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IMMUNOSCINTIGRAPHY |
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Department of Surgical Oncology and Radiotherapy Regional Cancer Centre, Medical College P.O., Trivandrum - 695011, Kerala, India. |
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| ABSTRACT: Immunoscintigraphy Is defined as visualisation of tumour or draining lymph nodes by the use of radio labelled monoclonal antibodies directed against a tumour associated antigen. The technique was first used In 1970s, however the results were poor. The advancements In the techniques of Molecular Oncology, isolation of specific antigens as potential targets, advancements in nuclear medicine, availability of newer labelling agents and hand held gamma probe has helped us to improve visualisation. Thetechnique is yet to be incorporated in standard management strategy, however, due to the sensitivity of the technique it has already started creating waves. Keyword : Immunoscintigraphy, monoclonal antibodies, fragmented antibodies, SPECT. Clinical trials. INTRODUCTION : The first attempt at tumour visualisation using mono-clonal antibodies (MAb) directed at carcino-embryonic antigen (CEA) was made in early 70s. Though successful in murine model the technique could not be perfected in humans due to large amount of circulating CEA in non malignant tissue. The antibodies used were polyclonal anti-CEA labelled antibodies raised in goats. The second generation Tc labelled human serum albumin mimics the circulating part of the antibody and can be subtracted to distinguish tumour from non tumour uptake (subtraction imaging), thus Improving visualisation. The hybridoma techniques gave new Inputs to the development of immunoscintigraphy. Using this technique it was possible to use MAb directed against specific site antigens. The good results obtained from patients with colorectal, breast, ovarian carcinoma and lymphoma led to the improvement of antibodies labelling techniques and increase in its use in the diagnosis and treatment. The main problem encountered was to distinguish selective from non-specific uptake and poor signal to background ratio. This review will deliberate on technical advances made in the field of immunoscintigraphy and review the results of various clinical studies In breast, colorectal, prostate and ovarian carcinomas and tymphomas. INTACT ANTIBODIES FOR IMAGING: Initial attempts at Immuno-scintigraphy were made using intact antibodies. The problem associated with the use of intact antibody was its decreased sensitivity due to binding with circulating antigens and delayed clearance from the system exposing individuals to greater radiation exposure. USE OF FRAGMENTED ANTIBODIES (F'Ab) FOR IMAGING: Mach et al. in 1980 proposed the use of antibody fragments in place of intact IgG to improve clearance. They demon-strated that uptake in terms of percent injected dose per gm tumour (%ID/g) was same for intact and fragment antibodies whereas with fragment antibody the tumour activity was considerably lower. This was later confirmed in patients with colorectal carcinoma. The higher tumour to background activity using this technique enhanced the visualisation of even smaller tumour masses. Delaloye et al, in 1986 reported visualisation of colorectal cancer deposits in 82% patients studied with I labelled F(ab)2 and 89% visualisation in patients studied with FAb of the same anti CEA MAb using emission tomography. Use of Antibody Cocktail for imaging: To overcome the hetero-geneity of antigen ex-pression inorder to improve tumour visualisation a combination of MAb directed against different tumour associated antigens (TAA) or against different epitopes of the same antigen are used. This mixture of monoclonal antibodies is sometimes called antibody cocktail. The concept was first advocated by Chaetal et al, in 1984, Using this method they found a higher sensitivity (77%) in patients injected with two radio labelled antibodies directed against different antigens of colorectal carcinoma (17-1A/19-9 or anti CEA 202/19-9) compared to patients receiving either 17-1 A/19-9 (59%) or 19-9 (66%) alone. The results were further confirmed by Baum et al, in 1986. Similar results were observed by Matz Ku et al, with three different antimelanoma MAbs 149.53, 225-28 and 763.34. The use of radioimmunococktails damped when similar results were obtained by use of single MAb's later. Short-Lived High Count Rate Radionuclides: Earlier investigators unanimously used as commonest labelling material. Later attempts were made to replace it as it requires 364 KeV-gamma emission and because of emerging importance of beta emission that prevents injecting higher activities. It was later replaced by Tc 99 and In for labelling Monoclonal antibodies in radioimmuno-scintigraphy. Although In has favourable scanning characteristics it is not easily available and its use is expensive. Buraggi et al. in 1985 compared HMW-MAA 225.285 antibody and fragment imaging using I, I, TC and in I Labelling. They made two observations, first the clearance of I labelled fragment was faster then Intact antibody and second the Tc labelled antibody fragment had the faster clearance). This showed that using high count rate radionuculeolides it was possible to detect tumours of 1 cm size. Single Photon Emission Computed Tomography (SPECT): Availability of high count gamma emitters and development of a rotating gamma camera made SPECT an attractive option. By using this technique the sensitivity of imaging improved considerably. In