria and a CA-125–determined response being classified as true positives (vide supra).

View larger version (27K): [in this window] [in a new window]   Fig 3. Progression-free survival of responders versus nonresponders as assessed by (A) standard criteria and (B) CA-125 criteria in patients treated with paclitaxel. (A) Progression-free survival data are available on 28 of 36 standard criteria responders and 76 of 77 nonresponders; (B) progression-free survival data are available on 27 of 36 CA-125 responders and 74 of 75 nonresponders.

False-Positive Rates for Platinum and Paclitaxel Are Similar and Low Using CA-125 as Response Criteria
A false-positive result reflects clinical disease progression despite a decreasing level of CA-125, which is suggestive of response. Tables 3 and 4 list false-positive CA-125 assessment rates of 2.2% (one of 45 patients) and 2.98% (two of 67) for patients treated with platinum and paclitaxel, respectively. Inspection of the case notes of the single false-positive patient treated with platinum (Table 3) revealed clear clinical progression on physical examination despite a decreasing level of CA-125. In the two false-positive patients treated with paclitaxel (Table 4), one patient was considered a responder by CA-125 only because of a single unusually high CA-125 level that may have been erroneous. This single value was 10 times that of a series of values recorded immediately preceding and after this high CA-125 level was recorded. The second patient had a new pleural effusion confirmed on chest X-ray after physical examination, despite a response according to CA-125 criteria. In summary, if CA-125 alone is used as a response criteria, 2% to 3% of patients would be managed as responders but would in fact have clinical progressive disease. These data are similar whether patients are treated with platinum or paclitaxel.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Assessing response according to CA-125 is cheaper and easier than performing serial CT scans, but it is crucial to determine whether using CA-125 criteria is as reliable as using standard criteria. This study addressed three questions with respect to CA-125 assessment: (1) the validity of using CA-125 assessment in clinical trials, (2) the validity of using CA-125 for assessing response to paclitaxel, and (3) the validity of using CA-125 assessment in individual patients.

There is no doubt from this study that response rates according to CA-125 are similar to standard response rates as previously described.⁵ This suggests that for evaluation of clinical trials, either method of response evaluation seems satisfactory. The data demonstrate statistically indistinguishable response rates, despite combining data from six different trials, first- and second-line trials, and trials using two different drugs. In addition to response, there was a remarkable similarity in the rates of false-positive and false-negative assessment between the two different treatments. The improved progression-free survival of patients with stable disease as determined by standard criteria and a CA-125–determined response compared with those without a CA-125–determined response argues for the management of these patients as responders. As described previously,⁵ CA-125 assessment is possible in two thirds of patients undergoing first-line treatment, whereas only one third of patients are assessable on CT scan. CA-125 criteria are therefore more widely applicable than standard criteria in both clinical trials and everyday practice. For patients undergoing second-line treatment, our data does not allow a valid analysis, as the trials studied all have an entry requirement of assessable disease as determined by WHO criteria.

Doubt has been cast about the reliability of CA-125 in monitoring response to paclitaxel. Eisenhauer et al,¹⁸ in studying 391 patients treated with paclitaxel as a second-line agent, defined CA-125 response as serial decreases in CA-125 levels and found that although 49% of patients demonstrated a CA-125 response, only one third of these patients responded as determined by standard criteria. These serial decreases in CA-125 levels were not defined according to the criteria used by our group,⁵ but when our criteria were used, the false-positive rate of CA-125–defined response from these data was reduced to 2.1% (data provided by Dr Eisenhauer, but not shown). Pearl et al¹⁹ studied the rate of CA-125 decrease by regression analysis in 66 patients. Patients with progressive disease had significantly lower rates of regression than did those patients with stable disease or response. Improved progression-free survival was found for responders if determined by standard criteria (P < .05) but not if determined by CA-125 regression curves, although the latter group just barely failed to reach significance (P = .0589). Davelaar et al²⁰ used as a response criterion the ratio between the CA-125 values before the first and after the fourth course of paclitaxel and analyzed 77 patients. There was a highly significant difference in survival between CA-125–defined responders and nonresponders, but no difference when WHO response criteria were used. This study also demonstrated significantly improved progression-free survival of CA-125 responders compared with nonresponders treated with paclitaxel. Davelaar et al²⁰ demonstrated similar improvements in progression-free survival using both CA-125 and standard criteria to evaluate response. These data further support the hypothesis proposed in our study that CA-125 criteria are as accurate as standard criteria in predicting response in patients treated with paclitaxel. The overall impression of these studies is that although not all authors found a statistically significant correlation between CA-125–defined response and efficacy, the use of precise definitions seemed to improve this correlation.

