Archivesof
Arch Gynecot Obstet (1990) 247:107-116
Gynecology and Obstetrics © Springer-Verlag1990
Originals Imaging of ovarian cancer with radiolabelled monoclonal antibodies D. L. van Kranenburg 1, M. J. P. G. van Kroonenburgh 1, J. B. Trimbos 2, G. J. Fleuren 3, and E. K. J. Pauwels 1 Departments of 1Diagnostic Radiology, Division of Nuclear Medicine, ZGynecology,and 3pathology, University Hospital Leiden, Leiden, The Netherlands
Summary. This article presents the state of the art of immunoscintigraphy (IS) of ovarian cancer. We will review the monoclonal antibodies (MoAbs) used in clinical trials: (HMFG1/2, OC125, H317, H17E2, NDOG2 and 791T/ 36). We conclude that none of the afore mentioned MoAbs are clearly superior and that IS cannot yet replace laparotomy for the diagnosis of overian cancer but may have a role in the follow-up of ovarian cancer, in timing second-look surgery and assessing the response/TD treatment.
Key words: Radioimmunoscintigraphy - Ovarian cancer - Monoclonal antibodies Introduction Ovarian cancer is one of the main causes of death due to cancer in women. In The Netherlands it ranks fourth after breast cancer, colon cancer and gastric cancer (van Ginneken and van der Vlist 1985). Unfortunately, the incidence of ovarian cancer is still increasing (American Cancer Society 1981). The F6deration Internationale de Gyn6cologie et Obst6trique (FIGO) distinguishes the four stages of disease: I: confined to the ovaries; II: disease limited to the pelvis; III: spread of disease into the peritoneal cavety and IV: distant metastases; the respective five year survival rates are 66%, 45%, 13% and 4%. The majority of patients have stage III or IV disease at the time of first diagnosis (Einhorn et al. 1985). The definitive diagnosis is made by exploratory laparotomy or diagnostic laparoscopy. Since the conventional diagnostic procedures such as X-ray, computer tomography (CT), ultrasonography (US) and magnetic resonance
Offprint requests to: Prof. Dr. E. K. J. Pauwels, University Hospital Leiden, Department of Diagnostic Radiology, Division of Nuclear Medicine, Building 1, C4-Q, P.O. Box 9600, NL-2300 RC Leiden, The Netherlands
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imaging (MRI) are not tissue specific, laparotomy is the gold standard against which other tests are compared. Laparotomy and laparoscopy can be associated with morbidity (Gallup et al. 1987) and it has been said that a secondlook laparotomy should only be done in oncology centers, doing clinical trials (Ho et al. 1987). Recently, more specific diagnostic procedures have been developed, using monoclonal antibodies (MoAbs) against tumor associated antigens. MoAbs can be used for monitoring the therapeutic response by immunoserology (Bast et al. 1983), for immunolocalisation through scintigraphy and for immunohistological examination of surgical specimens (Kenemans et al. 1985). The purpose of this study is to present the state of the art of immunoscintigraphy (IS) of ovarian cancer.
Literature data
MoAbs raised against tumor associated antigens on tumor cells can be labelled with a radionuclide and injected intravenously in patients suspected of having that particularly malignancy. Images made at predetermined intervals visualize the distribution of the MoAb. HMFG. Two murine MoAbs were raised against a component of the membrane of human milkfat globules: HMFG1 and HMFG2. They react strongly with the lactating breast and also with a host of neoplasms of epithelial origin, such as adenocarcinoma of the breast, ovaries and digestive system (Epenetos et at. 1982). There is a weak reaction with non-lactating breast tissue and a few other normal epithelial tissues. HMFG1 and HMFG2 are thus not tumor-, but tissuespecific. The patients participating in the studies were usually women suspected of having primary ovarian cancer or who were believed to have metastases or a recurrence of a previously removed tumor. The IS and the subsequent laparotomy were usually performed within 24 h. In all studies (Table 1), these MoAbs were conjugated with the radionuctide 1-123. A relatively large-scale study was undertaken by Shepard et al. (1983). A total of 51 patients were subjected to IS, 25 retrospectively and 26 prospectively. Thirty-nine women had ovarian cancer, 31 of them in stage III or IV. In 95% of the cases, scintigraphic results correlated with the situation found at subsequent operation. Most false-position findings were in the prospective study. In two cases benign tumors were imaged positively, as were 2 patients with colon cancer. Pateisky et al. (1985) reported 4 out of 25 cases in which IS was the only noninvasive method giving tumor visualization. False-negative results were obtained in one patient with a small tumor, and in another with a germ cell tumor, while the single false-positive was due to faulty reading of the immune scan. The tumor/non-tumor ratio (T/N) varied between 1.4 to 2.8 (Pateisky et al. 1985), which is apparently sufficiently high to make other techniques for tumor visualization unnecessary. IS demonstrated a 0.8 cm tumor (Epenetos et al.
