(Green et al., 1990). We have used this method to compare two antibody preparations in the clinical development of RIT. RIT had produced good response rates in radiosensitive tumours such as lymphoma when large amounts of radionuclide are given (Kaminski et al., 1993; Press et al., 1993). However, common epitheial tumours such as colorectal and breast carcinoma have not yet been treated so successfully because of their greater radioresistance, which diminishes the therpeutic ratio. In spite of this, responses to therapy have been reported , and it is likely that moderate increases in efficency in delivery of antibodymediated delivery of radiation could establish radioimmunotherapy as a useful form of therapy for metastatic colorectal carcinoma.Intact IgG antibodies with a molcular weight (MW) of 150 kilodaltons (kDa) may not penetrate well from blood through endothelium and extravascular tissues to the tumour (Yokota et al., 1992). It is proposed that F(ab% antibodies (MW 100 kDa) will achieve more effective penetration because of their smaler molcular size and that this will significantly improve the prospects for effective radioimmunotherapy of colorectal cancer.

The anti-mouse antibody response was examined in patients receiving repeated i.v. therapy with radiolabelled mouse monoclonal antibody (MAb) to carcinoembryonic antigen (CEA): 131I anti-CEA was given approximately every 2 weeks with cyclosporin A, to suppress the anti-mouse antibody response. Two schedules of cyclosporin A--intermittent therapy for 6 days with each course of anti-CEA and continuous therapy--were compared. Suppression of the immune response in the intermittent high-dose (3 patients) and continuous low-dose groups (4 patients) was equivalent, but the latter regimen was less toxic. Repeated therapy led to the formation of small amounts of anti-mouse antibody, but provided that cyclosporin A was continued it did not prevent further therapy or lead to an increase in the rate of clearance of anti-CEA from blood. Without cyclosporin A no more than 2 courses of antibody therapy could be given. Patients received up to 4 doses of 131I anti-CEA. The nadir platelet count was related to the half-life of 131I anti-CEA in blood. Thrombocytopenia limited the amount of 131I anti-CEA that could be given and determined the interval between treatments. Effective suppression of the anti-antibody response is possible and this study has determined that myelosuppression is the principal obstacle to repeated therapy with radiolabelled antibody.

Summary Tumour localisation of anti-tumour antibodies varies greatly between patients. Factors which may be responsible for this have been investigated in 56 patients with colorectal carcinoma with a view to improving radioimmunotherapy. Thirty-seven to seventy-four MBq of 1254-labelled mouse monoclonal antibody to CEA, was given intravenously and tumour resected 70-480 h later. Percentage injected activity kg-' (% inj.act kg-') in tumour, was inversely correlated with the time interval between injection and operation (P = 0.004). To assess the influence of other parameters on localisation, patients were divided into two time groups according to time interval between injection and operation, 70-120 h (n = 33) and 144-480 h (n = 23). In neither group was there a significant correlation of % inj.act kg-' with time. The % inj.act kg-' in tumour showed a significant correlation with that in the blood for both groups (P = 0.005 and P = 0.01). There was no significant correlation for either time group between % inj.act kg- ' (Begent et al., 1985;Martin et al., 1988;Begent, 1990). There is great variability in uptake of antibody in individual tumours in patients and the factors influencing this are poorly understood. Distribution of injected antibodies within tumours is not uniform (Griffith et al., 1988;Pedley et al., 1990

Radioimmunoguided surgery (RIGS) using an anti-CEA (A5B7) monoclonal antibody has been assessed in 52 patients (43 primary excisions and nine second look procedures) undergoing surgery for colorectal carcinoma. The antibody localized in 97.8 percent of primary tumours and in 88.8 percent of the principal tumor in second look procedures. Additional information concerning the extent of primary tumor was obtained in 11 of 43 patients (25.5 percent) undergoing excision of primary carcinoma and five of nine patients (55 percent) in the second look series. Incorrect information was obtained about the extent of the primary tumour in six patients (11.3 percent), whereas no incorrect information was obtained during second look procedures. RIGS correctly predicted the subsequent Dukes' staging in 77 percent of first look cases (sensitivity 65 percent, specificity 90 percent), although accurate identification of individual nodes was impossible. The technique influenced the surgical procedure performed in 2 of 43 cases (4.6 percent) in primary surgery and in three of nine patients undergoing second look laparotomy (33 percent). RIGS in primary colorectal carcinoma may provide additional information concerning extent of locally advanced tumors in particular and the principle that the subsequent surgery may be influenced has been established. The technique appears to have a greater role in second look procedures where it may help determine the extent of recurrent tumour. Larger follow-up series are required to define how the additional information provided by this technique may best be exploited.

Summary Local recurrence of colorectal cancer may result from failure to assess accurately the extent of tumour at operation. It has been suggested that peroperative radioimmunolocalisation may improve this assessment. The degree to which this is possible has been studied using a hand-held gamma detecting probe and comparing two '25I-labelled monoclonal antibodies to colorectal tumours. The antibodies were to fetal colonic microvillus membrane (FMID10) and to carcinoembryonic antigen (A5B7). Sixty-nine per cent (9/13) of the FMlDIO and 98% (43/44) of A5B7 labelled tumours took up significant amounts of antibody with a tumour to normal colon ratio of more than 1.5:1. The uptake was significantly better for A5B7 with a median tumour to normal colon ratio of 3.3 (1. al., 1984;Martin et al., 1985;O'Dwyer et al., 1986;Martin et al., 1986;O'Dwyer et al., 1987). Only 72-76% of tumours in these patients had significant uptake of these antibodies and the mean time needed for adequate concentration of antibody in tumour compared to normal tissue was 16 days.In order to improve on these results the characteristics of an ideal antibody would be: (a) that it is taken up by all tumour deposits; (b) the uptake should be rapid so that surgery does not have to be delayed; and (c) the antibody should achieve as high a tumour to normal tissue ratio as possible to enable small quantities of tumour to be detected. We have therefore compared two different antibodies in 50 consecutive patients, first to validate the method of peroperative radioimmunolocalisation and second to assess which of these antibodies has the better characteristics. Patients and methodsFifty consecutive patients with colorectal carcinoma gave informed consent to enter the trial. Patients received potassium iodide and potassium perchlorate to block thyroid uptake of antibody. Skin testing for allergey to the antibody was carried out as described previously (Begent et al., 1986). Following this 1 mCi of '25I-labelled antibody was injected intravenously and an attempted curative resection was carried out 4-10 days later. Of the 50 patients studied 24 were male and 26 female. The median age was 69 years (range 38-82 years). Seven patients had synchronous tumours making a total of 57 tumours. There were 41 primary resections and nine second look laparotomies. Eleven patients were randomised to FMlDIO and 39 to A5B7. After a preliminary analysis of results, FMlDIO was abandoned.Monoclonal antibodies FMIDIO This is a mouse monoclonal IgGl antibody to fetal colonic microvillus membrane which showed a good localisation to human carcinoma xenografts in nude mice and appeared immunohistochemically to bind to tumour cells (Hennigan et al., 1988). ASB7 This is a mouse monoclonal IgGl antibody to carcinoembryonic antigen (anti-CEA) (Harwood, 1986;Pedley, 1987)