CA 125 regression: A model for epithelial ovarian cancer response

Meyer et al.

ported a mild decrease in mean arterial pressure after PGE 2 administration for mid trimester pregnancy termination in patients with severe preeclampsia receiving antihypertensive agents. None of these patients had serious complications. The time interval between PGE 2 administration and the circulatory collapse and myocardial infarction in our patient would imply a relationship between these events. Preexisting coronary artery disease did not complicate this case. We propose that PGE 2 acted synergistically with the antihypertensive therapy to cause profound hypotension, resulting in coronary hypoperfusion and myocardial infarction. PGE 2 has a short biologic half-life, and the rapid recovery from cardiovascular shock observed in this case also is compatible with

August 1991 Am J Obstet Gynecol

a causal relationship. PGE 2 -induced coronary artery spasm seems unlikely because it has been shown to possess coronary artery relaxant effects." In any case PGE 2 should be used with caution in patients receiving vasoactive antihypertensive medications, especially when preexisting cardiac disease or risk factors are present.

REFERENCES 1. Sampson MB, ThomasonJL, Tomasi AM, Work BA. Pregnancy termination in patients with pregnancy-induced hypertension or eclampsia at less than 22 weeks' gestation. AM J OBSTET GYNECOL 1982;143:474-5. 2. Schror K, Berg-Becker M, Nookhwun C. The specificity of prostaglandin E2 (PGE2) in reducing coronary vascular resistance: a comparison with adenosine. Basic Res Cardiol 1978;73:287-97.

CA 125 regression: A model for epithelial ovarian cancer response Richard E. Buller, MD, PhD, Michael L. Berman, MD, Jeffrey D. Bloss, MD, Alberto Manetta, MD, and Philip J. DiSaia, MD Orange, California, and Iowa City, Iowa The rate of decline of CA 125 in effectively treated epithelial ovarian cancer is described by the exponential regression curve CA 125 = EXP [i - 8 (days after surgery)]. In this equation i, the y-axis intercept, measures initial tumor burden whereas 8, the slope of the regression curve, is determined by the extent of cytoreductive surgery and the subsequent response to chemotherapy. Departure from the regreSSion curve uniformly results in progressive disease. In patients whose cancers had been completely removed, we calculated the mean half-life of CA 125 to be 10.4 days (range 4 to 21). In this case 8 = 0.0835 and characterizes the ideal regression rate. The model predicts that high-dose cisplatin chemotherapy (8 = 0.0671) is more effective than low-dose cisplatin (8 = 0.0380) (p < 0.03) in eliminating residual cancer. Because 8 can be calculated within 2 to 3 months of treatment and then compared with 8 for the ideal regression curve and with the values of 8 reported for standard chemotherapy, evaluation of any new treatment protocol can be facilitated with this method. (AM J OSSTET GYNECOL 1991 ;165:360-7.)

Key words: CA 125, exponential regression, chemotherapy Ovarian carcinoma is the fourth most common cause of death among American women. 1 Aggressive surgical From the Division of Gynecologic Oncology, Departments of Obstetrics and Gynecology, University of California, Irvine, Medical Center, and the Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The University of Iowa. Received for publication February 15, 1991 .. accepted February 27, 1991. Reprint requests: Richard E. Buller, MD, PhD, The University of Iowa, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Iowa City, IA 52242. 6/112921J

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cytoreduction and subsequent cisplatin-based chemotherapy have helped prolong disease-free survival for women with advanced disease. 1.2 Our ability to monitor disease status during therapy has been facilitated by measurement of the tumor-associated antigen CA 125. Bast et al.' and others4 • 5 have shown that changes in serum CA 125 levels reflect progression or regression of epithelial ovarian cancer >90% of the time. That is to say, increases in serum CA 125 levels reflect disease progression whereas declines in serum CA 125 levels reflect a response to therapy. Thus by monitoring CA