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Immunosdntigraphy of ovarian cancer Table 1. Overview of clinical trials with HFMG" Study
MoAb
No. of patients
Epetenos et al. (1982)
HMFGt/2
12
Shepherd et al. (1983)
HMFG1/2
20
Epetenos et al, (1984)
HMFG1/2
10
Granowska et al. (1984a)
HMFG1/2
22
Granowska et al. (1984b)
HMFG2
40
Pateisky et al. (1985)
HMFG2
25
Epetenos et al. (1985)
HMFG2
1
Granowska et al. (1986)
HMFG2
30
Shepherd et al. (1987)
HMFG2
51
Sensitivity (%)
Specificity (%)
Accuracy (%)
Prevalence (%)
100
100 80
100
87 90
71
95
20
88
68
67 95
60
Labeled with mI
1985a), undetected by CT and US, while Granowska and coworkers (1986) were able to demonstrate a 0.5 cm tumor. The percentage of injected dose of antibody taken up by the tumor varied from 0.2% to 2.6% (Epenetos et al. 1984). 0C125. This murine antibody was developed by Bast and coworkers (1981) through immunization with serous cystadenocarcinoma, the most prevalent type of ovarian cancer. It recognizes the antigen CA125, which is associated with more than 80% of all epithelial ovarian neoplasms, mostly of non-mucinous cell type. Part of the CA125 antigen is shed into the circulation. Elevated or rising CA125 serum levels nearly always indicate tumor recurrence or progression (Atack et al. 1986, Niloff et al. 1986, Alvarez et al. 1987, O'Conell et al. 1987), but normal levels do not rule out the presence of disease. Finding an elevated level of CA125 in the serum of patients with an ovarian cancer recurrence (Doherty et al. 1986), led investigators to assess the usefulness of OC125 in radioimmunodetection. The OCt25 was labeled with 1-131 in most studies, only in two studies was In-111 used (Table 2). This appeared to give better contrast in the pelvic region, but exposes the liver to high radioactivity (Hunter et al. 1987). The T/N ratio varied from 1.8 (Barzen et al. 1987) to 2.5 (Chatal et al. 1987). The uptake per gram of tumor tissue was slightly higher after intraperitoneal (i.p.) injection and
D, L. van Kranenburg et al.
110 Table 2, Overview of clinical trials with OC125" Study
MoAb
No. of patients
Doherty et al. (1986)
OC125 b
11
Haisma et al. (1988)
OC125
15
Barzen et al. (1987)
OC125/ anti-CEA
Herry et al. (1987)
OC125
Baum et al. (1987) Chatal et al. (1987) Hunter et al (1987) a
Labeled with 131I;
Sensitivity (%)
Specificity (%)
Accuracy (%)
86
75
82
30
90
70
83
42
93
OC125
18
100
OC125/ 1-19-9
29
72
86
OC125b/ 1-19-9
23
88
50
Prevalence (%)
73
100
80
100
b labeled with rain
less aspecific liver and bone marrow uptake was seen than after intravenous (i.v.) injection (Haisma et al. 1988). Instead of using intact antibodies F(ab')2 fragments were preferred, since their clearance in normal tissue is faster than that of whole antibodies, while their clearance in tumors is comparable. Another favorable feature is the lack of an Fc fi'agment. This eliminates binding of the monoclonal antibodies to Fc receptor positive cells of the reticuloendotheliat system and reduces non-specific binding. It was found that formation of the expected CA125-OC125 immunecomplex formation did not interfere with the scintigraphic imaging (Chatal et al. 1987; Haisma et al. 1986). In a study undertaken by Herry et al. (1987) IS was performed on 42 patients. Of the 41 pelvic tumors present, 38 were demonstrated by IS. Two of those not seen were more than 2 cm in diameter. IS Clearly gave better results than CT and US in locating pelvic recurrences, but identified only 2 out of 8 liver metastases (Herry et al. 1987). Haisma et al.'s research (1988), comparing different routes of administration, deserves special attention. After i.v. injection, 50% of the tumor sites was visualized, whereas only one tumor was not demonstrated after i.p. injection of antibody. In a prospective study by Chatal et al. (1987) 29 patients were examined scintigraphically. According to the tumor marker found in their blood (CA125, associated with serous, or CA-19-9, associated with mucinous ovarian tumors) OC125 or 1-19-9 were used for IS. Judged by the total amount of tumor site found, the sensitivity (72%) was clearly better than that of conventional procedures (US 47% and CT 63%). The immunoscintigram was able to localize
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Immunoscintigraphyof ovarian cancer Table 3. Overviewof clinicaltrials with 791T/36, NDOG2, H17E2 and H317
Study Symondset al. (1985) Davies et al. (1985) Epetenos et al. (1985) Critchleyet al. (1986) Epetenos et al. (1986)
MoAb
No. of patients
Sensitivity Specificity Accuracy Prevalence (%) (%) (%) (%)
791T/36~
12
NDOG2b
15
92
H17E2c
6
80
H317b H17E2/ H317b
18 13
82 77
83 87
87 100
57
72 100
a Labeled with 131I; b labeled with 123I; ° labeled with rain sites not seen with US in 13 cases and those missed by CT in 8 cases. Falsenegative outcomes were due to peritoneal seedlings, small tumor volume and bladder radioactivity. Hunter et al. (1987) conducted a research trial in which the antibody scan was compared with CT, the OC125 blood level and second-look findings. When compared to second-look laparotomy, IS gave 2 false-positives, one due to granulation tissue and one because of antibody accumulation in the uterus. The 2 false-negatives were due to microscopic disease. As for the CA125 levels, 20% of the patients had a negative value at presentation, mainly because of small tumor volume.
H317 and H17E2. Both of these MoAbs are directed against placental alkaline phosphatase (PLAP). It appears that 35% of ovarian cancer patients (Van Nagell et al. 1981) have an elevated serum PLAP level. In a study by Critchley et al. (1986) 18 women treated for primary ovarian cancer were examined for possible recurrences by means of an H317 scan (Table 3); this enabled 2 patients, who were clinically tumor free, to receive treatment in time. There were no false-positives among the patients with a PLAP negative tumor or with pelvic inflammatory disease (Epenetos et al. 1986a). There appeared to be no correlation between serum PLAP level, the amount of tumor PLAP expression and a positive scan, but positive serum levels always indicated tumor presence. The high incidence of PLAP on ovarian neoplasms, the fact that H317 does not react with the smoking associated PLAP and the relatively high T/N found (Epenetos et al. 1986b), might make this antibody suitable for treatment. NDOG2. This MoAb is also directed against PLAP. Immunohistology showed that 70% of the ovarian cystadenocarcinomas reacted with NDOG2. Davies et al. (1985) reported 15 patients with suspected primary of confirmed ovarian cancer, who underwent IS (Table 3). Eleven women were chosen on the basis of
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their tumor PLAP expression, while this was unknown in the remaining 4 patients. The T/N ratio ranged between 1.4 and 4.8. The images underwent computersubtraction, giving 1 false-positive. Two of the patients with a false-negative result had microscopic peritoneal seedlings; the original tumors later appeared to be PLAP-negative. Finally, in 2 patients who appeared to be clinically free of tumor, IS showed otherwise. 791T/36. This MoAb was originally raised against osteogenic sarcoma. The 791T/ 36 probably binds to an as yet unknown antigen in malignant ovarian tumors. One trial is known (Table 3) in which 12 patients treated for ovarian cancer were examined for recurrent tumor (Symonds et al. 1985). All but one had a positive scan, 5 of these needed no image-subtraction (in this case Tc-99m labeled erythrocytes and free pertechnetate were used to simulate the distribution of antibody remaining in the circulation). The negative scan was in a patient with a benign cyst. One patient with a recurrence received therapy on the strength of the scan result. In 2 other patients IS was repeated after 6 months and produced early evidence of persistent tumor.
