الطلقة السحرية لعلاج السرطان اخر ابحاث د ماهر الاعصر مع هيئة الطاقة الذرية

Magic Bullet

Early Detection & Management

of

Colon and Liver Cancers

By using

Mono Clonal Antibodies



ROLE OF IMMUNOSCINTIGRAPHY USING TC-99M

LABELLED MONOCLONAL ANTI – CEA ANTIBODIES

IN THE DETECTION OF COLO-RECTAL CARCINOMA



G. Ziada, H. Moustafa, Sh. El-Haddad and M. El-Aaser



Centre of Oncology and Nuclear Medicine of Kasr El-Eini Hospital

Cairo University, Egypt (NEMROCK)



ABSTRACT:



Twelve patients with colorectal carcinoma confirmed histopathologically and associated with high serum CEA level and underwent preoperative immunoscintigraphy (planar and SPECT projections) followed by operative resection with postoperative histopathological examination. Immunoscintigraphy showed sensitivity of 85.5%, specificity of 60% and accuracy of 66.6% in detection of para-aortic lymph nodes involved as compared to 0%, 25% and 25% in abdominal sonography respectively. Concerning the liver involvement, there was higher sensitivity of 100% and accuracy of 91% of immunoscintigraphy in comparison to 50% and 66.6% in abdominal sonography respectively. Imaging procedure at 4 and 24 hours postinjection with planar and SPECT studies were useful for proper localization of involved sites and to differentiate between malignant and benign lesions. Immunoscintigraphy is a safe procedure and the preparation of the kit of monoclonal antiCEA antibody is rapid with labelling efficiency more than 95% and with no adverse reaction.



INTRODUCTION:

Colo-rectal carcinoma is one of the most frequent carcinomas associated with morbidity and mortality.

The poor prognosis of recurrent colo-rectal carcinoma may be improved by a more efficient control of tumor through the earlier detection with curative resection of colo-rectal carcinoma. Endoscopy, ultrasonography and C.T. scanning are traditional methods for staging work up. CEA as a tumor marker is essential in follow up of colorectal carcinoma, however it has non-specific elevation in chronic smokers and inflammatory bowel disease. Immunoscintigraphy using radiolabelled monoclonal antibodies directed against the carcinoembryonic antigen (CEA) was first described by Mach et al [1] for the detection of colo-rectal carcinomas and their recurrences. Since then, a large number of monoclonal antibodies labelled with different radionuclides such as Iodine-131, Iodine-123 or Indium-111 [2]. Recently, a new technique for labelling of monoclonal anti-CEA antibodies with Tc-99m has been described by Schwarz [3]. This approach allows an almost quantitative labelling of the antibodies with Tc-99m.

This study is aiming to determine the feasibility and accuracy of using Tc-99m labelled monoclonal anti-CEA antibodies in detection of colo-rectal carcinoma and its metastatic spread compared to other methods of investigation as well as with operative data.



PATIENTS AND METHODS:

Twelve patients with colo-rectal carcinoma and high CEA level in the serum were refered to the Nuclear Medicine Unit of Kasr El-Eini Centre of Radiation Oncology and Nuclear Medicine (NEMROCK) from October 1991 to October 1992. The study included ten males and two females. Eleven patients had rectal carcinoma and one patient had colon carcinoma and all patients were histopathologically adenocarcinoma with different grades of differentiation. CEA serum level of the patients was ranged from 12 up to 30 ng/ml (Normal level up to 6 ng/ml). All patients were subjected to full medical history and examination; laboratory investigations; radiological investigations (including chest X-ray, Barium enema and abdominal sonography); lower GIT endoscopy and biopsy. Detection of colo-rectal carcinoma by immunoscintigraphy using 600-1800 mbq of Tc-99m labelled with 2 mg of monoclonal anti-CEA antibodies (431/26) of mouse origin.Quality control of the labelling yield using thin layer chromatography (TLC) showed labelling efficiency
Grater than 95%.The labelled monoclonal antibodies were injected slowly byintravenous route and every patient was observed for any adverse reaction.

Immunoscintigraphic images over the abdomen;pelvis the chest were performed using siemens gamma canera acquiring 500-1000 k counts using low energy high resolution parallel hole all purpose collimator attached to Microdelta computer. Planner images were done at 10 min.post-injection and both planner and spect images were subjected to surical intervention giving a full report about the primary lesion, the draining lymph nodes up to the para-aortic groups and the condition of the liver. Biopsy was taken from each site for pathologic examination.
Correlation of operative histopathologic dataaas standard parameter with immunoscintigraphy in detection of colo-rectalcarcinoma and its metastatic spread in comparison to other Imaging modalities were evealuated.



RESULTS:



There were no side effects secodary to the infused monoclonal antibodies fragment in all the patients.



