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Immunoscintigraphy of Recurrences of Gynecologic Carcinomas

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Immunoscintigraphy of Recurrences of Gynecologic Carcinomas Immunoscintigraphy of Recurrences of Gynecologic Carcinomas Jean-FrançoisChatal, Pierre Fumoleau, Jean-Claude Saccavini, Philippe Thedrez, Chantal Curtet, Alicia Bianco-Arco, Alain Chetanneau, Patrick Peltier, Mireille Kremer, and Yves Guillard Unite Inserm U-211, UER de Médecine; Centre RenéGauducheau, Quai Moncousu Nantes; and Compagnie ORIS Industrie Gzfsur Yvette, France Ina first, retrospectivestudy,15 patientswith knownovariancarcinomawereinjectedwith 13110C125 F(ab')2monoclonal antibody (MAb).The sensitivityof immunoscintigraphybased on the numberof the tumorsiteswas 67% (12/18). In a second,prospectivestudy,29 patientswith gynecologiccarcinomawereinjectedwith 1311-OC125F(ab')@(24)or 13119@9 F(ab')@(5)MAbsaccordingto the histologictype. Basedon the numberof testedanatomic sites,sensitivitywas 72%andspecificity86%.Intwo patientsinjectedwith both‘311-OC-125 F(ab')@and1251-NSF(ab')@(nonspecificimmunoglobulin)1 and4 daysbeforetumorresection, tumor uptake of the specific antibody was 2.2 and 4.5 times greater than that of NS. Immunoscintigraphic results were complementary with those of ultrasonography and computedtomography.Finally,in one patientinjectedsuccessivelywith 1311-OC125F(ab')@ and1111n-DTPA-OC125F(ab')@,the recurrenttumorwasvisualizedwith bothradionuclides, with 1111nproviding better abdominal tumor contrast but causing much greater liver radioactivity than 1311. J Nuci Med 28:1807—1819,1987 pithelial ovarian cancers still have poor prognosis, logic type (5). This antibody recognizes an antigen, CA with an overall 5-year survival rate of @30%(1). A 125, associated with ovarian carcinomas particularly of recent study concerning 770 patients reported a 5-year the serous type, and is shed into the circulation where survival rate of <10% for stages III and IV (FIGO it can be assayed by an immunoradiometric method classification), the most common stages at the time of (6, 7). Likewise, antibody 19-9 recognizes an antigen a first diagnosis (2). After initial surgery, treatment designated CA 19-9, associated with mucous carcino generally includes a chemotherapy regimen for ad mas (8), that is also shed into the circulation where it vanced stages with macroscopic residue and chemo can be assayed by the same method. therapy and/or abdominopelvic irradiation for early By serial biologic monitoring with both markers de stages without macroscopic residue. Following chemo pending on histologic type, recurrences can be detected therapy, second-look surgery is usually carried out to early in patients who previously reached a state of confirm possible complete remission (3). When corn complete remission (7). It is then important to be able plete remission is thus confirmed in patients initially to confirm recurrences by visualization, which is the with stages III and IV, a recurrence subsequently occurs role of immunoscintigraphy(IS), in order to provide in 25% of cases with poor prognosis (4). It would further effective surgical treatment. The aim of the therefore be important to be able to detect such recur present study was to specify the diagnostic value of IS rences early, before the appearance of clinical signs, in both by examining patients with previously known and the hope of improving therapeutic effectiveness. localizedtumor sites and, especially,in a prospective A rnonoclonal antibody (MAb) designated OC 125 view, by comparing the efficiency ofthe technique with has been produced after immunization by a serous that of conventionaldiagnosticmethods. ovarian cystadenocarcinorna, the most common histo METhODS Received Sept. 19, 1987; revision accepted June 11, 1987. For reprints contact: Jean-Francois Chatal, MD, U.21 1Inserm, Antibodies UER de Médecine,1, rue Gaston Veil, 44035 Nantes Cedex 01, Two MAbs were usedin this study.—OC125 and 19-9— France. with the choice depending on the type of marker that had Volume 28 •Number 12 •December1987 1807 significantlyincreasedserumconcentrationrelativeto normal initial 10-mm elliptical rotation. Then, with the patient in the values. MAb OC 125 was produced and made commercially same position, a second 40-mm rotation was performed after available'; its characteristics have been previously reported a 20% energy window was centered on the 1311photopeak. (5). F(ab')2 fragments were obtained after pepsin digestion, For each recording, 6-mm-thick transverse, sagittal, and cor and their purity was tested by SDS electrophoresis and high onal sections were then reconstructed using data filtering. The performance liquid chromatography (HPLC) on a TSK 3000 same reconstruction with thicker sections (12 mm) did not column. There were neither Fab' fragments nor intact anti change the interpretation of the images. The normal pattern body in the preparations. The F(ab')2 fragments were labeled ofan ECT section was characterized by patchy, heterogeneous with iodine-i 31 (1311) using the iodogen method, with a distribution with many foci more or less