Discussion While IS is good at the visualization of tumors, one must be cautious about the sensitivity of the method. Chatal et al. (1987), Epenetos et al. (1984) and Herry et al. (1987) report sensitivities based on the number of tumor sites located, but in most studies one wonders whether positive scans detected all areas in which cancer was present. In one instance images of equivocal quality were judged to be positive if a tumor was found at laparotomy (Epenetos et al. 1985b). Furthermore, in some cases IS was compared with second-look laparotomy, and in others only with CT findings (Pateisky et al. 1985, Hunter et al. 1987, Chatal et al. 1987). Another complicating factor is that few authors are specific about the nature of the pelvic mass imaged (primary or residual disease, tumor recurrence or metastases), making it difficult to assess the exact role IS plays in detecting these various kinds of tumors. A high sensitivity usually means lower specificity. An example of this is the study of Granowska et al. (1986); a sensitivity of 95% was achieved with a specificity of 20%. The author concludes that the antibody, in this case HMFG2, does not determine whether or not a pelvic mass is due to overian cancer. The most accurate MoAbs seem to be those directed against PLAP; H17E2 and H317, showing less reactivity, if any, with normal tissue. Unfortunately, not all ovarian neoplasms express PLAP. The overall specificity is rather low. OC125 does compare favorably with HMFG, showing less reactivity with nonovarian tissue, as demonstrated through IS (Granowska et al. 1984a, 1984b). On the whole IS is quite accurate, being correct more often than US and CT and was frequently able to give important clinical information, unobtainable by
Immunoscintigraphy of ovarian cancer
113
other noninvasive methods (Pateisky et al. 1985, Herry et al. 1987, Epenetos et al. 1985a, 1985b). In these same studies IS sometimes missed a site that was demonstrated by US or CT. Chatal et al. (1987) reviewed the clinical value of CT, US and MRI for detecting ovarian cancer. By simply analysing all reports in the literature relating to this matter, he came up with a specificity of 95% for both CT and US, the sensitivities for US, CT and MRI being respectively 58%, 80% and 85%. When comparing these percentages with those obtained in the various studies using IS (Tables 1-3), IS does not differ so much from CT or US. As CT, US and IS use different criteria, these methods should be regarded as complementary. Its lack of specificity makes IS less useful for demonstrating primary tumor or for screening. Since most false-negative results occur with small tumors (Shepherd et al. 1987, Patzeisky et al. 1985, Chatal et al. 1987) or peritoneal seedlings (Chatal et al. 1987), second-look laparotomy remains the gold standard. IS has potential in assessing the extent of tumor (primary or metastatic) before operation and in monitoring the response to treatment in patients with extensive disease. The fact remains that the T/N ratio and, more important, the percentage of the injected dose of antibody taken up by the tumor, are still low. There are all kinds of techniques to enhance tumor visualization, but these will not increase the MoAb uptake by the tumor. This might be improved by injecting a cocktail of MoAbs (Rankin and McVie 1983), since the majority of tumors have heterogenous antigen expression (Baldwin and Byers 1986). The route of antibody administration could make a difference to the quality of the image. The i.p. administration of OC125 seems promising (Haisma et al. 1988). On the other hand, Ward et al. (1987) demonstrated that i.v. administration of HMFG2 resulted in consistently higher levels of antibody in solid tumor. The fact that the investigations were performed using different antibodies and different tumors might explain these differences. Another point worth examining is the smallest volume of tumor detected. Few authors mention this, but Granowska et al. (1986), were able to detect tumors of less than 0.5 cm diameter and if others can do this IS might prove to be a very valuable tool. We believe that IS cannot replace second-look laparotomy. Its importance lies mainly in the follow-up of ovarian cancer patients and might be helpful in timing second-look surgery and in directing biopsies. As long as there are still false-negatives, the search for an improved MoAb must continue. Of the most recently developed ones, two seem very promising. OV632 raised against nonmucinous ovarian carcinomas, appeared to be sufficiently specific to differentiate between primary and secondary cancer in an immunohistological study (Fleuren et al. 1987). Another promising antibody is OVTL3 (Epenetos et al. 1987a, Poels et al. 1986). No ovarian cancer of epithelial origin has yet been found to be OVTL3 negative. Although these antibodies have potential their real significance needs to be assessed in clinical trials. MoAbs may be useful in the therapeutic treatment of ovarian cancer; for example cytotoxic agents could be linked to radionuclides (Baldwin et al. 1986),
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or irradiation could be antibody-guided. Epenetos et al. (1987 b) have used the former method successfully in a small number of patients and other clinical trials are undeway.
Acknowledgements. The authors thank R. Vatkema, M.D., for advice and Ms. Y. E. J. Soons and Mrs. M. Boer for typing the manuscript.
