GYNECOLOGIC

ONCOLOGY

37, 260-263 (1990)

Serum Squamous Cell Carcinoma Antigen in the Monitoring of Radiotherapy Treatment Response in Carcinoma of the Cervix HEXTANY. S. NGAN, S. Y. W. CHAN, L. C. WONG, D. T. K.

CHOY,*

AND

H. K. MA

Department of Obstetrics and Gynaecology, University of Hong Kong, Queen Mary Hospital, and *Department of Radiotherapy, Queen Mary Hospital, Hong Kong Received August 16, 1989

Hospital in 1987 and 1988. They ranged in age from 28 to 91 (mean 55.6). The stage of carcinoma and the number and percentage of patients with increased serum SCC levels are listed in Table 1. Sixty-one patients (38.9%) had a serum SCC level below 1.6 rig/ml. Ninety-six patients (61.1%) had a SCC level above 1.5 rig/ml. There were significantly more patients with a SCC level above 1.5 rig/ml with advancing stage of disease (P < 0.01) (Table 1). The modalities of initial treatment of these 157 patients are shown in Table 2. In this study, only patients with stage I to IV tumor who were to be treated with radiotherapy and who had a high pretreatment SCC level were further monitored by serial SCC assays. Patients with recurrent disease were excluded. There were 71 patients with high SCC levels scheduled for radiotherapy treatment, but 9 patients defaulted and 1 patient was still receiving external radiotherapy (ERT). Therefore, only 61 patients were INTRODUCTION studied. Of these 61 patients 23 had their SCC levels Squamous cell carcinoma antigen (SCC) is a subfrac- assayed weekly for the entire course of irradiation, which tion of tumor antigen TA-4, which was isolated from consisted of 4 weeks of ERT delivering 4000 cGy to the squamous cell carcinoma by Kato and Torigoe [l]. SCC pelvis and two applications of ICR at l-week intervals has been found in 54-67% of squamous cell carcinomas delivering a total of 9000 cGy to point A and 5500-6000 of the cervix [2,3] and its level correlates with the stage cGy to point B 7-10 days after ERT. In 28 patients, the and extent of the disease [2-41. Maruo et al. reported SCC level was assayed only after completion of ERT the use of SCC to monitor nine patients receiving ra- and on completion of the entire course of radiotherapy. diotherapy and showed that the SCC level returned to In 10 patients only pre- and post-treatment SCC levels normal in patients who were successfully treated [2]. The were assayed. All 61 patients underwent cervical biopsy aim of this study is to determine the value of the use of on completion of ERT and on completion of radiotherapy. Presence of residual tumor was defined as the presSCC in assessing tumor response to radiotherapy. ence of viable tumor cells in a cervical biopsy taken 2 weeks after completion of radiotherapy. There were 6 MATERIALS AND METHODS patients with residual tumor in this study and they all For 157 patients with newly diagnosed or recurrent received further treatment. Assay of XC level. SCC level was measured in serum squamous cell carcinoma of the cervix, the pretreatment serum SCC level was assayed in the Department of stored at - 20°C by radioimmunoassay using the SCCRIABEAD kit from Dainabot Laboratory (Tokyo, JaGynecology, University of Hong Kong, Queen Mary

In this study, squamous cell carcinoma antigen (SCC) was detected in 96 of 157 patients with squamous cell carcinoma of the cervix and the percentage of patients with raised SCC levels increased with the stage of disease (P < 0.01). The use of serial SCC assays and cervical biopsy histology during the course of radiotherapy to predict tumor response to irradiation was assessed. In patients who were given external h-radiation before intracavitary radium, a high SCC level or the presence of viable tumor cells in the biopsy was found to be of no predictive value. However, at completion of radiotherapy, i.e., after intracavitary radium application, patients with persistently high SCC levels had a significantly higher incidence of residual tumor than patients whose SCC levels returned to normal (P < 0.01). In 60% of patients with a persistently high SCC level, viable tumor was found in the cervical biopsy at the end of radiotherapy. On the other hand, only 5.4% of patients whose SCC level returned to normal had residual tumor. 0 1990 Academic Press, Inc.

OLWO-8258Brl $1.50 Copyright 0 1990by AcademicPress,Inc. All rights of reproductionin any form reserved.