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125 levels during treatment, it has been possible to predict response to therapy in the absence of clinically measurable disease and to prognosticate survival. 6 - 1o Most clinical trials still rely on second-assessment celiotomy to determine the initial effectiveness of chemotherapy because survival data, which are the only realistic end point of treatment efficacy, can take years to generate. Simply measuring serum CA 125 levels before second-assessment celiotomy is not helpful because the negative predictive value in a patient with stage III or stage IV epithelial ovarian cancer is only 50%.11 Reliance on second-assessment celiotomy is costly. Awaiting accrual of survival data can be inefficient. Such an approach may result in missed opportunities to initiate phase II drug studies in women with a small tumor burden before depletion of marrow reserves. This study was designed to develop a model of tumor response by considering the serum CA 125 level as a continuous variable that is reflective of tumor growth or regression for those epithelial ovarian cancers that are marker positive. As the model was developed, we used it to characterize the initial clinical responsiveness of CA 125-secreting epithelial ovarian cancers. The model can be used to compare the relative efficacy of different therapeutic regimens. In a separate communication we will show how initial responsiveness is predictive of findings at second-look celiotomy and translates into overall survival.

Material and methods Sixty-four patients with advanced ovarian epithelial carcinoma who were treated at the University of California, Irvine (DCI), or its affiliated hospitals, beginning in January 1986 through June 1990, form the population of this study. Women treated during this time interval who were marker negative or who did not have sequential measurements of serum CA 125 levels beginning early in therapy could not be evaluated. Patient characteristics and follow-up are summarized in Table 1. The average age at diagnosis was 62.6 years (range 43 to 80). Eighty-four percent of patients in this study had stage III or stage IV disease. Ninety-four percent of the lesions were grade 2 or 3. We also included two patients with dual primary endometrial and ovarian lesions that were confined to the pelvis and were CA 125 positive. All histologic types of epithelial ovarian cancer were included. Seventeen patients died of progressive or recurrent ovarian carcinoma during the study interval. Three patients died apparently of causes other than tumor recurrence 6.7, 6.8, and 35.9 months into therapy without evidence of disease. The mean follow-up for all patients was 15.6 months (range 2 to 48). Treatment consisted of biopsy only for seven patients, all operated on at outside facilities and referred

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Table I. Background data (64 patients) Age at diagnosis (yr, mean and range) Followup (days, mean and range) Deaths From cancer Other, without cancer FIGO stage IIA, lIB , lIC IlIA, IIlB, mc IV Unknown Dual primary Grade 1

2

3 Histologic type Serous Clear cell Endometrioid Undifferentiated

62.6 (43-80) 468 (60-1445) 17 3 6 42 12

2 2

4 21 39

41 2

4 17

to UCI for chemotherapy. In 13 patients cancer was completely resected whereas 26 underwent cytoreduction to residual cancer >2 em and 18 had residual disease <2 cm. All patients were treated with cisplatinbased chemotherapy. The chemotherapy regimens planned were as follows: CAP [cisplatin, approximately 50 mg/m2; doxorubicin (Adriamycin, Adria, Columbus, Ohio), approximately 50 mg/m2; and cyclophosphamide (Cytoxan, Bristol-Myers, Syracuse, N.Y.), approximately 50 mg/m2] in eight patients for eight cycles; low-dose cisplatin, approximately 50 mg/m2, and Cytoxan, approximately 500 mg/m2) in 30 patients for eight cycles; high-dose cisplatin approximately 100 mg/m2, and Cytoxan, approximately 1000 mg/m2, in 21 patients for four cycles. Other treatments included cisplatin, approximately 75 mg/m2, and primary intraperitoneal cisplatin or carboplatin plus intravenous Cytoxan or Adriamycin, or both, for five patients. Twentythree of the patients included in the study were randomized to treatment regimens on a Gynecologic Oncology Group protocol designed to compare high-dose and low-dose cisplatin chemotherapy. Four patients, two on the low-dose cisplatin regimen and two on CAP, did not complete the planned chemotherapy because of progression of disease. Statistical evaluations included least-squares regression analysis of CA 125 data as a function of time. Comparison of means was achieved by the unpaired Student t test requiring p < 0.05 for statistical significance. When categorical variables were analyzed, we used X2 with Yates' correction as indicated.