The early images at 10 min.post-injection showed blood pool activity . proper localization of site of the tumer involvement was evident at 4 hours postinjection.However,late images at 24 hours postinjection showed better visualization of primary site as well as metastatic sites.There was no uptake in thyroid region indicating high radiochemical purity (labelling efficiency greater than 95%).The scintigraphic tumor contrast was generally good in analogue films without the need of computer processing. SPECT images were performed at 4 and 24 hours post-injection wich allow better localization of primary lesion and differentiate between activity in the rectal region from bladder activity (Fig.1a&b).The primary lesion was detected in all the patient studied with 100% sensitivity, specficity and accurcy.The metastatic spread to lymph nodes was evident in 2 cases in pelvis,6 cases in para-aortic region and 2 cases in left supra clavicular region which was not palpable clinically.At level of para-aoritc lymph nodes,6 out of 8 patients were matched with laparotomy data,whileas the other 2 patients gave false negative results by immunoscintigraphy.The sensitivity, specifity and accurcy of immunoscintigraphy in evaluation of para-aortic lymph nodes in relation to laparotomy was 85.58, 60% and 66.6% respectively (Tab.I&II) .

On evaluation of metastatic spread to liver,7 out of 12 patients showed possible metastatic spread (6 patients were matched to laparotomy data,while one patient showed false opsitive result.The sensitivity, specificity and accurcy of immunoscintigraphy for detection of metastatic liver lesions were 100% in sonography respectively (Tab.I&II).

Late images of the liver at 24 hours postinjection were very essential to differentiate between malignant and bengin lesion in the liver (Fig.2a&b). The antibody uptake in liver metastases was variable some presenting as hot as spots (Fig.3a); other as cold lesions (Fig.3b).



DISCUSSION:



The advent onoclonal antibodies stimulated a renewed interest in tumor imaging using radiolabelled antibodies. This technology may provide a simple single test to study primary site of malignancy and list metastatic spread for the presence of cancer simultaneously.The release of carcinoembryonic antigen (CEA) by colo-rectal cancer lead to the early application of radioimmunoscintgrsphy (RIS) in its management. In

This study,injection of radiolabelled monoclonal antibodies was well tolerated by all the 12 patients studies with no Adverse reactions. Similar data was reported by Baum et al. And Muxi et al [4,5]. The tumor uptake of specific antibodies increases with time during first 24 hrs. As early at 10 min. postinjection, blood pool images showed nonspecific uptake, whereas; late images at 24 hours post-injection were essential to clarify site of primary lesion and metastatic spread in pelvis and abdomen. Although some pathologic lesions were evident at 4 hr. post-injection, but correlation with 24 hours post-injection images were essential as benign lesions may disappear in late images, similar results reported by Granowska and Britton [6]. SPECT images were essential in evaluation of primary lesion especially those in the rectum to differentiate from bladder activity.



The sensitivity and accuracy in detection of primary colorectal tumors were 100%. Whereas Muxi et al reported a global sensitivity and accuracy of 59.7% for detection of primary tumors and pelvic recurrence which may be related to performing SPECT in ONLY 5 OUT OF 46 OF THEIR PATIENTS [5].



Although the primary lesion was undifferentiated adenocarcinoma in 8 out of 12 patients (66.6% of cases) but immunoscintigraphy was capable of detecting all lesions inspite of the fact that CEA is a differentiated antigen poorly produced by undifferentiated tumors [8].



As regards metastatic L.N. spread, immunoscintigraphy showed 85.5% sensitivity and 66.6% accuracy compared to laparotomy data. However, non of those cases were evident on sonography; this may be related to operator dependence. All cases with metastatic liver disease seen on surgical laparotomy were detected by immunoscintigraphy; with the addition of one false positive case. Only 50% of positive cases were detected by sonography; this indicates that immunoscintigraphy is a more sensitive and accurate techniqu for detection of metastatic spread in liver. Late images at 24 hours were essential to separate benign lesions in the liver of egyptian patients with dominance of schistosomiasis associated with hepatic periportal fibrosis and formation of regenerating nodules.



Such nodules may be seen in early images but disappeared in late images (Fig. 3a&b). Liver metastasis may appear either cold or hot nodules or mixed [4,5]. However, the majority of lesions in this study were cold which may indicate necrotic lesions with less vascularity as there is usually inverse correlation between tumor mass and uptake depending on the vascularity [7].



To conclude, radioimmunoscintigraphy is effective diagnostic modality in diagnosis of colorectal cancer in addition to convential radiology and endoscopy to evaluate the extent of the disease and its metastatic spread. Its application may be needed in follow up of patients specially those with Duke C. stage with 50% of recurrence rate at one year end, also to identify site of recurrence in coloretal patients postoperatively with elevated serum CEA or those with normal CEA but has abnormal mass detected by C.T. scan to differentiate viable tumor from postoperative fibrosis.



ACKNOWLEDGEMENT:



The author are grateful to International Atomic Energy Agency (IAEA) for its help and offering the kit of anti-CEA monoclonal antibodies (MoAb 431/26) used in our work. [Project Research no 324 RC-EGY-6597]