References Alvarez RD, To A, Boots LR, Shingleton HM, Hatch KD, Hubbard J, Soong SJ, Potter ME (1987) CA125 as serum marker for poor prognosis in ovarian malignancies. Gynecol Onco126:284-289 American Cancer Society (1981) Cancer facts and figures 1981. American Cancer Society, New York Atack DB, Nisker JA, Allen HH, Tustanoff FR, Levin L (1986) CA125 surveillance and secondlook laparotomy in ovarian carcinoma. Am J Obstet Gynecol 154:287-289 Baldwin RW, Byers VS (1986) Monoclonal antibodies in cancer treatment. Lancet I:603-605 Barzen G, Langer M, Becker R, Koppenhagen K, Felix R (1987) Radioimmunoscintigraphy (RIS) of ovarian cancer with iodine-131 labelled F(ab')2 fragments of anti-CEA and OC125. Advances in the applications of monoclonal antibodies in clinical oncology, London, May 6-8 Bast RC, Freeny M, Lazarus H, Nadter LM, Colpin RB, Knapp RC (1981) Reactivity of a monoclonal antibody with human ovarian carcinoma. J Clin Invest 68:1331-1337 Bast RC, Klug TL, St John E, Jenison E, Niloff JM, Lazarus It, Brukowitz R, Leuwitt T, Griffiths T, Parker R, Zunawsk VR, Knapp RC (1983) A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. N Engl J Med 309:883-887 Baum RP, Albrecht M, Thaler CJ, Happ J, Manegold K, Berthold F, Buhl R, Lorenz M, H6r G (1987) Immunoscintigraphy of ovarian cancer with monoclonal antibody OC125: first results. Nuktearmedizin 26:417 Chatal J, Fumoleau P, Saccavini J, Thedrez P, Gurtet C, Bianco-Anco A, Chetanneau A, Pettier P, Kuemer M, Guillard Y (1987) Immunoscintigraphy of recurrences of gynecologic carcinomas. J Nucl Med 28:1807-1819 Cfitehley M, Brownless S, Patten M, McLaughin PJ, Tromans PM, MeDicken IW, Johnson PM (1986) Radionuclide imaging of epithelial ovarian turnouts with 1-123 labelled monoclonal antibody (H317) specific for placental-type alkaline phosphatase. Clin Radio137:107-112 Davies JO, Davies ER, Howe K, Jackson PC, Pitcher EM, Sadowski CS, Stiwat GM, Sunderland CA (1985) Radionuclide imaging of ovarian tumours with 1-123 labelled monoclonal antibody (NDOG2) directed against placental alkaline phosphatase. Br J Obstet Gynaecol 92:277-286 Doherty PW, Griffin T, Rusckowski M, Gionet M, Hunter R, Hnatowich DJ (1986) The potential utility of In-Ill labeled OC125 antibody in patients with gynecological tumors. J Nucl Med [Suppl] 27:881 Einhorn N, Nilsson B, Sjovatl K (1985) Factors influencing survival in carcinoma of the ovary. Cancer 55:2015-2019 Epenetos AA, Mather S, Granowska M, Nimmon CC, Hawkins LR, Britton KE, Shepherd JH, Taylor-Papadimitriou J, Durbin H, Malpas JS (1982) Targeting of iodine-123-1abelled tumorassociated monoclonat antibodies to ovarian, breast, and gastrointestinal tumors. Lancet II:9391005 Epenetos AA, Shepard JH, Britton KE, Hawkins LR, Nimmon CC, Taylor-Papadimitriou J, Durbin H, Malpas JS, Mather S, Granowska M, Duke D, Bodmer WF (1984) Radioimmunodiagnosis of ovarian cancer using 1-123 labelled, tumour-associated monoclonal antibodies. Cancer Detect Prev 7:45-49 Epenetos AA, Shepard JH, Britton KE, Mather S, Taylor-Papadimitriou J, Granowska M, Durbin H, Nimmon CC, Hawkins LA, Malpas JS, Bodmer WF (1985 a) 1-123 radioiodinated antibody imaging of occult ovarian cancer. Cancer 55:984-987 Epenetos AA, Hooker G, Durbin H, Bodmer WF, Snook D, Regent R, Oliver R, Lavender JP (1985 b) Indium labeUed monoclonal antibody to placental alkaline phosphatase in the detection of testis, ovary, and cervix. Lancet II:350-353
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Epenetos AA, Carr D, Johnson PM, Bodmer WF, Lavender JP (1986a) Antibody-guided radiolocalisation of turnouts in patients with testicular or ovarian cancer using two radioiodinated monoclonal antibodies to placental alkaline phosphatase. Br J Radio159:117-125 Epenetos AA, Snook D, Durbin H, Johnson PM, Taylor-PapadimitriouJ ( 1986b) Limitations of radiolabeled monoclonal antibodies for localization of human neoplasms. Cancer Res 46:3183-3191 Epenetos AA, Lavender JP, Kenemans P, Poels L (1987a) Early results of the monoclonal OVTL3 in specific detection of ovarian cancer. J Clin Oncol 5:160 Epenetos AA, Munro AJ, Stewart S, Rampling R, Lambert H, McKenzie CG, Souther P, Rahemtulla A, Hooker G, Sivolapenko GB, Snook D, Courtney-Lock N, Dhokia B, Krausz T, Taylor-PapadimitriouJ, Durbin H, Bodmer WF (1987b) Antibody-guidedirradiation of ovarian cancer with intraperitoneally administered radiolabeled monoclonal antibodies. J Clin Oncol 5:1890-1899 Fleuren GJ, Coercamp EG, Nap M, van de Brock LJCM, Warnaar SO (1987) Immunohistological characterization of a monoclonal antibody (OV632) against epithelial ovarian carcinomas, Virchows Arch [A] 4t0:481-486 Gallup DG, Talledo OE, Dudzunski MR, Brown KW (1987) Another look at the secondassessment procedure for ovarian epithelial carcinoma. Am J Obstet 157:590-596 Granowska M, Britton KE, Shepard JH (1984a) The detection of ovarian cancer using 1-123 monoclonal antibody. Radiobiol Radiother 25:153-160 Granowska M, Shepard J, Britton KE, Ward B, Mather S, Taylor-Papadimitriou J, Epenetos AA, Carroll MJ, Nimmon CC, Hawkins LA, Slevin M, Flatman W, Home J, Burchell J, Durbin H, Bodmer W (1984b) Ovarian cancer: diagnosis using 1-123 monoclonal antibody in comparison with surgical findings. Nucl Med Commun 5:485-499 Granowska M, Britton KE, Shepard JH, Nimmon CC, Mather S, Ward B, Osborne RJ, Slevin MJ (1986) A prospective study of 1-123 labeled monoclonal antibody imaging in ovarian cancer. J Clin Oncol 4:730-736 Haisma HJ, Battaile AI, Knapp RC, Zurawski VR (1986) Immune complexes of OC125-CA125 following intravenous injection of the radiolabelled monoclonal antibody into ovarian cancer patients. Br J Cancer 54:533 Haisma HJ, Moseley KR, Battaile AI, Griffiths TC, Zurawski VR, Knapp RC (1988) Biodistribution pharmacokinetics and imaging of 1-131 labelled OC125 in ovarian cancer. Int J Cancer [Suppl I 2:2 Herry JY, Kerbrat P, Bourget P, Toussaint C (1987) Immunoscintigraphy (IS) of ovarian carcinoma using the OC125 monoclonal antibody labelled with iodine-131. European Nuclear Medicine Congress, Budapest, August 24-28 Ho AG, Beller V, Speyer JL, Colomto N, Wernz J, Beckman EM (1987) A reassessment of the role of second-look laparotomy in advanced ovarian cancer. J Clin Oncol 5:1316-1321 Hunter RE, Doherty P, Thomas WS, Griffin TW, Gionet N, Hnatowich D J, Bianco JA, Dillon MB (1987) Use of Indium-ill labeled OC125 monoclonal antibody in the detection of ovarian cancer. Gynecot Onco127:325-337 Kenemans P, Verheijen RHM, Leloux AM, Poels LG (1985) Prospects and applications of monoclonal antibodies in gynecological ontology. Europ J Gynecol Reprod Biol 19:340-347 Niloff JM, Knapp RC, Lavin PT, Halkasian GB, Berck JS, Hortel R, Whitney S, Zurawski VR, Bast RC (1986) The CA125 assay as a predictor of clinical recurrence in epithelial ovarian cancer. Am J Obstet Gynecol 155:56-60 O'Conell GJ, Eamonn R, Murphy KJ, Prefontaine M (1987) Predictive value of CAI25 for ovarian carcinoma in patients presenting with pelvic masses. Obstet Gyneco170:930-932 Pateisky N, Philipp K, Skodler WD, Czerwenka K, Hamilton G, Burchell J (1985) Radioimmunodetection in patients with suspected ovarian cancer. J Nucl Med 26:1369-1376 Poels LG, Peters D, Megen YV, Vooijs GP, Verheyen R, Willemen A, van Niekerk CC, Jap P, Mungyen G, Kenemans P (1986) Monoclonal antibody against human ovarian tumour associated antigen. JNCI 76:781-791 Rankin EM, McVie JG (1983) Radioimmunodetection of cancer: problems and potential. Br Med J 287:1402-1405 Shepherd JH, Epenetos AA, Britton KE, Ward BG, Granowska M, Bodmer WF (1983) Radioimmune diagnosis of ovarian carcinoma using tumor-associated monoclonal antibodies. Gynecol Oncol 53:134
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Shepherd JH, Granowska M, Britton KE, Mather S, Epenetos AA, Ward BG, Slevin S (1987) Tumor-associated monoclonal assessment of ovarian cancer. Br J Obstet Gynaecol 94:160-167 Symonds EM, Perkins AC, Pimm MV, Baldwin RW, Hardy JG, Williams DA (1985) Clinical implications for immunoscintigraphy in patients with ovarian malignancy: a preliminary study using monoclonal antibody IT/36. Br J Obstet Gynaecol 92:270-276 Van Ginneken JKS, van der Vlist WP (1985) Kankersterfte in Nedefland laatste 30 jaar meer dan verdubbeld. Kanker 9:4-9 Van Nagell JR, Donaldson ES, Hanson MB, Guy EC, Paulik EJ (1981) Biochemicals in plasma and tumors of patients with gynecologic malignancies. Cancer 48:495-501 Ward BG, Mather SJ, Hawkins LR, Crowther ME, Shepherd JH, Granowska M, Britton KE, Slevin M (1987) Localization of radioiodine conjugated to the monoclonal antibody HMFG2 in human ovarian carcinoma: assessment of intravenous and intraperitoneal routes of administration. Cancer Res 47:4719-4723 Received May 16, 1989/Accepted December 11, 1989
Arch Gynecot Obstet (1990) 247:107-116
Gynecology and Obstetrics © Springer-Verlag1990
Originals Imaging of ovarian cancer with radiolabelled monoclonal antibodies D. L. van Kranenburg 1, M. J. P. G. van Kroonenburgh 1, J. B. Trimbos 2, G. J. Fleuren 3, and E. K. J. Pauwels 1 Departments of 1Diagnostic Radiology, Division of Nuclear Medicine, ZGynecology,and 3pathology, University Hospital Leiden, Leiden, The Netherlands
Summary. This article presents the state of the art of immunoscintigraphy (IS) of ovarian cancer. We will review the monoclonal antibodies (MoAbs) used in clinical trials: (HMFG1/2, OC125, H317, H17E2, NDOG2 and 791T/ 36). We conclude that none of the afore mentioned MoAbs are clearly superior and that IS cannot yet replace laparotomy for the diagnosis of overian cancer but may have a role in the follow-up of ovarian cancer, in timing second-look surgery and assessing the response/TD treatment.