Model development Levels of CA 125 were plotted against time with the day of surgical cytoreduction recorded as time O. If a

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Table II. Model development p

Condition

r

Linear Preoperative*-first normalt Preoperative-no normal:!: Pretreatment-first normal Pretreatment§-no normal

-0.86 -0.91 -0.87 -0.93

0.030 0.031 0.058 0.065

Exponential Preoperative*-first normalt Preoperative-no normal:!: Pretreatment§ - first normal Pretreatment-no normal

-0.98 -0.97 -0.97 -0.96

0.0009 0.0052 0.0072 0.0345

6460 7243 4692 5561 9.090 9.288 9.067 9.427

128 190 90 138 0.1000 0.1155 0.0995 0.1198

*Includes a preoperative CA 125 level in the regression analysis. tlndudes all postoperative CA 125 levels up to and including the first level <35 U1m!. :!:Includes all postoperative levels of CA 125 up to, but excluding, the first level <35 U I m!. §The first data point is postoperative in this analysis.

patient underwent biopsy only, with the vast majority of tumor left in situ, time 0 was the first day of chemotherapy. CA 125 levels in serum drawn preoperatively were assigned to day 0 in the absence of serum drawn on the day of surgery. Thirty-two patients had preoperative CA 125 levels measured. For the rest the first determination was after surgery and before the first dose of chemotherapy, which was begun on mean postoperative day 19 (range 4 to 42). We performed regression analysis of the data to evaluate both linear and exponential decay patterns. Most patients did not have CA 125 levels measured every few days after the initiation of therapy. Therefore we tested the effects of omitting some data points in a known setting where complete CA 125 data were available. The four possible combinations evaluated were: (1) preoperative CA 125 available, with data plotted to include all postoperative levels up to and including the first normal CA 125 level, :535 U Iml; (2) preoperative CA 125 level and only elevated postoperative CA 125 levels (>35 U Iml); (3) postoperative CA 125 levels only, to the first normal level; (4) only elevated postoperative CA 125 levels. The results of this analysis for a typical patient are shown in Table II. The models tested were: Serum CA 125 level = i - s (days after surgery) (linear regression) [1] Serum CA 125 level = EXP(i - s [days after surgery]) (exponential regression) [2] where EXP = 2.718, i is the y-axis intercept, which reflects initial tumor burden of CA 125-secreting cells, and s is the slope of the regression curve, which is representative of the rate of disappearance of CA 125 from the serum. This rate reflects the composite effects of surgical cytoreduction and effective chemotherapy. When data are plotted, it is more convenient first to perform a natural logarithmic transformation on equation 2, which gives equation 3:

In (serum CA 125) = i - s (days after surgery) [3] Equations 2 and 3 are mathematically equivalent. Table II shows that for each set of data the correlation coefficient r is the highest for the exponential model. When r approaches 1.0, a linear relationship exists; the lower the r value, the looser the relationship. When an analysis of variance of the regression curve is carried out as determined by the F ratio test, the exponential model gives p values with a higher significance than the corresponding linear model. In each case the best-fit, lowest p value is represented by the data where preoperative levels of CA 125 are included in an analysis that proceeds through the first normal level of CA 125 (r = 0.98, P < 0.0009). However, by virtue of the high r and low p values for each of the four combinations of data points, we conclude that the exponential model can be used to approximate sand i even if we are unsure of the preoperative level of CA 125 or precisely when the CA 125 level normalized. The CA 125 regression curve for a typical patient who responds completely to therapy is represented by the solid line in Fig. 1. In this case r = - 0.98 and p < 0.0009. This plot results in a straight line. When the combination of surgery and chemotherapy is ineffective, as for the patient whose CA 125 data is plotted as the dashed line in Fig. 1, r = - 0.09 implies a poor fit of the model. The F ratio approaches 0 and p is much greater than 0.05 (p = 0.86) for the best-fit regression line. This analysis was carried out for all of the 64 patients. It was possible to calculate s within 30 to 60 days of surgery. In 12 patients serum CA 125 levels never normalized, and clinical progression of disease occurred. For these patients a regression curve that used all data points up to the first increase in serum CA 125 was generated. The mean number of data points for all patients was 4.5 (range 2 to 10). For 54 patients, three or more measurements of CA 125 were available. For 10 patients only two data points were

