The use of serial CA 125 concentrations to monitor endometriosis in infertile women

Johnson, Egerman, and Moorhead

amniotic fluid volume in patients receiving parenteral tocolysis after premature rupture of the membranes. AM] OBSTET GVNECOL 1989;161:784-7. 7. Amon E, Lewis SV, Sibai BM, Villar MA, Arheart KL. Ampicillin prophylaxis in preterm premature rupture of the membranes: a prospective randomized study. AM] OBSTET GVNECOL 1988;159:539-43.

DR. FRANK GREISS, Mooresville, North Carolina. When did you do the analysis of the amniotic fluid volume? Did you do it immediately or later? DR. JOHNSON (Closing). I agree with Dr. Carter that it would be interesting to have a better idea about the

September 1990 Am J Obstet Gyneco1

nutritional status of these patients, since that characteristic could have some bearing on the tendency to reseal. About the only way to achieve this is to look at body habitus and the weight distribution to the height of the patient, although that is certainly a very inaccurate measure of nutritional status. The fact that anemia did not seem to be more common in either population seems also a crude indication that their nutritional status was comparable. In answer to Dr. Greiss' question, in general the amniotic fluid volume estimates were done shortly after the diagnosis of rupture of the membranes and certainly within 1 to 2 days after admIssIon.

The use of serial CA 125 concentrations to monitor endometriosis in infertile women Donald E. Pittaway, MD, PhD Winston-Salem, North Carolina To evaluate the potential use of CA 125 concentrations in monitoring women with endometriosis, serial determinations were correlated with the clinical course of the disease and pregnancy rates. Preoperative CA 125 concentrations were obtained in 134 consecutive infertile women with endometriosis. Seventy-Six (57%) women had values ~16 U/ml and were followed up for 18 months. At the 6-, 12-, and 18-month intervals, pregnancies occurred in 18 of 45 (30%), 14 of 24 (58%), and 5 of 12 (42%) women in the good prognosis group, respectively; pregnancy rates in the poor prognosis group were 1 of 31 (3%),2 of 33 (6%), and 0 of 26 (0%) women (p < 0.001). Changes in the CA 125 values correlated with the surgical findings in 24 of the 26 women (92%) who had a second-look operative procedure. The study supports the use of serial CA 125 concentrations to assist in the management of women with endometriosis. (AM J OesTET GVNECOL 1990;163:1032-7.)

Key words: CA 125, endometriosis, infertility Endometriosis frequently persists or recurs after treatment,'·3 and often cannot be detected or differentiated by pelvic examination from postsurgical changes. Also, occult foci may be missed even at laparoscopy or laparotomy and result in incomplete surgical removal or destruction of the endometriosis.' Consequently, endometriosis often presents a difficult diagnostic and therapeutic challenge to the clinician. Recently, elevations of CA 125, a serum marker for From the Section on Reproductive Endocrinology, Department ofObstetrics and Gynecology, Bowman Gray School of Medicine. Presented as Official Guest at the Fifty-second Annual Meeting of the South Atlantic Association of Obstetricians and Gynecologists, Palm Beach, Florida, January 28-31, 1990. Reprint requests: Donald E. Piuaway, MD, PhD, Section on Reproductive Endocrinology, Department of Obstetrics and Gynecology, Bowman Gray School of Medicine, 300 S. Hawthorne Road, Winston-Salem, NC 27103.

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human epithelial ovarian cancer, have been observed in women with endometriosis. 5.' In addition, the serum concentrations of CA 125 have been observed to correlate with the clinical stage and the clinical course of the disease," 8 and an earlier study has suggested that the changes of CA 125 may have predictive value for pregnancy.9 Consequently, this prospective study was undertaken to evaluate further the usefulness of serial determinations in monitoring infertile women after the diagnosis and surgical treatment of endometriosis.

Material and methods Preoperative CA 125 concentrations were obtained in 134 consecutive infertile women with endometriosis from whom informed consent had been obtained. Seventy-six (57%) women had values ~16 Vlml (which is considered elevated in our laboratory), and were followed up for 18 months. Twenty-six of 41 women who

Volume 163 Number 3

had not conceived underwent a second operative procedure between 12 to 18 months (19 conservative and seven hysterectomy). The characteristics of the initial study population and the subgroup with elevated CA 125 concentrations are listed in Table 1. Preoperative evaluation of the couples included semen analysis, postcoital testing, hysterosalpingography, and endometrial biopsy specimen. The surgical treatment of endometriosis was performed by the author and individualized to either operative laparoscopy with electrocoagulation and/or carbon dioxide laser, or conservative laparotomy. The severity of the endometriosis was staged according to the revised American Fertility Society classification. ' °In women with endometriomata, danazol (800 mg/day) was administered for 3 months after surgery. Two patients required donor insemination for a significant male factor, and eight received clomiphene citrate to correct either oligoovulation (five women) or luteal inadequacy (three women). CA 125 was measured in duplicate with an immunoradiometric assay (Centocor, Malvern, Pa.), which has been modified for use in women with endometriosis, and previously described in detail." The CA 125 levels were not used to influence management decisions, and were evaluated at the completion of the study. The women were considered as having a good prognosis if the postoperative CA 125 concentrations decreased by at least 40% to levels < 16 U I ml. Women whose CA 125 concentrations failed to meet these criteria initially or whose levels later increased to ~ 16 U I ml, suggesting recurrence, were placed in a poor prognostic group. The data were evaluated with a X2 analysis with Yates' correction, and Fisher's exact test. Correlation of the changes in CA 125 values with the clinical course were analyzed with the use of the K test. 12 A Pvalue < 0.05 was considered statistically significant. Results

