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Satumomab Pendetide: Preliminary Review of its Use in the Diagnosis of Colorectal and Ovarian Cancer

Clinical Immunotherapeutics, ISSN: 1179-190X, Vol: 3, Issue: 5, Page: 395-408
1995
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Synopsis Satumomab pendetide is a modified murine-derived monoclonal antibody directed at the human tumour-associated glycoprotein TAG-72. Immunoscintigraphy with radiolabelled indium In-111 satumomab pendetide can detect primary or recurrent colorectal and recurrent/residual ovarian malignancy, although expression of TAG-72 by some benign ovarian tumours limits its use in the detection of primary ovarian cancer. Positive scans are highly predictive of disease in patients with colorectal cancer and, to a lesser extent, in those with recurrent/residual ovarian cancer However, the low negative predictive value precludes use of negative results to guide clinical decisions. Compared with computed tomography, indium In-111 satumomab pendetide immunoscintigraphy has greater utility for detecting extrahepatic abdominal and pelvic lesions. Its ability to detect occult disease (including carcinomatosis) is noteworthy. Indium In-111 satumomab pendetide is well tolerated, but the development of human antimurine antibodies currently limits this agent to single use. Immunoscintigraphy with indium In-111 satumomab pendetide is likely to contribute to the management of patients with colorectal or ovarian cancer by detecting occult or recurrent disease, determining the extent and resectability of malignancy and clarifying equivocal findings of other diagnostic tests. Further clinical trials will help define the precise clinical role of this agent, but it appears to be a welcome addition to available diagnostic tests for colorectal and ovarian malignancy. Pharmacology Satumomab pendetide is a conjugate of murine-derived monoclonal antibody B72.3 and a linker-chelator moiety which is radiolabelled with indium (In). This agent is directed at the human tumour-associated glycoprotein TAG-72, which is present in >80% of ovarian and colorectal carcinomas; its binding to noncancerous tissue is limited. Conjugation with In does not affect the immunoreactivity of satumomab pendetide and the resulting complex is stable for up to 8 days in vivo. The ability of this agent to localise in tumour tissue has been demonstrated in clinical studies using planar gamma camera imaging supplemented by single photon emission computed tomography (SPECT). The mean volume of distribution of indium In-111 satumomab pendetide is 3.9L, suggesting limited extravascular diffusion. Following intravenous administration, the agent rapidly accumulates in the liver, spleen, kidneys and bone marrow, with subsequent slow elimination from these sites. Varying activity can also be seen in the blood pool, female nipple, urinary bladder, intestines and non-tumour lesions showing inflammatory or traumatic changes. The plasma elimination half-life of indium In-111 satumomab pendetide is 45 to 64h; plasma and renal elimination occur at rates of 50 and 4.9 ml/h, respectively. The liver is probably the major route of metabolic elimination of the conjugate, with the urinary route accounting for most In excretion. Diagnostic Utility The diagnostic utility of indium In-111 satumomab pendetide for colorectal or ovarian cancer has been demonstrated in several preliminary studies and confirmed in 2 multicentre trials. In a multicentre trial of 192 patients with suspected or proven primary or recurrent colorectal cancer, per-patient sensitivity was 69%, specificity was 76%, and positive and negative predictive values were 97 and 19%, respectively. These findings indicate that positive scan results can be treated with confidence, but negative images are of doubtful clinical value. 19 occult malignant lesions were detected in 17 of 174 patients with colorectal carcinomas. The overall imaging performance of indium In-111 satumomab pendetide immunoscintigraphy was similar to that of computed tomography (CT), but indium In-111 satumomab pendetide imaged a greater proportion of pelvic and extrahepatic abdominal lesions and a lesser proportion of hepatic lesions than CT. The combined sensitivity of these two techniques (88%) was therefore greater than that of either alone (68 and 69%). Subgroup analysis showed that indium In-111 satumomab pendetide immunoscintigraphy might be of particular use in patients with suspected recurrent disease, those with elevated or rising carcinoembryonic antigen (CEA) levels, and those with occult extra-abdominal or extrapelvic tumours. Among 103 patients with suspected ovarian cancer, indium In-111 satumomab pendetide immunoscintigraphy showed greater per-patient sensitivity (95 vs 58%), accuracy (76 vs 58%) and negative predictive value (88 vs 29%), but lesser specificity (50 vs 60%) and positive predictive value (72 vs 83%) in those with initial versus recurrent/residual disease. Expression of TAG-72 by benign tumours probably contributed to the low specificity in patients with suspected primary disease. The lower sensitivity among patients with recurrent disease may reflect the more frequent occurrence of small (≤2cm) tumours in this group. Occult lesions were detected in 20 of 71 patients. Immunoscintigraphy was judged to have changed the presurgical estimate of disease extent in 27% of patients and potentially changed surgical management of 16%. In a comparison of immunoscintigraphy and CT in a subset of 101 patients with suspected ovarian cancer, indium In-111 satumomab pendetide showed greater per-patient sensitivity (69 vs 44%), but lower specificity (54 vs 79%). It also detected proportionally more lesions (69 vs 44%) in patients with biopsy-proven adenocarcinomas and showed greater imaging sensitivity than CT in patients with recurrent malignancy. Indium In-111 satumomab pendetide imaging capability increases with increasing TAG-72 levels, increasing tumour size (>2cm) and extrahepatic location of tumours (accumulation of In by the liver limits the utility for hepatic lesion detection). The presence of TAG-72 in serum does not appear to adversely affect imaging performance. Tolerability Indium In-111 satumomab pendetide was well tolerated in multicentre trials of patients with suspected or proven colorectal (n = 227) or ovarian (n = 108) cancer. Adverse effects were noted in ≤3.5% of patients and comprised itching, fever, mild elevation of blood pressure, nausea, facial oedema and rash. These were graded mild to moderate in severity and all resolved spontaneously or with appropriate treatment. No clinically significant changes in laboratory values were recorded. Positive human antimurine antibody (HAMA) titres developed in about one-third of patients, but were reported to disappear in about half of those affected within 4 to 12 months of infusion. Dosage, Administration and Imaging In patients with colorectal or ovarian cancer the recommended dose of satumomab pendetide is 1mg, radiolabelled with 5 mCi of indium chloride, intravenously administered over 5 minutes. Immunoscintigraphy is performed with a gamma camera to obtain planar anterior and posterior images. Optimal imaging is achieved 72 to 96 hours post-infusion, and follow-up sessions may be performed at up to 120 hours (supplemented by SPECT if necessary) to clarify equivocal findings. Indium In-111 satumomab pendetide is currently recommended for single use only, as the clinical effects of repeated administration have not been adequately evaluated. © 1995, Adis International Limited. All rights reserved.

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