'See and treat' at colposcopy--achieving the standard.

The National Health Service Cervical Screening Programme has issued quality standards for the colposcopy service nationally. One standard is that for women who undergo treatment at their first colposcopy clinic visit, 90% should have proven cervical intra-epithelial neoplasia (CIN) on histology. We have assessed data from a teaching hospital colposcopy clinic over a 9-year period to assess the criteria that should be satisfied in order to achieve this target. We propose that only those women with severe dyskaryosis on the referral smear and a colposcopic appearance of CIN 2 or 3, or those in whom the colposcopic appearance suggests CIN 3 with any grade of dyskaryosis undergo treatment at their first visit.

Phase I open study of the effects of ascending doses of the cytotoxic immunoconjugate CMB-401 (hCTMO1-calicheamicin) in patients with epithelial ovarian cancer.

PURPOSE: We have performed a phase I study of the cytotoxic immunoconjugate CMB-401 in women with epithelial ovarian cancer (EOC). CMB-401 is a directed chemotherapy that comprises a genetically engineered human antibody against polymorphic epithelial mucin, to which is attached covalently two to three molecules, on average, of the cytotoxic antibiotic calicheamicin. The primary objectives of this two-centre study were to identify end-organ toxicities and to establish the maximum tolerated dose (MTD). PATIENTS AND METHODS: Thirty-four patients aged 37-75 years with progressive EOC not amenable to platinum/standard therapy, and with satisfactory WHO performance status (0-2) were recruited. Patients had received a mean of 3.2 previous chemotherapeutic regimens with a median interval since last chemotherapy of 182 days (range 34-1217). Patients received up to four cycles of a dual infusion of 35 mg/m2 hCTMO1 'predose' followed by doses of CMB-401 which were increased for each cohort--a regimen which minimises drug uptake in normal tissues whilst enhancing delivery to the ovarian tumour. CMB-401 dosing commenced at 2 mg/m2 and progressed via seven cohorts to 16 mg/m2. RESULTS: CMB-401 was generally well tolerated. However, transient fever and emesis occurred, necessitating routine prophylaxis, and increasingly significant malaise was reported as the dose increased. WHO grade 3-4 toxicities, irrespective of causality, included: anaemia 21%, granulocytopenia 9%, thrombocytopenia 9%, liver transaminases 3%, sepsis 3%, haemorrhage 6%, nausea/vomiting 76%; pulmonary 6%, and conscious state/somnolence 6%. The MTD was reached at 16 mg/m2. During the study four patients had a greater than 50% reduction in CA125, and three patients had radiological evidence of reduction in tumour bulk. CONCLUSIONS: CMB-401 appears to have an acceptable toxicity profile with demonstrable activity against EOC.

Biodistribution of 111In-labelled engineered human antibody CTM01 (hCTM01) in ovarian cancer patients: influence of prior administration of unlabelled hCTM01.

mAb hCTM01 binds a carcinoma-associated antigen, the MUC1 gene product. The antigen is also present in the circulation, and administration of 111In-labelled hCTM01 results in the formation of immune complexes with enhanced accumulation in the liver. To avoid the unwanted effect of circulating radioactive immune complexes, a strategy to remove the circulating antigen was investigated using a split-dosage schedule. Eleven patients suspected of having ovarian carcinoma were injected with 1 mg/kg unlabelled hCTM01, 1 h before receiving 0.1 mg/kg 111In-labelled hCTM01 (100 M Bq). The amount of radioactivity was determined in resected tumour tissue, various normal tissues and blood samples obtained at laparotomy 6 days postinjection (p.i.). In all patients, the circulating antigen decreased to its nadir after the unlabelled antibody infusion and immune complex formation was demonstrated. Uptake in tumour deposits 6 days p.i. was 11.1 times higher than in normal tissues (P < 0.0001) and 5.9 times higher than in blood (P < 0.0001). 111In activity in liver tissue was comparable to 111In uptake in tumour tissue, and considerably lower than previously reported in patients not pretreated with unlabelled antibody. The split-dosing strategy would appear to be advantageous for use of hCTM01 as a specific carrier for the delivery of cytotoxic agents to patients with ovarian cancer.