CA 125 regression

Volume 165 Number 2

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available. If these patients are excluded, the mean r value for the regression curves was - 0.94 indicating that the data fit the model quite well. Tumor grade, tumor stage (according to International Federation of Gynecology and Obstetrics), and the extent of cytoreductive surgery are several parameters that can influence survival of the patient with ovarian cancer. To develop our model more completely, we investigated the influence of these factors on the regression parameters i and s. These data appear as Table Ill. Residual disease. Residual disease was quantitated as none, largest nodule >2 em, or in between these two parameters. Patients whose tumor was not resected were distinguished from the groups with residual disease and analyzed separately. The values of sand i were calculated for these data, which were stratified on the basis of residual disease, and are presented in Table Ill. This table shows the trend for more rapid regression of CA 125 as the volume of residual disease decreases from the biopsy-only cases where s is 0.0331 to a value of 0.0835 for the cases with no residual disease. The difference between the two extreme values of s is significant at a p level of 0.015 . The difference between the rate of regression for biopsy-only cases and residual disease of <2 em is also significant (p < 0.015). No other pairwise comparisons of s reached significance. The values of i reflect the initial tumor burden. The i values were not statistically different between groups. The group of patients from Table III who underwent complete resection of ovarian cancer also provides us with the data necessary to calculate the serum half-life of CA 125. When this group of patients is considered as a whole, the mean serum half-life of CA 125 is calculated to be 10.8 ± 5.5 days (range 4 to 21 days). Stage of disease. Clinical experience dictates that tu-

Table III. Factors influencing regression parameters i and s s

Factor

Residual disease None < 2cm :22cm AIl* FIGO stage II III IV

Tumor grade 1 2 3

(mean ± SD)

13 18 26 7

0.0835 0.0471 0.0526 0.0331

8 44 12

0 0. 814 ± 0.0469 5.996 ± 0.725 0.0533 ± 0.0451 6.936 ± 1.693 0.0446 ± 0.0295 7.636 ± 1.912

4 21 39

0.0275 ± 0.0077 5.788 ± 0.808 0.0561 ± 0.0436 7.423 ± 1.397 0.0576 ± 0.0452 6.814 ± 1.837

± ± ± ±

0.0473 0.0313 0.0486 0.0165

i (mean ± SD)

6.566 6.494 7.343 7.373

± 1.956

± 1.629

± 1.411 ± 2.171

*Laparotomy performed with biopsy; cytoreductive surgery not done.

mor burden generally increases with the stage of disease. We tested our model on this point by stratifying patients on the basis of FIGO stage and generated values for i and s. These data are also shown in Table Ill. The y-axis intercepts, which are reflective of the initial tumor burden, increased from 5.996 to 6.936 to 7.636 as stage advanced from II to III to IV. Only the difference in i for stages II and IV reached statistical significance (p < 0.04). When the values of s were compared pairwise between stages, again only the difference between stage II and stage IV was significant (P < 0.05). This result is consistent with the fact that all of the patients with stage II had no residual disease, while the patients with stage IV usually had bulky residual disease. Tumor grade. Table III shows the results of application of the model when the patients were stratified

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Table IV. Clinical correlation of regression parameters i and 5 s (mean ± SD)

Clinical course

Progression Recurrence Disease-free

13 31 20

z (mean ± SD)

0.0250 ± 0.0240 7.3148 ± 1.594 0.0497 ± 0.0326 6.7097 ± 1.504 0.0783 ± 0.0475 7.0837 ± 2.024

Table V. Chemotherapy effects s

Regimen

CAP Low-dose cisplatin High-dose cisplatin

(mean ± SD)

6 25 17

z

(mean ± SD)

0.0320 ± 0.0186 6.826 ± 2.439 0.0380 ± 0.0276 6.542 ± 1.215 0.0671 ± 0.0549 7.888 ± 1.546

on the basis of tumor grade. There was a trend toward more rapid response by the more undifferentiated tumors: The value of 5 increased with increasing grade. The difference in tumor burden was significant only when grade 1 tumors were compared with grade 2 tumors (p < 0.03). Clinical correlation. The clinical relevance of the parameters 5 and i was determined by grouping the patients according to their response to therapy. Three broad classifications were used: (1) progressive disease during chemotherapy, (2) complete response to therapy on the basis of clinical evaluation and normalization of the serum CA 125 level, followed by recurrence of cancer, and (3) a complete response to therapy with no current evidence of cancer. The mean values of 5 and i were calculated for these groupings and are displayed in Table IV. This table shows that the tumor burden, as reflected by i, was the same for all groups (p > 0.24). On the other hand, there was a steady increase in the rate of decline of the serum CA 125 level, from those with progressive disease (5 = 0.0250), to those who responded then had recurrence (5 = 0.0497), to those who remain without disease (5 = 0.0783). All pairwise comparisons of 5 were statistically significant (p < 0.02). Thus the more rapid the decline in serum CA 125 level, as measured by 5, the greater the likelihood of clinical response and cure. Chemotherapeutic regimen. Finally, we investigated the effects of different chemotherapy regimens. Values of 5 and i were calculated on the basis of our exponential model. These results appear in Table V. Table V shows that the patients in the high-dose cisplatin group had a higher value of i (p < 0.04) only when compared with the value of i for the low-dose cisplatin-treated group. Other pairwise comparisons, e.g., high versus CAP (P = 0.23), and low versus CAP (p = 0.68), were not

