Prechemotherapy serum CA125 level as a predictor of survival outcome in epithelial carcinoma of the ovary

Cfinical Oncology (1991) 3:32-36 © 1991 The Royal College of Radiologists

Clinical Oncology

Original Article Prechemotherapy Serum CA125 Level as a Predictor of Survival Outcome in Epithelial Carcinoma of the Ovary N. G . P. D a v i d s o n 1, S. K h a n n a 1, P. H . K i r w a n 2 a n d D . B i r c u m s h a w 1 Departments of 1Radiotherapy and Oncology, and 2Obstetrics and Gynaecology, Leicester Royal Infirmary, Leicester LE1 5WW, UK

Abstract. A total of 55 patients with epithelial ovarian carcinoma treated with platinum-based chemotherapy were followed for a minimum period of 2 years. Of these 22 patients had a prechemotherapy serum CA125 level of <50 ku/1 and 33 patients had a serum CA125 level of ~>50 ku/1. The 5-year actuarial survival of the two groups were 75% and 10% respectively. Prechemotherapy CA125 level taken 4 weeks after debulking surgery may predict the eventual survival outcome in epithelial ovarian cancer patients who undergo chemotherapy treatment. Keywords: Ovarian carcinoma; Serum CA125 level; Chemotherapy

INTRODUCTION The identification of serum factors to monitor the course of ovarian epithelial carcinomas has been considered for many years. An important advance was made by Bast et al (1981), who developed a murine monoclonal antibody that reacted with a glycoprotein antigen (CA125) derived from a human ovarian tumour cell line using a mouse somatic cell hybridization technique. This antibody was used to develop a commercially available radioimmunoassay that measured CA125 in serum (Bast et al, 1983). Elevated serum levels of CA125 (>35 u/ml) were detected in only 1% of 888 apparently healthy people, in 6% of 143 patients with nonmalignant disease and in 82% of 101 patients with epithelial ovarian carcinoma. Since then the possible role of CA125 in the management of ovarian cancer has been studied Correspondence and offprint requests to: Dr S. Khanna FRCR, Consultant in Radiotherapy and Ontology, Leicester Royal Infirmary, Leicester LE1 5WW, UK.

extensively and the following useful information documented: 1. Serum CA125 levels are elevated in most patients with ovarian malignancies, including epithelial, stromal and germ cell tumours whatever the stage (Alvarez et al., 1986). 2. Rising CA125 levels are a reliable indicator of progressive disease but levels falling into the normal range do not always indicate eradication of tumour (Fish et al., 1987). 3. There is a positive correlation between the prechemotherapy serum level of CA125 and the quantity of tumour (Canney et al., 1984; Fish et al., 1987). 4. Elevated CA125 levels prior to second-look laparotomy are predictive of tumour being present but normal CA125 levels are not a reliable indicator of absence of tumour (Alvarez et al., 1986). 5. Rising CA125 levels during post-treatment are often predictive of disease recurrence (Alvarez et al., 1986). However, only a few reports have correlated the initial CA125 level and survival. Parker et al. (1988) correlated survival with initial level of CA125 in 42 patients with a median follow-up of 10 months and found a significant survival advantage for patients with a CA125 level of less than 250 u/ml. Martoni et al. (1986) studied 60 patients with ovarian cancer and concluded that the CA125 basal levels do not seem to have prognostic value with regard to response or survival, but their minimum follow-up period was only 3 months. This report considers on the basis of a minimum follow-up of 2 years, the survival outcome of 55 patients with epithelial ovarian carcinoma who had preehemotherapy serum CA125 levels of <50 ku/1 or ~>50 ku/1 and underwent treatment with platinum-based chemotherapy.