260

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IN CERVICAL

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CARCINOMA

TABLE 1 Stage of Cervical Carcinoma and SCC Level” SCC level

Stage IA IB IIA IIB IIIA IIIB IV Recurrent Total

Number of patients

>1.5 rig/ml

cl.6 t&ml

11 40 28 29 5 18 3 23 157

Number

%

Number

%

11 24 13 4 1 2 1 5 61

100 60 46 14 20 11 33 22 39

0 16 15 25 4 16 2 18 %

0 40 54 86 80 89 61 78 61

* Stage vs SCC level: P < 0.01.

pan). The sensitivity limit of the assay was 0.1-150 rig/ml. A serum SCC level above 1.5 rig/ml was considered raised, as recommended by Dainabot [51. Analysis of the results. The pattern of the changes in SCC level during radiotherapy, and particularly the SCC levels on completion of ERT and on completion of the entire course of irradiation, was observed. Different patterns could be discerned. The authors attempted to relate the different patterns to the outcome of treatment. The significance of a raised SCC level at the end of ERT and on completion of radiotherapy was also studied. The FIG. 1. Changes in the SCC level during the period in which the presence of viable residual tumor in cervical biopsy tis- initial 4000 cCy of ERT was administered (on semilogarithmic scale). sue after completion of radiotherapy was used as an indicator of poor outcome to treatment. For statistical therapy. The changes in SCC levels are shown in Fig. analysis, x2 test was used. 1. Only 2 of 23 patients (8.7%) had an increase in SCC level during the initial 2000 cGy of ERT. Eight of twentyRESULTS three patients (34.8%) had stationary SCC levels during Changes in SCC level during ERT. Twenty-three pa- the same period. Among these 8 patients, 3 (37.5%) were tients had serial weekly SCC level assays during radio- found to have residual tumor at the end of radiotherapy. TABLE 2 Stage of Cervical Carcinoma, Modalities of Treatment, and Pretreatment SCC Level Radiotherapy

Surgery

Chemotherapy

No treatment

Stage

NSCC”

HSCC

NSCC

HSCC

NSCC

HSCC

NSCC

HSCC

IA IB IIA IIB IIIA IIIB IV Recurrent Total

-

13 13 24 4 16 1 4 75

11 20 1 32

-

4 12 4 1 2 1 1 25

-

-

-

-

-

-

-

-

’ NSCC, normal SCC level; HSCC, high SCC level.

3 1 4

3 3

1 1

1

7 I

-

1

1 7 10

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NGAN ET AL.

In 13 of 23 patients (56.5%) there was a progressive decrease in SCC level during radiotherapy. Of these 13 patients, 3 (23.1%) had residual tumor. There was no statistically significant relationship between the different patterns of changes in SCC level and the occurrence of residual tumor. After administration of 2000 cGy irradiation, 7 of the 23 patients (30.4%) had a normal SCC level. After 3000 cGy, 10 of 23 patients (43.5%) had a normal SCC level. At the completion of 4000 cGy, 12 of 23 patients (52.5%) had a normal SCC level. XC level and cervical biopsy histology on completion of ERT. Of 51 patients 35 (68.6%) had a normal SCC level on completion of ERT. Two of these thirty-five patients (5.7%) had residual tumor. Sixteen patients had a high SCC level on completion of ERT and four of these patients (25.0%) had residual tumor (Table 3). No tumor cells were seen in the cervical biopsy specimen in 22 of 51 patients, and 1 of these 22 patients (4.5%), on repeat biopsy at the end of radiotherapy, showed residual tumor. However, of the 29 patients with a positive cervical biopsy, 5 (17.2%) had residual tumor on completion of the entire course of radiotherapy. There was no statistically significant relationship between persistently high SCC level or positive cervical biopsy at the end of ERT and the occurrence of residual tumor. XC level and cervical biopsy histology on completion of radiotherapy. Two weeks after completion of radiotherapy, 5 of 61 patients (8.2%) had raised SCC level (Table 4). Of the 56 patients with a normal SCC level, 3 (5.4%) had residual tumor. Three of the five patients with a high SCC level (60%) had residual tumor. A persistently high SCC level at the end of radiotherapy was significantly related to the presence of residual tumor (ZJ < 0.01). Of 55 patients with negative cervical biopsy at the end of radiotherapy, 2 (3.6%) had a high SCC level. Both patients had persistently high SCC level 1 and 3 months after treatment without evidence of disease. The SCC level returned to normal later and remained normal, and there was no evidence of disease after 12 and 17 months of follow-up. TABLE

3

SCC Level and Cervical Biopsy Histology on Completion of ERT XC level Cervical biopsy No tumor Positive Total

cl.6 rig/ml

>I.5 rig/ml

14 (1)

8 (0) g (4) 16 (4)

21 (1) 35 (2)

a Number of residual tumors in parentheses.

TABLE 4 SCC Level and Cervical Biopsy Histology on Completion of Radiotherapy XC Cervical biopsy No tumor Positive Total

level

1.5 rig/ml

Total

53 3 56

2 3 5

55 6 61

a Cervical biopsy vs XC level: P < 0.01.