earlier studies using tomoscintigraphy, Berche et al. showed that 16 of 19 (84%) tumours were visualised against 9/23 (39%) visualised by rectilinear scans. These results were later confirmed by other studies. Later in 1985, Lumbrosod et al. superimposed colour coded CT and SPECT Images to get precise localisation of abnormal foci of antibody uptake. This technique was later used to enhance characterisation of CT images. Multistep Labelling Techniques: High circulating and normal organ activity is a problem for Immuno- scintigraphic visualisation of small lesions. Even by the use of above methods at times it is not possible to get a good signal background ratio. By using multistep labelling technique using secondary antibodies directed against primary labelled antibody it is possible to get accelerated clearance of non tumour bound primary labelled antibody. Later researchers using avidin blotin labelling techniques further improved this process. This technique used biotinylated antibodies and In labelled avidin or streptavidin or streptavidin - conjugated MAb's followed by Injection of radiolabelled biotin. Beside two step, a three step approach has also been proposed by the same author. All these techniques showed an enhanced tumour imaging by drastically decreasing the background activity. Locoregional Admini-stration of Antibodies: Locoregional administration was tried to improve the tumour visualisation by increasing tumour uptake. This is carried out either by intradermal injection or injection in pleural or peritoneal cavity. For imaging pelvic tumours or recurrent seedlings intra peritoneal administration was found to be superior to intravenous administration, it was best for micronodules or imaging tumour cell clusters. The work was pioneered by Ms. Senekowitsch who showed that the uptake and visualisation was better after intraperitoneal administration in nude mice with peritoneal carcinomatosis and was further improved by using infusion pumps. Visualisation of lymphnode, metastasis after intradermal Injection was attempted in breast cancer. The visualisation was very good however, it never gained much interest as the surgeons were not willing to accept Immunoscintigraphy as an evaluation tool compared to histopathology. Clinical Trials Using Immunoscintigraphy for Tumour Imaging Most of the clinical data on Immunoscintigraphy comes from tumour imaging of colorectal, ovarian cancer and melanoma and very little from breast cancer. Similarly most of the data on lymphnode imaging is from melanoma, lymphoma, breast cancer and prostate cancer. Over 30 clinical studies were carried out for Imaging of gastrointestinal cancers between 1980 and 1993. During this period approximately 1750 patients were evaluated with a sensitivity of 79%. Average specificity was 85% with 81% accuracy. The first studies carried out In 1980 by Mach et al had a sensitivity of 41-53% which by 1990s increased to 90-97% by use of ln or Tc labelling and set of fragmented antibody for imaging. The detection rates varied from anatomical sites being less for detection of hepatic lesions due to increased Concentration of radiolabelled antibodies in liver reducing signal background ratio. In the ovarian cancer since 1982 approximately 20 studies were performed totalling about 600 patients. The sensitivity was at a uniform 80-100% and specificity 45-100%. The accuracy however ranged from 70-90%. These studies were performed using different antibodies (HMFG1,HMFG2,OC125, MOV 18, B72.3, OV-TL3, NCRC-48 and SM3) and various labelling agents (1, I, and TC,)in various combinations. Average sensitivity of these studies was found to be 78%, specificity 80% and accuracy 77%). Between 1984-1993 more than 1600 patients underwent imaging for melanoma, all the patients were studied with F(ab)2 fragment of MAb 225.285 receding HMW-MAA. The average sensitivity was found to be 70%, specificity 94% and accuracy 84%. In one large multicentric study involving 493 patients with 728 lesions over all sensitivity was 79% for patients and 70% for lesions. Five patients had a false positive diagnosis and 125 correct negative diagnosis hence specificity was 96% and accuracy 84%. The nodal detection in prostatic cancer by using monoclonal anti-prostatic acid phosphatase (PAP) antibodies labelled with I showed very good sensitivity and specificity. Leroy et al. in 1989 injected anti PAP antibody in periprostatic space of 32 patients and found a sensitivity of 93% and specificity of 83% in detecting lymphnode metastasis. CONCLUSIONS: In the last two decades since its first use, important advances have been made in radio Immunoscintigraphy. The advances are mainly in understanding radiokinetics, pharmaco-logy, choice of labelling agents and advances in radio detection. The advances have not only helped in detecting low volume tumours which could not have been visualised by conventional imaging modalities but has also helped in reducing the number of unnecessary surgeries. The concept has gained ground in melanoma and in prostate cancer however for other sites it is still in experimental phase. Beside imaging, the method is also been used for radioimmunotherapy for selectively targeting the disease. At the moment this seems to be a big leap forward with an immense future potential. Address for correspondence: Dr. Manoj Pandey (Assistant Professor) Surgical Oncology Regional Cancer Centre Trivandrum, Kerala-695011, INDIA Tel.: 0471-442541, 522238 Fax: 0471-447454,441394 E-mail-rcctvm@md2.vsnl.net.in |
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