significant. Evaluation of treatment response, as measured by the value of 5, showed a significant difference for high-dose cisplatin chemotherapy compared with low-dose cisplatin (p < 0.03) but not the CAP regimen (p = 0.14). Similarly, there was no difference between the CAP regimen when compared with the low-dose cisplatin regimen (p = 0.62). For the purpose of these analyses, patients who had complete cytoreduction were removed to prevent bias. The ideal CA 125 regression curve is generated by monitoring serum levels after complete resection of cancer. For any chemotherapeutic regimen designed, comparison of the rate of CA 125 regression relative to the ideal regression curve provides a measure of its relative effectiveness. The more effective the treatment, the closer the regression line comes to the ideal. Fig. 2 illustrates this point. This figure results from plotting the mean regression curves, which have been normalized for the same tumor burden (i), for complete resection, high-dose cisplatin therapy for residual disease, and low-dose cisplatin therapy for residual disease. When high-dose cis platinum therapy is used, CA 125 regression approaches that seen for the patient with complete cytoreduction; this value is statistically different from that of low-dose cisplatin therapy (p < 0.03). These data also justify the omission from analysis of patients whose cancers are completely resected when types of chemotherapy are compared. For those patients 5 approaches the ideal regression curve by virtue of the surgery alone, so that there can be no difference on the basis of chemotherapy over the short term. Contingency tables were constructed to evaluate the possible influence of tumor grade, extent of residual disease, or FICO stage. Table VI shows the distribution of covariables for the different chemotherapies. In each instance the calculated value of X2 was low and not statistically significant. Thus the different chemotherapy groups were homogeneous from the standpoint of those variables that could have introduced bias. There was a statistically different mean age between chemotherapy groups. Patients treated with the highdose cisplatin regimen were slightly younger (mean 59 years) than the group treated with the low-dose cisplatin (mean 66 years) (p = 0.006). There was no age difference between the high-dose cisplatin group and the CAP chemotherapy group (p = 0.25).

Comment Most authors" 5. 8. 12. 13 agree (1) that for CA 125positive tumors the level of CA 125 reflects tumor burden and (2) that for a given individual the change in CA 125 level accurately reflects disease status. These observations hold true even when there is no radiologic or physical evidence of residual disease after cytore-

CA 125 regression

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365

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60

80

Fig. 2. Cisplatin dose-response curve. Comparison of rate of decline in serum CA 125 levels for patients with residual disease treated with low-dose cisplatin-Cytoxan (0--0) or high-dose cisplatinCytoxan (x--x) to ideal regression curve (L;--L;) generated from patients with no residual disease. LN (35) = 3.56, which is considered the normal level of CA 125. LN, Natural logarithm.

ductive surgery. That is to say, a rising CA 125 level correlates well with disease progression and a falling CA 125 level accurately reflects the combined effects of surgery and or effective chemotherapy. This formula provides a model to measure the rate of change of serum CA 125 level as a function of initial tumor burden and subsequent response to treatment: Serum CA 125 level = EXP(i - s (days after surgery]) The value of s can be calculated within 30 to 60 days of initial surgery for the patient who is started promptly on a regimen of chemotherapy. The value of s reflects the composite effects of surgery and effective chemotherapy. For most patients it is not possible to separately quantitate the relative effects of surgery alone versus those of chemotherapy alone. However, we can approximate these relative effects with the use of data that have been stratified on the basis of residual disease from Table III. The seven patients who had biopsy only and did not undergo cytoreductive surgery are essentially a group treated by primary chemotherapy. The 13 patients who had no residual disease after surgery are our closest approximation to surgery alone even though they also received chemotherapy. The difference in s between these groups was significant at the p < 0.02 level, which indicates that cytoreductive surgery is more effective than chemotherapy in producing an initial therapeutic response. This result lends support to the approach of most gynecologic oncologists, who reoperate on patients with ovarian cancer who are referred after an open-and-close operation at an outside institution. lU 7 The mean serum half-life of 10.8 days that we report is larger than the 4.8-day half-life reported by Canney