Key words: Radioimmunoscintigraphy - Ovarian cancer - Monoclonal antibodies Introduction Ovarian cancer is one of the main causes of death due to cancer in women. In The Netherlands it ranks fourth after breast cancer, colon cancer and gastric cancer (van Ginneken and van der Vlist 1985). Unfortunately, the incidence of ovarian cancer is still increasing (American Cancer Society 1981). The F6deration Internationale de Gyn6cologie et Obst6trique (FIGO) distinguishes the four stages of disease: I: confined to the ovaries; II: disease limited to the pelvis; III: spread of disease into the peritoneal cavety and IV: distant metastases; the respective five year survival rates are 66%, 45%, 13% and 4%. The majority of patients have stage III or IV disease at the time of first diagnosis (Einhorn et al. 1985). The definitive diagnosis is made by exploratory laparotomy or diagnostic laparoscopy. Since the conventional diagnostic procedures such as X-ray, computer tomography (CT), ultrasonography (US) and magnetic resonance
Offprint requests to: Prof. Dr. E. K. J. Pauwels, University Hospital Leiden, Department of Diagnostic Radiology, Division of Nuclear Medicine, Building 1, C4-Q, P.O. Box 9600, NL-2300 RC Leiden, The Netherlands
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imaging (MRI) are not tissue specific, laparotomy is the gold standard against which other tests are compared. Laparotomy and laparoscopy can be associated with morbidity (Gallup et al. 1987) and it has been said that a secondlook laparotomy should only be done in oncology centers, doing clinical trials (Ho et al. 1987). Recently, more specific diagnostic procedures have been developed, using monoclonal antibodies (MoAbs) against tumor associated antigens. MoAbs can be used for monitoring the therapeutic response by immunoserology (Bast et al. 1983), for immunolocalisation through scintigraphy and for immunohistological examination of surgical specimens (Kenemans et al. 1985). The purpose of this study is to present the state of the art of immunoscintigraphy (IS) of ovarian cancer.
Literature data
MoAbs raised against tumor associated antigens on tumor cells can be labelled with a radionuclide and injected intravenously in patients suspected of having that particularly malignancy. Images made at predetermined intervals visualize the distribution of the MoAb. HMFG. Two murine MoAbs were raised against a component of the membrane of human milkfat globules: HMFG1 and HMFG2. They react strongly with the lactating breast and also with a host of neoplasms of epithelial origin, such as adenocarcinoma of the breast, ovaries and digestive system (Epenetos et at. 1982). There is a weak reaction with non-lactating breast tissue and a few other normal epithelial tissues. HMFG1 and HMFG2 are thus not tumor-, but tissuespecific. The patients participating in the studies were usually women suspected of having primary ovarian cancer or who were believed to have metastases or a recurrence of a previously removed tumor. The IS and the subsequent laparotomy were usually performed within 24 h. In all studies (Table 1), these MoAbs were conjugated with the radionuctide 1-123. A relatively large-scale study was undertaken by Shepard et al. (1983). A total of 51 patients were subjected to IS, 25 retrospectively and 26 prospectively. Thirty-nine women had ovarian cancer, 31 of them in stage III or IV. In 95% of the cases, scintigraphic results correlated with the situation found at subsequent operation. Most false-position findings were in the prospective study. In two cases benign tumors were imaged positively, as were 2 patients with colon cancer. Pateisky et al. (1985) reported 4 out of 25 cases in which IS was the only noninvasive method giving tumor visualization. False-negative results were obtained in one patient with a small tumor, and in another with a germ cell tumor, while the single false-positive was due to faulty reading of the immune scan. The tumor/non-tumor ratio (T/N) varied between 1.4 to 2.8 (Pateisky et al. 1985), which is apparently sufficiently high to make other techniques for tumor visualization unnecessary. IS demonstrated a 0.8 cm tumor (Epenetos et al.
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Immunosdntigraphy of ovarian cancer Table 1. Overview of clinical trials with HFMG" Study
MoAb
No. of patients
Epetenos et al. (1982)
HMFGt/2
12
Shepherd et al. (1983)
HMFG1/2
20
Epetenos et al, (1984)
HMFG1/2
10
Granowska et al. (1984a)
HMFG1/2
22
Granowska et al. (1984b)
HMFG2
40
Pateisky et al. (1985)
HMFG2
25
Epetenos et al. (1985)
HMFG2
1
Granowska et al. (1986)
HMFG2
30
Shepherd et al. (1987)
HMFG2
51
Sensitivity (%)
Specificity (%)
Accuracy (%)
Prevalence (%)
100
100 80
100
87 90
71
95
20
88
68
67 95
60
Labeled with mI
1985a), undetected by CT and US, while Granowska and coworkers (1986) were able to demonstrate a 0.5 cm tumor. The percentage of injected dose of antibody taken up by the tumor varied from 0.2% to 2.6% (Epenetos et al. 1984). 0C125. This murine antibody was developed by Bast and coworkers (1981) through immunization with serous cystadenocarcinoma, the most prevalent type of ovarian cancer. It recognizes the antigen CA125, which is associated with more than 80% of all epithelial ovarian neoplasms, mostly of non-mucinous cell type. Part of the CA125 antigen is shed into the circulation. Elevated or rising CA125 serum levels nearly always indicate tumor recurrence or progression (Atack et al. 1986, Niloff et al. 1986, Alvarez et al. 1987, O'Conell et al. 1987), but normal levels do not rule out the presence of disease. Finding an elevated level of CA125 in the serum of patients with an ovarian cancer recurrence (Doherty et al. 1986), led investigators to assess the usefulness of OC125 in radioimmunodetection. The OCt25 was labeled with 1-131 in most studies, only in two studies was In-111 used (Table 2). This appeared to give better contrast in the pelvic region, but exposes the liver to high radioactivity (Hunter et al. 1987). The T/N ratio varied from 1.8 (Barzen et al. 1987) to 2.5 (Chatal et al. 1987). The uptake per gram of tumor tissue was slightly higher after intraperitoneal (i.p.) injection and
D, L. van Kranenburg et al.