More controversial is the reliability of CA-125 in individual patient management. This study examines how many patients would have been mismanaged if CA-125 alone was used to assess response. CA-125 criteria may be unreliable in specific clinical situations such as coincidental paracentesis. This procedure can result in the decline in CA-125 levels due to the removal of antigen in the ascitic fluid and a reduction in nonspecific production of CA-125 by stimulated peritoneum. In addition, prior administration of murine antibodies invalidates CA-125 data, as the expected stimulation of antimurine antibodies will render all CA-125 kits using murine antibodies inaccurate.

We have shown that the false-positive rate is low (< 3%). Disease progression would have been missed in three patients; however, in two of these patients, progressive disease was evident on examination with confirmation of the findings by a simple chest X-ray in one instance. We conclude that in the context of a CA-125 response, sequential CT scans may not help in management and that CA-125 assessment with physical examination is sufficient, as suggested previously.²⁵ The high false-negative rate demonstrated in this study suggests that approximately one in five patients without CA-125 response are objective responders, and such patients may be undertreated if management was based on CA-125 alone. In this study, we were unable to identify any confounding variables that could explain the high false-negative rate.

The use of precise CA-125 progression criteria¹⁶ may help in making management decisions for individual patients. If failure to progress as defined by CA-125 progression criteria was used in addition to CA-125 response criteria, the potential for undertreating missed responses (false-negative patients as determined by CA-125 criteria) would be avoided. We were unable to formally analyze this, because CA-125 data were insufficient to fulfill our precise criteria for CA-125–defined progressive disease. However, in a separate study of 114 patients receiving paclitaxel, we found that CA-125 can accurately predict progression in patients treated with this drug.²⁶ Although these criteria were designed primarily for use in clinical trials, they may help to further define the use of CA-125 in individual patient management.

Assessing response by any criteria in ovarian cancer is notoriously difficult. It has been shown that standard response criteria are liable to error rates at least as high as those of CA-125.^27,28 Studies have shown that CT and ultrasound can give substantially different impressions of response in as many as 45% of patients and do not always alter patient management.²⁵ In a recent independent radiologic review of more than 400 patients with advanced ovarian cancer treated with topotecan, 31% of claimed responses were rejected, reducing the overall response rate from 24% to 16%.²⁹

In conclusion, we have shown that CA-125 criteria can be substituted for conventional criteria in clinical trials to assess response to treatment with platinum and paclitaxel, the two main drugs used in treating ovarian cancer. For individual patient management, in the context of a CA-125–defined response, CT scanning is unlikely to add to patient management, particularly if patients are carefully assessed by physical examination. For CA-125 nonresponders, one in five patients may be undertreated and CT scans may still be of value in management. The use of carefully validated CA-125–defined response and progression criteria may reduce the number of CT scans used in managing patients with epithelial ovarian cancer.

	ACKNOWLEDGMENTS

 
We thank Soeren Bensen for his help with statistics, in addition to all of the patients, clinicians, and biochemists, without whom this study would have been impossible.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Bast RC, Klug TL, St John E, et al: A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. N Engl J Med 309:883-887, 1983[Abstract]

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5. Rustin GJ, Nelstrop AE, McClean P, et al: Defining response of ovarian carcinoma to initial chemotherapy according to serum CA-125. J Clin Oncol 14:1545-1551, 1996[Abstract/Free Full Text]

6. Niloff JM, Knapp RC, Lavin PT, et al: The CA 125 assay as a predictor of clinical recurrence in epithelial ovarian cancer. Am J Obstet Gynecol 155:56-60, 1986[Medline]

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11. Ng LW, Homesley HD, Barrett RJ, et al: CA-125 values predictive of clinical response during second-line chemotherapy for epithelial ovarian cancer. Am J Clin Oncol 12:106-109, 1989[Medline]

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16. Rustin GJ, 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[Abstract/Free Full Text]

17. Rustin GJ, Nelstrop AE, Crawford M, et al: Phase II trial of oral altretamine for relapsed ovarian carcinoma: Evaluation of defining response by serum CA-125. J Clin Oncol 15:172-176, 1997[Abstract/Free Full Text]

18. Eisenhauer EA, ten Bokkel Huinink WW, Swenerton KD, et al: European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: High-dose versus low-dose and long versus short infusion. J Clin Oncol 12:2654-2666, 1994[Abstract/Free Full Text]

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26. Rustin G, Nelstrop A, Bolis G, et al: Use of CA-125 to assess activity of topotecan versus paclitaxel in relapsed ovarian carcinoma measured by response and early progression. Proc Am Soc Clin Oncol, 1997 (abstr 1256)

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Submitted September 8, 1998; accepted October 5, 1998.

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