Table VI. Stratification of covariables between modes of chemotherapy Chemotherapy Covariable

Residual disease None <2 em :2:2 em All FIGO stage II III

IV Grade I

2 3

Age of patients (yr, mean ± SD)

High-dose cisplatin

CAP

2 1 1 4

5 10 14

I

5 20 5

2 14 5

2 10 18 66 ± 9

8 12 61 ± 10

6 I

I

3 4 59 ± 7

I

4 4 12 I

I

et a1.,4 who used data from a single patient with completely resected early disease to determine half-life. The difference is explained by the fact that our data base included patients with stage III and IV disease who undoubtedly had residual microscopic foci of cancer that were favorably influenced by chemotherapy. The half-life of CA 125 in other patients also was as short as 4 days even though they had residual macroscopic disease. In these cases the residual disease was either extremely sensitive to chemotherapy or not responsible for secreting CA 125 into the serum. Thus we prefer to report the mean serum half-life and to use it, rather than the minimum half-life value of 4 days, to calculate the ideal regression curve. Most patients did not have CA 125 levels measured

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every few days after the initiation of therapy. Before this retrospective study, our standard was to check CA 125 levels immediately before each cycle of chemotherapy. Careful evaluation of the data in Table II indicates that the unavailability of data points from the preoperative time inclusively through normalization of the CA 125 levels does not seriously affect our calculated values of sand i. For the incomplete data sets, the model was still useful since the r values ranged from - 0.98 to - 0.96 and p ranged from 0.0009 to 0.03345. Our standard now is to measure serum CA 125 before surgery, several days after surgery, on the first day of chemotherapy, and weekly during the initial 6 weeks of chemotherapy to try to refine calculated values of s. The principle of generating a regression curve is not new. Schlaerth et aL l s applied this concept to gestational trophoblastic neoplasia in 1981, thereby identifying patients who would require chemotherapy on the basis of departure from the normal regression curve of 13human chorionic gonadotropin. Our study characterizes regression curves for the coelomic epithelial antigen CA 125 in epithelial ovarian cancers and also suggests that clinical outcome can be predicted reliably on the basis of these curves. By logical extension, regression curves that use other tumor markers such as NBI70K, CA 19-9, lipid-associated sialic acid, etc., could be described similarly for those tumors that elaborate these tumor-associated antigens. Furthermore, we suggest that these regression curves or a multivariate regression curve for a spectrum of tumor-associated antigens might predict clinical outcome even more precisely. Studies have shown that ovarian epithelial carcinomas have heterogeneous immunohistochemical staining properties for CA 125. 13 We do not have evidence at this time that the chemotherapeutic response of the CA 125-secreting cells is the same as that of those that do not secrete CA 125. If our model is to accurately describe effective treatment of epithelial ovarian cancer, this factor forms a critical assumption. Further justification of this assumption can be generated by studying simultaneous markers, which are secreted by different cell types, as well as by using second-assessment celiotomy and disease-free survival as additional end points. These analyses will form the basis of a subsequent report. Our model also assumes that there is a relationship between the amount of residual tumor after cytoreductive surgery and the serum CA 125 level. It is true that ascites 19 and other confounding variables such as tumor grade, histologic type, and heterogeneity may influence the serum level of CA 125; however, these parameters will be constant for a given patient. When mean pooled values of s for different treatment regimens are compared, it is thus critical to have enough het~rogeneity between cohorts so that one covariable does not skew interpretation of the data.