In Figs. 1 and 2 are shown the flow charts for the 45 women in the intial good prognostic group and the 31 women in the initial poor prognostic group, respectively. The number of women in each prognostic group and the number of women who achieved pregnancy are indicated at 6-month intervals. The combined pregnancy rates at the 6-, 12-, and 18-month intervals were 19 of 76 (25%), 16 of 57 (28%), and 5 of 38 (13%) women. During the same time intervals, pregnancies occurred in 18 of 45 (30%), 14 of 24 (58%), and 5 of 12 (42%) women in the good prognostic group, and in 1 of 31 (3%), 2 of 23 (6%), and 0 of 26 (0%) women in the poor prognostic group (p < 0.001). The pregnancy rates at 12 months are listed in Table II, according to the stage of endometriosis at the initial procedure. Overall, the pregnancy rates were significantly higher

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Table I. Characteristics of study population with endometrium Initial group (n = 134) Patient characteristics

Age (yr)

<26 26-29 30-35 >35

Infertility Primary Secondary Duration of infertility (mo)

12-23 24-59 >59

Stage of endometriosis* Minimal Mild Moderate Severe

I

Elevated CA 125 (n = 76)

I

%

No.

9 50 59 16

7 37 44 12

4 30 30 12

5 39 39 16

95 39

71 29

60 16

79 21

35 74 25

26 55 19

20 41 15

26 54 20

18 35 55 26

13 26 41 19

5 14 31 26

7 18 41 34

No.

%

*Revised American Fertility Society classification. 10

in the good prognostic group (p < 0.001), and this difference achieved statistical significance in both the moderate (p < 0.001) and severe (p < 0.02) stages of endometriosis. The surgical findings in 24 of 26 women (92%) who had a second-look procedure correlated with the changes in the CA 125 values (p < 0.001). Endometriosis was found in 23 women, and the two women in whom the values did not correlate had mild disease that was not suggested by values of CA 125, which were < 16 U/ml. Comment

This study confirms and extends the observations in 100 infertile women with endometriosis who were followed up for 1 year." In this earlier investigation, women with elevated preoperative CA 125 concentrations had significantly lower pregnancy rates (45%) than those of women with nonelevated levels (63%). The changes in CA 125 levels had no predictive value in women with nonelevated preoperative concentrations. However, the pregnancy rates were significantly lower in women with elevated preoperative levels whose CA 125 concentrations failed to decrease as compared with the pregnancy rates of women whose concentration decreased. For this reason, a group of women with elevated preoperative CA 125 levels were selected to be followed up until pregnancy occurred or up to 18 months after treatment. In this study, the predictive value of the changes in the pre- and postoperative CA 125 concentrations was again observed, but in addition,

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Pittaway

September 1990 Am J Obstet Gyneco1

45 Women

I

6 Months

27 Not pregnant

18 Pregnant

I

i

Good prognosis

Poor prognosis

24

3

I

I

10 Not pregnant

14 Pregnant

12 Months

3 Not pregnant

12 (1 Lost to follow-up)

I

i

Good prognosis 7

I

i

18 Months

Poor prognosis

3 Pregnant

r

5 Not pregnant

4 Not pregnant

Fig. 1. Flow chart for the initial good prognostic group

31 Women

I

6 Months

30 Not Pregnant

1 Pregnant

I

Poor prognosis

I

12 Months

2 Pregnant

28 Not pregnant

I

26 (2 Lost to follow-up)

I

Good prognosis 5

18 Months

2 Pregnant

I

3 Not p'regnant

Poor prognosis 21

I

21 Not pregnant

Fig. 2. Flow chart for initial poor prognostic group.

subsequent spontaneous changes such as an increase in levels or changes after retreatment with a reduction in levels also have predictive value for subsequent pregnancy rates. A high degree of correlation between the surgical findings at a second-look procedure and the changes in CA 125 was found as was seen also in previous observations. 7 • B However, the degree of correlation is probably inflated because of a number of methodologic

biases in the present study. First, only women who had not conceived after 1 year were candidates for a secondlook procedure, and second, not all these women were surgically evaluated. Third, women who had obvious recurrence by pelvic examination or symptoms consistent with recurrence would be more likely to undergo another surgical procedure, which is further supported by the high proportion of women who received hysterectomy in this group. Nonetheless, a significant

Serial CA 125 concentrations

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Table II. Pregnancy at 12 months according to stage of endometriosis Poor prognosis

Good prognosis

I

Stage

No.