SCC level and treatment of residual growth. Three of the six patients with residual tumor had a high SCC level. One patient underwent a radical hysterectomy and her SCC level returned to normal. One patient had a laparotomy which showed paraaortic node metastases. Her SCC level returned to normal after radiotherapy to the paraaortic area and chemotherapy. The remaining patient had further radiotherapy because of inoperable stage III disease and had persistent disease with a high SCC level. Two of the three patients with residual tumor in whom the SCC level returned to normal were treated by radical hysterectomy. The remaining patient was treated with gold grain implant in the vagina. At the time of this report, their SCC levels remained normal. No tumor recurrence was detected in these three patients. DISCUSSION

In this study, the SCC level rose in 61.1% of our patients with squamous cell carcinoma of the cervix, and the incidence of raised SCC levels increased with the stage of disease (P < 0.01). These findings agree with those of others [2-41. SCC is said to be a better tumor marker of carcinoma of the cervix than carcinoembryonic antigen (CEA) because it is more specific to squamous cell carcinoma which constitutes more than 90% of the histological cell types in cervical cancer [81. CEA was raised in only 27-47% of patients with cervical cancer [3,6,7]. Furthermore, SCC has a short plasma half-life of 20 min [2]. Therefore, it is more sensitive as a tumor marker. In the study by Maruo et al., the SCC level returned to normal within 3 weeks of successful radiotherapy treatment of cervical cancer [2]. However, it took 16 weeks for the CEA level to return to normal after successful radiotherapy [2]. In the present study, 8.7% of patients showed an increased SCC level and 34.8% showed a stationary SCC level during the initial Total 2000 cGy of irradiation. This is contrary to the results 22 (1) reported by Maruo et al. [2]. Eight of their nine cervical 29 (5) cancer patients who were receiving radiotherapy and 51 (6) showing a good response had a temporary rise in SCC level during the same period of irradiation. We also

USE OF SCC TO MONITOR RADIOTHERAPY

showed that there was no correlation between the pattern of changes in XC level and the occurrence of residual tumor. The majority of cervical cancers showed regression on gross examination after the initial 4000 cGy of ERT; hence it is sometimes diflicult to determine if there is residual growth by clinical examination. On completion of ERT, only half of the radiation dosage has been delivered; thus, the presence of viable tumor cells in cervical tissue may not indicate that the growth is radioresistant. As shown in this study, cervical biopsy after 4000 cGy was not a reliable indicator of radioresistance. On the other hand, the absence of tumor cells in the biopsied cervical tissue does not represent radiosensitivity because it is possible that the wrong site on the cervix was sampled. XC, because it is a tumor marker released into the systemic circulation, should be a more reliable indicator of the presence of a small tumor. In this study, the SCC level after 4000 cGy of irradiation was of no predictive value with respect to the presence of residual growth. However, after completion of radiotherapy, a persistently high SCC level was associated with a high probability of residual growth. In those patients who had residual tumor and a high SCC level and had received further treatment, SCC was shown to be a good tumor marker. In conclusion, SCC monitoring during radiotherapy treatment of carcinoma of the cervix is of limited value in assessing for the presence of residual growth. However, it is useful in predicting the presence of residual

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tumor after completion of radiotherapy. In the patient who has a persistently high SCC level after completion of radiotherapy, a thorough search for tumor is indicated.

REFERENCES 1. Kato, H., and Torigoe, T. Radioimmunoassay for tumor antigen of human cervical squamous cell carcinoma, Cancer 40, 1621-1628 (1977). 2. Maruo, T., Shibata, K., Kimura, A., Hoshina, M., and Mochizuki, M. Tumor associated antigen TA-4 in the monitoring of the effects of therapy for squamous cell carcinoma of the uterine cervix, Cancer 56, 302-308 (1985). 3. Senekjian, E. K., Young, J. M., Weisei, P. A., Spencer, C. E., Magic, S. E., and Herbs& A. C. An evaluation of squamous cell carcinoma antigen in patients with cervical squamous cell carcinoma, Amer. J. Obstet. Gynecol. 157, 433-439 (1987). 4. Kato, H., Morioka, H., Tsutsui, H., Aramaki, S., and Torigoe, T. Value of tumor-antigen (TA-4) of squamous cell carcinoma in predicting the extent of cervical cancer, Cancer 50, 1294-1296 (1982). 5. Yabushita, H., et al. Clinical application of serum SCC assays in squamous cell carcinoma of the cervic, World Obstet. Gynecol. 39(9), 937-945 (1987). [in Japanese] 6. Khoo, S. K., Daunter, B., and Mackay, E. Carcinoembryonic antigen and µglobulin as serum tumor markers in women with genital cancer, ht. J. Gynecol. Obstet. 16, 388-393 (1979). 7. Ito, H., Kurihara, S., and Nishimura, C. Serum carcinoembryonic antigens in patients with carcinoma of the cervix, Obstet. Gynecol. 51, 468-471 (1978). 8. Dodd, J. K., Henry, R. J. W., Tyler, J. P. P., and Houghton, C. R. S. Cervical carcinoma: A comparison of four potential biochemical tumor markers, Gynecol. Oncol. 32, 248-252 (1989).

Serum squamous cell carcinoma antigen in the monitoring of radiotherapy treatment response in carcinoma of the cervix.

In this study, squamous cell carcinoma antigen (SCC) was detected in 96 of 157 patients with squamous cell carcinoma of the cervix and the percentage ...
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