August 1991 Am J Obstet Gynecol

Within biologic systems, dose-response curves generally are sigmoidal in shape. 2o In humans, it is unclear whether treatment with 50,75 , o r ~100 mg/m2 of cisplatin per cycle reaches the plateau region of a typical dose-response curve or merely moves along the linear region of the curve. Ozols et aJ.21 and others"·2. have inferential evidence that taking cisplatin doses to toxic levels may favorably affect survival. When traditional methods of survival analysis are used, the studies necessary to prove this point may t ake years to mature. The model we have developed provides an eloquently simple means of addressing such clinically relevant issues in a timely fashion. We suggest that various treatment regimens be compared on the basis of the value of s relative to the ideal regression curve, as we have done by comparing low-dose cisplatin chemotherapy with high-dose cisplatin chemotherapy in Fig. 2. While our study groups were homogeneous with regard to surgical stage, grade, and extent of resection, there was a statistically younger patient population treated with the high-dose cisplatin regimen than with the low-dose regimen. Even though 36% of our patients were treated on a randomized basis, there was probably a tendency to treat the older patients whose treatment was not randomly assigned with a "less toxic regimen" in the 1986 to 1988 era. In general, there is agreater tendency for recurrence of disease in older patients 25 so that there could be an age bias influence of our results. On the other hand, there was also a statistically larger tumor burden (p < 0.04) for the high-dose regimen than for the low-dose regimen. Thus, since these are potentially offsetting influences, we must have additional patient accrual to solidify the evidence that the high-dose cisplatin regimen is more effective than the low-dose regimen. In conclusion, the decline in serum CA 125 levels in patients with effectively. trea ted epithelial ovarian cancer follows an exponential regression. These regression curves may be used to generate in vivo dose-response curves and to compare chemotherapeutic regimens. Strong divergence from the ideal regression curve uniformly results in treatment failure. Divergence can be determined within 30 to 60 days of initial surgery. When it occurs, we must begin trials of alternative chemotherapy that is designed to overcome drug resistance earlier than has been the case traditionally. The time has come to utilize the full weight of CA 125 data to make treatment decisions rather than to wait for the findings at second look or the rea ppearance of bulky disease. REFERENCES 1. DiSaia Pj, Creasman WT, eds. Clinical gynecologic oncology, 3rd ed. St. Louis: CV Mosby, 1989:325-416. 2. Ozols RF. Chemotherapy of ovarian cancer. In: DeVita VT, Hellman S, Rosenberg SA, eds. Updates to principles and practice of oncology. Philadelphia : jB Lippincott, 19RR vol

<). I _ 1 <)

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3. 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] Med 1983;309:883-7. 4. Canney PA, Moore M, Wilkinson PM,]ames RD. Ovarian cancer antigen CA 125: a prospective clinical assessment of its role as a tumour marker. Br ] Cancer 1984;50: 765-9. 5. Vergote IB, Bormer OP, Abeler VM. Evaluation of serum CA 125 levels in the monitoring of ovarian cancer. AM] OBSTET GYNECOL 1987;157:88-92. 6. Lavin PT, Knapp RC, Malkasian G, Whitney CW, Berek ]C, Bast RC. CA 125 for the monitoring of ovarian carcinoma during primary therapy. Obstet Gynecol 1987;69:223-7. 7. Niloff ]M, Knapp RC, Lavin PT, et al. The CA 125 assay as a predictor of clinical recurrence in epithelial ovarian cancer. AM] OBSTET GYNECOL 1986;155:56-60. 8. Kivinen S, Kuoppala T, Leppilampi M, Vuori], Kauppila A. Tumor-associated antigen CA 125 before and during the treatment of ovarian carcinoma. Obstet Gynecol 1986;67:468-72. 9. Mogensen 0, Mogensen B, Jakobsen A. Predictive value of CA 125 during early chemotherapy of advanced ovarian cancer. Gynecol Oncol 1990;37:44-6. 10. VanDerBurg MEL, Lammes FB, VanPutten WL], Stoter G. Ovarian cancer: the prognostic value ofthe serum halflife of CA 125 during induction chemotherapy. Gynecol Oncol 1988;30:307-12. 11. Rubin SC, Hoskins W], Hakes TB, et al. Serum CA 125 levels and surgical findings in patients undergoing secondary operations for epithelial ovarian cancer. AM] OBSTET GYNECOL 1989;160:667-71. 12. Zanaboni F, Vergadoro F, Presti M, Gallotti P, Lombardi F, Bolis G. Tumor antigen CA 125 as a marker of ovarian epithelial carcinoma. Gynecol Oncol 1987;28:61-7. 13. Maughan TS, Fish RG, Shelley M,]asani B, Williams GT, Adams M. Antigen CA 125 in tumor tissue and serum from patients with adenocarcinoma of the ovary. Gynecol Oncol 1988;30:342-6. 14. Hacker NF, Berek]S, Lagasse LD, Nieberg RK, Elashoff

15. 16.

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18.

19. 20. 21. 22.

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