110 Table 2, Overview of clinical trials with OC125" Study
MoAb
No. of patients
Doherty et al. (1986)
OC125 b
11
Haisma et al. (1988)
OC125
15
Barzen et al. (1987)
OC125/ anti-CEA
Herry et al. (1987)
OC125
Baum et al. (1987) Chatal et al. (1987) Hunter et al (1987) a
Labeled with 131I;
Sensitivity (%)
Specificity (%)
Accuracy (%)
86
75
82
30
90
70
83
42
93
OC125
18
100
OC125/ 1-19-9
29
72
86
OC125b/ 1-19-9
23
88
50
Prevalence (%)
73
100
80
100
b labeled with rain
less aspecific liver and bone marrow uptake was seen than after intravenous (i.v.) injection (Haisma et al. 1988). Instead of using intact antibodies F(ab')2 fragments were preferred, since their clearance in normal tissue is faster than that of whole antibodies, while their clearance in tumors is comparable. Another favorable feature is the lack of an Fc fi'agment. This eliminates binding of the monoclonal antibodies to Fc receptor positive cells of the reticuloendotheliat system and reduces non-specific binding. It was found that formation of the expected CA125-OC125 immunecomplex formation did not interfere with the scintigraphic imaging (Chatal et al. 1987; Haisma et al. 1986). In a study undertaken by Herry et al. (1987) IS was performed on 42 patients. Of the 41 pelvic tumors present, 38 were demonstrated by IS. Two of those not seen were more than 2 cm in diameter. IS Clearly gave better results than CT and US in locating pelvic recurrences, but identified only 2 out of 8 liver metastases (Herry et al. 1987). Haisma et al.'s research (1988), comparing different routes of administration, deserves special attention. After i.v. injection, 50% of the tumor sites was visualized, whereas only one tumor was not demonstrated after i.p. injection of antibody. In a prospective study by Chatal et al. (1987) 29 patients were examined scintigraphically. According to the tumor marker found in their blood (CA125, associated with serous, or CA-19-9, associated with mucinous ovarian tumors) OC125 or 1-19-9 were used for IS. Judged by the total amount of tumor site found, the sensitivity (72%) was clearly better than that of conventional procedures (US 47% and CT 63%). The immunoscintigram was able to localize
111
Immunoscintigraphyof ovarian cancer Table 3. Overviewof clinicaltrials with 791T/36, NDOG2, H17E2 and H317
Study Symondset al. (1985) Davies et al. (1985) Epetenos et al. (1985) Critchleyet al. (1986) Epetenos et al. (1986)
MoAb
No. of patients
Sensitivity Specificity Accuracy Prevalence (%) (%) (%) (%)
791T/36~
12
NDOG2b
15
92
H17E2c
6
80
H317b H17E2/ H317b
18 13
82 77
83 87
87 100
57
72 100
a Labeled with 131I; b labeled with 123I; ° labeled with rain sites not seen with US in 13 cases and those missed by CT in 8 cases. Falsenegative outcomes were due to peritoneal seedlings, small tumor volume and bladder radioactivity. Hunter et al. (1987) conducted a research trial in which the antibody scan was compared with CT, the OC125 blood level and second-look findings. When compared to second-look laparotomy, IS gave 2 false-positives, one due to granulation tissue and one because of antibody accumulation in the uterus. The 2 false-negatives were due to microscopic disease. As for the CA125 levels, 20% of the patients had a negative value at presentation, mainly because of small tumor volume.
H317 and H17E2. Both of these MoAbs are directed against placental alkaline phosphatase (PLAP). It appears that 35% of ovarian cancer patients (Van Nagell et al. 1981) have an elevated serum PLAP level. In a study by Critchley et al. (1986) 18 women treated for primary ovarian cancer were examined for possible recurrences by means of an H317 scan (Table 3); this enabled 2 patients, who were clinically tumor free, to receive treatment in time. There were no false-positives among the patients with a PLAP negative tumor or with pelvic inflammatory disease (Epenetos et al. 1986a). There appeared to be no correlation between serum PLAP level, the amount of tumor PLAP expression and a positive scan, but positive serum levels always indicated tumor presence. The high incidence of PLAP on ovarian neoplasms, the fact that H317 does not react with the smoking associated PLAP and the relatively high T/N found (Epenetos et al. 1986b), might make this antibody suitable for treatment. NDOG2. This MoAb is also directed against PLAP. Immunohistology showed that 70% of the ovarian cystadenocarcinomas reacted with NDOG2. Davies et al. (1985) reported 15 patients with suspected primary of confirmed ovarian cancer, who underwent IS (Table 3). Eleven women were chosen on the basis of
112
D. L. van Kranenburg et al.
their tumor PLAP expression, while this was unknown in the remaining 4 patients. The T/N ratio ranged between 1.4 and 4.8. The images underwent computersubtraction, giving 1 false-positive. Two of the patients with a false-negative result had microscopic peritoneal seedlings; the original tumors later appeared to be PLAP-negative. Finally, in 2 patients who appeared to be clinically free of tumor, IS showed otherwise. 791T/36. This MoAb was originally raised against osteogenic sarcoma. The 791T/ 36 probably binds to an as yet unknown antigen in malignant ovarian tumors. One trial is known (Table 3) in which 12 patients treated for ovarian cancer were examined for recurrent tumor (Symonds et al. 1985). All but one had a positive scan, 5 of these needed no image-subtraction (in this case Tc-99m labeled erythrocytes and free pertechnetate were used to simulate the distribution of antibody remaining in the circulation). The negative scan was in a patient with a benign cyst. One patient with a recurrence received therapy on the strength of the scan result. In 2 other patients IS was repeated after 6 months and produced early evidence of persistent tumor.