33

Serum CA125 Level and Survival Outcome in Ovarian Cancer Table 1. Patient characteristics

CA125 <50

CA125 ~>50

Total no. patients

Afive

Dead

Alive

Dead

CA125<50

CA125~50

11 5

4 2

2 2

17 12

15 7

19 14

Age <60 years ~>60 years

Figo stage I

6

1

II III IV

4 7 0

2 1 1

0 2 1 0

1 1 13 15

7 6 8 1

1 3 14 15

6 7 1 2 1

2 1 0 2 0

2 1 0 0 0

16 5 1 2 6

8 8 1 4 1

18 6 1 2 6

6 8 3

0 1 4

1 2 1

2 8 19

6 9 7

3 10 20

7 8 2 0 0

0 2 1 2 0

0 2 0 0 1

0 3 8 13 6

7 10 3 2 0

0 5 8 13 7

Histological type of tumour Serous Mucinous Endometroid Clear cell Undifferentiated

Grade Well differentiated Moderately differentiated Poorly differentiated

Disease status following surgery No residual < 2 cm residual 2-5 cm residual >5 cm residual No debulking

PATIENTS

AND

METHODS

From September 1985 to September 1987, 55 patients with epithelial ovarian carcinoma FIGO stage IC to IV were treated with platinum-based chemotherapy at Leicester Royal Infirmary. Their characteristics are given in Table 1. Staging was according to the system outlined by the FIGO cancer committee in 1985. All patients attended a combined gynaecological ovarian oncology clinic, staffed by a gynaecologist and a radiotherapist/ oncologist. Patients with ovarian tumours of 'malignant potential' (borderline tumours) were excluded. The median age of the patients was 57 years (range 26-74 years). The initial staging laparotomies were performed by the referring gynaecologists. Of the 37 patients who underwent total abdominal hysterectomy and bilateral salpingooopherectomy (TAH and BSO) 24 also had an omentectomy. Eleven patients had incomplete debulking surgery and seven patients had biopsy only. In patients who underwent debulking surgery residual disease was estimated at the time of operation according to the following scale - none, <2 cm, 2-5 cm or >5 cm residual disease. Chemotherapy was commenced 4 weeks after the initial laparotomy. Serum CA125 levels were mea-

sured on the initial day of chemotherapy and before each course of chemotherapy. Tumour antigen concentration in serum was measured using an immunoradiometric assay (ELSA) available from International - CIS (UK), London. Of the 55 patients 32 received single-agent platinum therapy and 23 received platinum-based combination chemotherapy (Table 2). A total of 44 patients received a minimum of six courses of chemotherapy and 11 patients received less than six courses; 13 patients received nine courses, three patients received eight courses and one patient received seven courses. Clinical response was assessed after 6 months. The assessment included a full clinical examination, full blood count, liver function tests, Table 2. Chemotherapy schedules Type of chemotherapy

CA125 <50

CA125/>50

Total CA125

Alive Dead

Alive Dead

<50

CAP 3 Cisplatin and 3 cyclophosphamide Paraplatin 10 Paraplatin and 0 ifosphamid¢ Cisplatin 1

~>50

0 2

1 0

5 0

3 5

6 0

1 2

2 0

18 7

11 2

20 7

0

0

0

1

0

CAP. cyclophosphamide, adriamycin, cisplatinum.

34

N.G.P.

serum CA125 levels, urea and electrolytes, chest Xray and a CT scan of the abdomen and pelvis. All patients have been followed-up regularly (minimum follow-up time 2 years). No one was lost to follow-up.

100

D a v i d s o n e t al.

-

-e- Stage I Stage II

80 -

Stage IV

70.~

60 -

>

50-

'~

40 -

30-

RESULTS

200

I: Pa,,e0ta,,vel patient died

Above

500 500

•

I

oooo

o

o

o o

450

@

----~ 4 0 0 "~

350

e~ I<

300

E 2

250

0

0

8 0 0

e

200

8

15O

O O

o

I O0

O 5O

0

8

o

n

S

!

o

i II

e

! III

! IV

Figo stage F i g . 1. S e r u m C A 1 2 5 l e v e l in e a c h F I G O

stage.