contrasted in relation specific activity of 3 mCi/mg. Immunoreactivity after ra to each other. Our interpretative criteria for considering dioiodination was tested by affinity chromatography using a whether a focus was pathologic required that this focus appear sandwichassay.CA 125antigenwaseluted through a sepha with the same contrast and localization features in at least rose column coupled to OC 125 MAb. The column was three superimposed sections and two tomographic planes. washed and the labeled MAb was then eluted through the Four to seven days after injection of the radioiodinated column. This sandwich assay was made possible by the repet antibody, planar scintiscans were recorded using an large field itive structure of the recognized epitope. The antigen-bound of-view gamma camera with a medium-energy collimator, fraction of the labeledantibody was eluted with a 3M am interfaced with a data processing system.@Anterior and lateral monium thiocyanate solution. The F(ab')2 fragments from views were recorded in order to cover the whole of the abdo 19-9 MAb were labeled with ‘@‘iusing the same method and men and pelvis. Before each scan, @mTcwas injected as in the with the same specific activity. The labeling efficiency ranged ECT study. from 80 to 90% with ‘31I-OC125 F(ab')@and from 90 to 95% Patients Studied with l3hI@l9@9F(ab')2. The immunoreactivity of MAb 19-9 From January 1983 to March 1986, 44 patients with gyn was tested in the same way as with MAb OC 125. The percentageofimmunoreactivitywascalculatedusingthe ratio ogic cancer underwent one or more immunoscintigraphic examinations. These patients can be divided into two groups of radioactivity of MAb eluted with NH4SCN to the sum of on the basis of the circumstances leading to scintigraphy. For MAb radioactivity not bound to antigen plus that eluted with 15 patients (Group I: mean age 58 yr, range 39 to 70 yr), NH4SCN. The percentages obtained were 47 ±4% with @I localization of the primary tumor or recurrence was deter OC 125 F(ab')2, and 80 ±5% with ‘@‘I-19-9F(ab')2. The mined by surgery, palpation of a mass, and/or ultrasonog immunoreactivity of MAb OC 125, the antibody most often usedin thisstudy,wasalsotestedby a cell-bindingassay.The raphy (US) or computed tomography (CT) that showed a tumor mass prior to IS (Table 1). For the other 29 patients cell line used (OVCAR NIH)t came from a serous ovarian adenocarcinoma and expressed the CA 125 antigen (9). (Group II: mean age61 yr, range39 to 79 yr), ISwasthe first Briefly,3. l0@cells were distributed in a round-bottom 96- examination performed prospectively when a recurrence was suspected on the basis of significant and persistent elevation well plate. One hundred microliters of @‘I-OC125 F(ab')2 of the serum concentration of one of the two markers (CA were added to each well and left to incubate 3 hr at room 125 or CA l9-9)(Table 2). A total of 36 immunoscintigraphic temperature with continuous shaking. After centrifugation examinations were performed in these 29 patients, with two and three successive washes, cell radioactivity was counted. examinations in five patients (Nos. 1, 3, 5, 7, 13) and three in The results were expressed in percentage oftotal activity used Patient 4. After IS, US and/or CT was performedblindly in for each well. In these conditions, the percentage obtained was Group II patientswithout knowingthe findingsofIS. A total 46%, whereas it was 1.5% with a nonspecific immunoglobulin of 32 US examinations were performed with a ALOKA SSD labeled in the same conditions. 85 1real-time equipment and 27 examinations were performed Scintigraphic Technique on the third generation CGR CE 10000 Scanner with a scan An activity of 1.5-2 mCi (55.5—74MBq) (—0.6mg) for duration of 3.4 sec. There were fewer US and, especially, CT planar scintigraphy and 2.5-3.5 mCi (92.5—129.5 MBq) (—1 examinations than IS examinations since some patients con mg) for emission computed tomography (ECT) was injected sidered the IS protocol too difficult and demanding and sub into each patient after obtaining informed consent. Thyroid sequently refused US and/or CT. uptake of free ‘@Iwas blocked by oral administration of The localization diagnosis for recurrence (Group II) was Lugol's solution (100 mg/day) for 8 days beginning 2 days confirmed by surgery in 14 cases, by concordant results of US before injection ofthe radioantibody. Each radioantibody was and CT in six cases and by the course of the disease, with injected intravenously over a period of'—30mm in an infusion eventual appearance of a palpable mass in the location of of 100 ml ofsaline solution. No skin test was performed before antibody uptake, in five cases. Absence of recurrence was this injection. Three and four days after injection of the confirmed by surgery in three patients and suggested by the radioantibody, ECT studies were performed using a rotating coursein anotherpatientovermorethan a year'stime.Finally, single-head gamma camera with a medium-energy collima in seven cases the diagnosis at this writing still remains unde tor.* The abdomen and pelvis were evaluated in two scans 3 termined.
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