Discussion While IS is good at the visualization of tumors, one must be cautious about the sensitivity of the method. Chatal et al. (1987), Epenetos et al. (1984) and Herry et al. (1987) report sensitivities based on the number of tumor sites located, but in most studies one wonders whether positive scans detected all areas in which cancer was present. In one instance images of equivocal quality were judged to be positive if a tumor was found at laparotomy (Epenetos et al. 1985b). Furthermore, in some cases IS was compared with second-look laparotomy, and in others only with CT findings (Pateisky et al. 1985, Hunter et al. 1987, Chatal et al. 1987). Another complicating factor is that few authors are specific about the nature of the pelvic mass imaged (primary or residual disease, tumor recurrence or metastases), making it difficult to assess the exact role IS plays in detecting these various kinds of tumors. A high sensitivity usually means lower specificity. An example of this is the study of Granowska et al. (1986); a sensitivity of 95% was achieved with a specificity of 20%. The author concludes that the antibody, in this case HMFG2, does not determine whether or not a pelvic mass is due to overian cancer. The most accurate MoAbs seem to be those directed against PLAP; H17E2 and H317, showing less reactivity, if any, with normal tissue. Unfortunately, not all ovarian neoplasms express PLAP. The overall specificity is rather low. OC125 does compare favorably with HMFG, showing less reactivity with nonovarian tissue, as demonstrated through IS (Granowska et al. 1984a, 1984b). On the whole IS is quite accurate, being correct more often than US and CT and was frequently able to give important clinical information, unobtainable by
Immunoscintigraphy of ovarian cancer
113
other noninvasive methods (Pateisky et al. 1985, Herry et al. 1987, Epenetos et al. 1985a, 1985b). In these same studies IS sometimes missed a site that was demonstrated by US or CT. Chatal et al. (1987) reviewed the clinical value of CT, US and MRI for detecting ovarian cancer. By simply analysing all reports in the literature relating to this matter, he came up with a specificity of 95% for both CT and US, the sensitivities for US, CT and MRI being respectively 58%, 80% and 85%. When comparing these percentages with those obtained in the various studies using IS (Tables 1-3), IS does not differ so much from CT or US. As CT, US and IS use different criteria, these methods should be regarded as complementary. Its lack of specificity makes IS less useful for demonstrating primary tumor or for screening. Since most false-negative results occur with small tumors (Shepherd et al. 1987, Patzeisky et al. 1985, Chatal et al. 1987) or peritoneal seedlings (Chatal et al. 1987), second-look laparotomy remains the gold standard. IS has potential in assessing the extent of tumor (primary or metastatic) before operation and in monitoring the response to treatment in patients with extensive disease. The fact remains that the T/N ratio and, more important, the percentage of the injected dose of antibody taken up by the tumor, are still low. There are all kinds of techniques to enhance tumor visualization, but these will not increase the MoAb uptake by the tumor. This might be improved by injecting a cocktail of MoAbs (Rankin and McVie 1983), since the majority of tumors have heterogenous antigen expression (Baldwin and Byers 1986). The route of antibody administration could make a difference to the quality of the image. The i.p. administration of OC125 seems promising (Haisma et al. 1988). On the other hand, Ward et al. (1987) demonstrated that i.v. administration of HMFG2 resulted in consistently higher levels of antibody in solid tumor. The fact that the investigations were performed using different antibodies and different tumors might explain these differences. Another point worth examining is the smallest volume of tumor detected. Few authors mention this, but Granowska et al. (1986), were able to detect tumors of less than 0.5 cm diameter and if others can do this IS might prove to be a very valuable tool. We believe that IS cannot replace second-look laparotomy. Its importance lies mainly in the follow-up of ovarian cancer patients and might be helpful in timing second-look surgery and in directing biopsies. As long as there are still false-negatives, the search for an improved MoAb must continue. Of the most recently developed ones, two seem very promising. OV632 raised against nonmucinous ovarian carcinomas, appeared to be sufficiently specific to differentiate between primary and secondary cancer in an immunohistological study (Fleuren et al. 1987). Another promising antibody is OVTL3 (Epenetos et al. 1987a, Poels et al. 1986). No ovarian cancer of epithelial origin has yet been found to be OVTL3 negative. Although these antibodies have potential their real significance needs to be assessed in clinical trials. MoAbs may be useful in the therapeutic treatment of ovarian cancer; for example cytotoxic agents could be linked to radionuclides (Baldwin et al. 1986),
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D.L. van Kranenburg et al.
or irradiation could be antibody-guided. Epenetos et al. (1987 b) have used the former method successfully in a small number of patients and other clinical trials are undeway.
Acknowledgements. The authors thank R. Vatkema, M.D., for advice and Ms. Y. E. J. Soons and Mrs. M. Boer for typing the manuscript.
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Shepherd JH, Granowska M, Britton KE, Mather S, Epenetos AA, Ward BG, Slevin S (1987) Tumor-associated monoclonal assessment of ovarian cancer. Br J Obstet Gynaecol 94:160-167 Symonds EM, Perkins AC, Pimm MV, Baldwin RW, Hardy JG, Williams DA (1985) Clinical implications for immunoscintigraphy in patients with ovarian malignancy: a preliminary study using monoclonal antibody IT/36. Br J Obstet Gynaecol 92:270-276 Van Ginneken JKS, van der Vlist WP (1985) Kankersterfte in Nedefland laatste 30 jaar meer dan verdubbeld. Kanker 9:4-9 Van Nagell JR, Donaldson ES, Hanson MB, Guy EC, Paulik EJ (1981) Biochemicals in plasma and tumors of patients with gynecologic malignancies. Cancer 48:495-501 Ward BG, Mather SJ, Hawkins LR, Crowther ME, Shepherd JH, Granowska M, Britton KE, Slevin M (1987) Localization of radioiodine conjugated to the monoclonal antibody HMFG2 in human ovarian carcinoma: assessment of intravenous and intraperitoneal routes of administration. Cancer Res 47:4719-4723 Received May 16, 1989/Accepted December 11, 1989