B

b

:

:

:

[]

i

I0-

Eleven of 55 patients showed no response to chemotherapy and received less than six courses of chemotherapy; 44 patients completed a maximum of six courses. Seven out of 44 patients had no residual disease following initial surgery and were not clinically evaluable. Of the remaining 37 patients 22, nine and six showed complete clinical response and stable disease respectively. The initial prechemotherapy serum CA125 level correlated well with the clinical stage and is shown in Fig. 1. The initial CA125 level was less than 50 ku/1 in 22 patients and equal to or greater than 50 ku/1 in 33 patients. The number of cases in each FIGO stage (I, II, III and IV) was 7, 6, 8 and 1 in the <50 ku/l group and 1, 3, 14 and 15 in the i>50 ku/l group respectively. In each stage 2/8, 3/9, 14/22 and 16/16 patients have died of recurrent disease. The 5-year actuarial survival for stages I, II, III and IV were

B

[]

r~

i

i

i

i

i

i

i

i

i

i

6

12

18

24

30

36

42

48

54

60

Time (months) F i g . 2. T h e 5 - y e a r a c t u a r i a l s u r v i v a l in e a c h F I G O

stage.

100 " ~

80 70

6o :~ 5o ~ 4o ~

30 20 10 J

0

i 6

i 12

! 18

i 24

i 30

i 36

i 42

i 48

i 54

i 60

Time(mon~s)

Fig. 3. The overall 5-year actuarial survival.

70%, 68%, 33% and 7% respectively (Fig. 2). The overall 5-year actuarial survival was 38% (Fig. 3). Following initial surgery seven patients did not have any residual disease and all seven had a prechemotherapy CA125 level of <50 ku/l. All seven patients are alive and well. Fifteen patients had residual disease of less than 2 cm in diameter; ten of whom had levels of CA125 <50 ku/l and two of these patients died. Residual disease greater than 2 cm in diameter was found in 26 patients; 5/26 had CA125 levels <50 ku/1 and three of them died; 21/26 patients had CA125 levels ~>50 ku/1 and all of them died. In seven patients debulking was not possible. All seven had initial CA125 levels >~50 ku/1 and six of them died. One patient showed complete clinical response to chemotherapy, and after receiving six courses underwent second look laparotomy and debulking. Histology showed residual disease and she received a further three courses of the same regime chemotherapy. She is alive and well 53 months after commencing chemotherapy. After a minimum follow-up of 2 years, 17/22 patients who had a prechemotherapy CA125 level of <50 ku/l and 3/33 patients who had a CA125 level of I>50 ku/1 are alive. The 5-year actuarial survival of patients with a prechemotherapy CA125 level of

Serum CA125 Level and Survival Outcome in Ovarian Cancer 1O0 90

-,,,.,._...

80" 70" 60" C

'E

50'

CA125 < 50

40"

CA125 _>50

30" 20" 0

10"

0

0

0

3'6

4'2

4~8

0------0

0 6

12

18

2'4

30

Time

5'4

60

(months)

Fig. 4. The 5-year actuarial survival according to prechemotherapy serum CA125 level.

Table 3. Chi 2 analysis

Stage

No. of deaths CA125 <50

CA125 ~>50

Obs

Exp

Obs

I and II III

3 1

3.824 5.091

2 13

chi2

4 8.915 (4-8"915)2 + 8.915

Combined death rate

Exp 1.176 8.910

5/17=0.294 14/22=0.636

15 10.086 (15-10"086)2 10.086

5.11P <0.03

Obs, observed; Exp, expected Stage IV omitted from the analysis.

35

vity to detect small tumour masses (Fish et al., 1987). Therefore, patients who have minimal residual disease following initial debulking surgery are likely to have a serum CA125 level of <50 ku/1. This has been confirmed in our study, by the 75%, 5-year actuarial survival of patients who had a prechemotherapy a CA125 level <50 ku/1 as opposed to 10%, 5-year actuarial survival for those with a CA125 level of i>50 ku/1. In our series the majority of stage IV patients (15/ 16) were in the CA125 I>50 ku/l group and this must have magnified the survival advantage shown by the CA125 <50 ku/1 group. However, in stages I and II 3/13 (23%) in the CA125 <50 ku/1 group and 2/4 (50% in the CA125 I>50 ku/l group have died). In stage III 1/8 (14%) in the CA125 <50 ku/l group and 13/14 (92%) in the CA125 I>50 ku/l group have died. Despite the small numbers these results show that the majority of deaths occurred in the CA125 I>50 ku/1 group and a postoperative serum CA125 level taken at 4 weeks could independently predict the eventual survival outcome in patients who undergo treatment with platinum-based chemotherapy. Acknowledgements. We wish to thank our gynaecological colleagues for referring the patients and Mrs V. McLachlan for typing the manuscript.