Pregnant (%)

Minimal Mild Moderate Severe

4 10 18 13

2 7 15 8

(50) (70) (83) (62)

TOTAL

45

32 (71)

No.

I

Total

I

Pregnant (%)

No.

1 4 13 13

0(0) I (25) 1(8) I (8)

5 14 31 26

2 8 16 9

(40) (57) (52) (35)

NS NS <0.001 <0.02

31

3 (10)

76

35 (46)

<0.001

change in CA 125 concentrations as defined in this study correlated with the status of the endometriosis in most of the women. Approximately 50% to 60% of women with endometriosis have CA 125 levels 2: 16 U I ml in our experience as a surgically oriented university-based referral practice. 79 With modification of commercially available assays, serial CA 125 determinations in this group of women appear to offer useful information about the status of endometriosis and the likelihood of achieving a pregnancy after surgical treatment. The changes in CA 125 could be used together with clinical parameters to assist in deciding whether and when surgical or medical retreatment should be considered. Women with a persistently poor prognostic profile of CA 125 values could be counseled to encourage them to think about one of the new technologic approaches such as in vitro fertilization or to begin the adoption process. How much the use of serial CA 125 determinations will assist or improve the overall management of endometriosis will require the results of randomized, prospective studies. REFERENCES I. Barbieri RL, Evans S, Kistner RW. Danazol in the treatment of endometriosis: analysis of 100 cases with a 4-year follow-up. Ferti! Steril 1982;37:737-46. 2. Buttram VC Jr, Reiter RC, Ward S. Treatment of endometriosis with danazol: report of a 6-year prospective study. Ferti! Steril 1985;43:353-60. 3. Wheeler JM, Malinak LR. Recurrent endometriosis: incidence, management, and prognosis. AM J OBSTET GyNECOL 1983;146:247-53. 4. Murphy AA, Green WR, Bobbie D, dela Cruz ZC, Rock JA. Unsuspected endometriosis documented by scanning electron microscopy in visually normal peritoneum. Ferti! Steril 1986;46:522-4. 5. Barbieri RL, Niloff JM, Bast RC Jr, Schaetzl E, Kistner RW, Knapp RC. Elevated serum concentrations ofCA 125 in patients with advanced endometriosis. Fenil Steril 1986;45:630-4. 6. Patton PE, Field CS, Harms RW, Coulam CB. CA 125 levels in endometriosis. Fertil Steril 1986;45:770-3. 7. Pittaway De, FayezJA. The use ofCA 125 in the diagnosis and management of endometriosis. Fertil Steril 1986;46: 790-5. 8. Pittaway DE. CA 125 in women with endometriosis. Obstet Gynecol Clin North Am 1989;16:237-52. 9. Pittaway DE. Evaluation of pre- and postoperative CA 125

Pregnant (%)

p Value

concentrations and pregnancy rates in women with endometriosis. Fertil Steril (In press). 10. The American Fertility Society. Revised American Fertility Society Classification of endometriosis: 1985. Fenil Steril 1985;43:351-2. 11. Pitta way DE. Assay characteristics of the immunoradiometric method for CA 125. Fertil Steril 1989;51:34850. 12. Cohen J. A coefficient of agreement for nominal scales. Educ Psychol Mens 1960;20:37-42.

Editors' note: This manuscript was revised after these discussions were presented. Discussion DR. JOHN A. BURlGO, West Palm Beach, Florida (Official Guest). Dr. Pittaway presented an excellent paper correlating the serum level of CA 125 with the likelihood of achieving pregnancy in patients treated for endometriosis. Most of us associate the clinical use of CA 125 with the diagnosis and management of patients with epithelial ovarian cancers. However, we know that elevations of serum CA 125 can also be associated with some normal physiologic conditions and disease states other than ovarian cancer. Elevations are associated with other malignancies including those of the endometrium, fallopian tube, breast, liver, lung, and pancreas, as well as with benign conditions including endometriosis, pelvic inflammatory disease, pleuritis, pericarditis, and pancreatitis. Elevations are also associated with non pathologic conditions such as pregnancy and menstruation. Dr. Pittaway's interest in the correlation between elevations in the serum level of CA 125 and conditions other than ovarian carcinoma precedes this study. In a previous paper he reported the correlation between elevated CA 125 and endometriosis.! In that study he reported that the degree of elevation of the antigen correlated significantly with the severity of disease and that changes in the clinical course of patients with endometriosis correlated with changes in the level of circulating antigen. In a more recent study he found that the level of serum CA 125 could be useful in distinguishing between patients with pelvic pain caused by endometriosis versus other causes of pelvic pain." He reported that a CA 125 level 2: 16 U I ml correlated with the presence of endometriosis in 80% of the patients and only 6% of patients with elevations had causes for