References <50 ku/1 is 75% as opposed to 10% for patients with a prechemotherapy CA125 level of i>50 ku/1 (Fig. 4). Log rank analysis (Table 3) shows a trend in favour of poor survival for patients with a CA125 level ~>50 ku/l.

DISCUSSION

In recent years optimism has flourished concerning the potential for curing epithelial ovarian cancer with extensive initial debulking surgery and chemotherapy. This is partly due to the high response rates produced by platinum-containing regimens. Several studies have shown that patients who have residual lesions <2 cm in diameter after initial debulking surgery have a better survival following chemotherapy than those with larger amounts of residual tumour (Vogl et al., 1983; Khanna et al, 1986; Hainsworth et al., 1988). Hawkins et al. (1989) examined serial CA125 measurements in 169 patients with epithelial ovarian cancer and found a significant clinical correlation with the level of serum CA125 and the amount of residual disease. It has been shown that the serum CA125 lacks sensiti-

Alvarez RD, To A, Boots LR, Shingleton HM, Hatch KD, Hubbard J e t al. (1986). CA125 as serum marker for poor prognosis in ovarian malignancies. Gynecologic Oncology, 26, 284-289. Bast RC, Feeney M, Lazarus H, Nadler LM, Colvin RB, Knapp RC (1981). Reactivity of a monoclonal antibody with human ovarian carcinoma. Journal of Clinical Investigation, 68, 13311337. Bast RC, Klug TL, St John E, Jenison E, Niloff JM, Lazarus H et al. (1983). A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. New England Journal of Medicine, 309, 883-887. Canney PA, Moore M, Wilkinson PM, James RD (1984). Ovarian cancer antigen CA125: a prospective clinical assessment of its role as a tumour marker. British Journal of Cancer, 50, 765-769. Fish RG, Shelley MD, Maughan T, Rocker I, Adams M (1987). The clinical value of serum CA125 levels in ovarian cancer patients receiving platinum therapy. European Journal of Cancer and Clinical Oncology, 23, 831-835. Hainsworth JD, Grosh WW, Buruen LS, Jones HW, Wolff SN, Greco FA (1988). Advanced ovarian cancer: long term results of treatment with intensive cisplatin based chemotherapy of brief duration. Annals of Internal Medicine, 108, 165-170. Hawkins RE, Roberts K, Wiltshaw E, Mundy J, McCready VR (1989). The clinical correlates of serum CA125 in 169 patients with epithelial ovarian cancer. British Journal of Cancer, 68, 634-637. Khanna S, Kirwan P, Naftalin NJ, Aukett RJ (1986). Treatment of stages II, III, and IV primary surface epithelial ovarian cancers by maximum bulk tumour reduction and combined chemotherapy with cyclophosphamide, doxorubicin and cisplatin. Clinical Radiology, 37, 187-191. Martoni A, Beilucco A, Marabini A, Orlandi C, Hate L, Bianchi D et al. (1986). CA125 monitoring during chemotherapy for

36

N . G . P . Davidson et al.

ovarian cancer. International Journal of Biological Markers, 1, 121--128. Parker D, Patel K, Alfred E J, Harnden-Mayor P, Naylor B (1988). CA125 and survival in ovarian cancer: preliminary communication. Journal of the Royal Society of Medicine, 81, 22.

Vogl ES, Pagans M, Kaplan BH, Greenwald E, Arseneau J, Bennett B (1983). Cisplatin based combination chemotherapy for advanced ovarian cancer. High overall response rate with curative potential only in women with small tumour burdens. Cancer, $1,2024-2030.

Received for publication February 1990 Accepted August 1990

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