A recent international survey on the size of clinical trials in cancer showed the frequent problem of slow patient accrual, which remains a major hindrance to progress. The survey also revealed that, although the design of most trials specified a fixed number of patients, subsequent experience revealed a much more flexible approach, with analysis of results, say, every 4--6 months. Conventional sequential methods are hardly ever used and unfortunately most trials proceed without any predetermined stopping rules. Some trial organizers use repeated significance tests on accumulating data as a guide to the detection of treatment differences, an approach that can be adapted to a more rigorous statistical framework as a "group sequential design". The major statistical principle involved is that the more often one analyses the data the greater is the probability of achieving a statistically significant result, even when the two treatments are equally effective. Group sequential designs require the adoption of a more stringent significance level to allow for repeated testing. If one intends up to 10 repeated analyses of the data, only a treatment difference significant at the 1% level would merit a decision to stop the trial. For any trial to implement a stopping rule successfully there must also be prompt feedback and processing of response and survival data ready for up-to-date analysis. Such efficiency is often lacking. The repeated presentation of interim results of a trial to participating investigators can seriously affect their future reaction, especially if there are interesting but non-significant differences. Thus, some secrecy about ongoing results is advisable if trials are to achieve an unbiased conclusion.

The influence of anaesthetics on the in vivo response of B16 melanoma to melphalan was studied using an in vitro cell-survival assay. Three anaesthetics were used, Saffan (Althesin) Sagatal (Nembutal) and Hypnorm. When Saffan was administered to tumour-bearing animals before melphalan there was a significant increase in tumour-cell kill. This effect was not observed with Sagatal or Hypnorm. Maximum increase in tumour-cell kill was achieved when Saffan was administered about 1 h before melphalan, and was dependent on Saffan dose. Clonogenic tumour-cell repopulation after melphalan was rapid (TD - 1 day) and the rate was similar from 2 levels of cell kill. When Saffan was combined with melphalan the repopulation rate was the same as with melphalan alone, and the increased cell kill was reflected in increased growth delay. The in vitro response of B16 melanoma cells to melphalan was unaltered by pretreatment with, or simultaneous exposure to Saffan. The results suggest that the mechanism of the enhanced cell kill in vivo is probably due to an indirect systemic effect, rather than a direct effect on the tumour cells.

Concentrations of misonidazole and its O-demethylated metabolite Ro 05-9963 in the plasma and saliva of 10 patients with malignant disease have been determined. A good linear correlation was established between plasma and saliva misonidazole concentration, and salivary sampling was found to be suitable for the estimation of a number of pharmacokinetic parameters. Data are also presented for serial tumour cencentrations of misonidazole and Ro 05-9963 in 3 of the 10 patients. Monitoring of salivary misonidazole concentration appears to be a useful alternative to plasma monitoring, particularly for those patients in whom plasma sampling is unsuitable or impossible.

Leucocyte-migration-inhibition test was used to study the immune reactions of leucocytes from 136 colorectal cancer patients, 43 patients with non-cancerous chronic colorectal diseases and 82 controls, with saline extracts of HT29 line. A positive inhibition was found in only 43% of colorectal cancer patients. It was higher in carcinomas of limited extension than in invasive ones (64% against 39%). Furthermore, operation by itself had a depressive effect on the reaction, as the positivity in 25 patients tested twice was 64% before operation and 32% after. Leucocytes from patients with non-cancerous chronic colorectal diseases gave many positive reactions (65%). The percentage of positivity was about the same for diseases with high, low or no risk of cancerization. Hence the antigen(s) of tumour extracts that react with patient's leucocytes are, at least partially, unrelated to cancer.

The formation of cyclic AMP was studied in normal liver, subcutaneous hepatomas derived from MH1C1 cells, and premalignant liver and primary hepatomas induced by the carcinogens 2-acetylaminofluorene (AAF) and 4-dimethylamino-azobenzene (DAB). While only very slight effects of prostaglandins (PG) were seen in slices of normal liver, all the hepatomas responded strongly to PGE1 and PGE2. The hepatomas also had increase PGE1-sensitive adenylate-cyclase activity. PGF1alpha and PGF2alpha did not increase the cAMP level significantly either in the liver or in the hepatomas. During AAF carcinogenesis the response to PGE1 increased slightly during the carcinogen feeding, and was greatly elevated only in the fully developed hepatomas. This is in contrast to the increase in adrenalin response seen during carcinogenesis, which starts much earlier, and reaches a peak value within 8--10 weeks. It is concluded that various hepatomas have elevated responsiveness to PGE1 and PGE2 as well as to adrenalin, but the course of change in the tissues' ability to respond to these agents during carcinogenesis is very different.

Post-mortem studies suggest that liver metastases obtain the majority of their nutrition from the hepatic artery; however, cytotoxic arterial perfusion with or without hepatic-artery ligation has not proved entirely successful as a therapeutic regime. In this study we have measured blood flow into colorectal liver metastases using xenon-133 (133Xe) clearance in patients undergoing surgery for colorectal cancer. Pre-operative measurements after direct parenchymal injection gave a mean flow of 41.5 +/- 22.5 ml/min/100 g which after hepatic arterial occlusion perfusion, was reduced to a mean of 5% of the pre-occlusion value. Dynamic blood-flow studies using the gamma camera were performed in the post-operative period by administration of 133Xe into both hepatic arterial and portal venous catheters. The initial distribution images indicated a predominant arterial perfusion to the metastases, but after hepatic-artery ligation, portal-vein perfusion to the metastases was statistically significantly increased. Hence, a compensatory haemodynamic mechanism exists which may account for the poor results of hepatic-artery ligation and perfusion alone. Images Fig. 2 Fig. 3 Fig. 4 Fig. 5

A panel of 5 different breast-cancer and 2 other cancer extracts was used to clarify the false-negative responses in patients with Stage I and II breast cancer and the false-positive responses in control subjects. Most patients with Stage I and II breast cancer who had an initially negative LAI response were positive when tested against the panel. The false negatives occurred because of (1) the experimental errors of the assay; (2) changes in the antigenic strength of the extracts; (3) antigenic heterogeneity of a few tumours and (4) lack of tumour-specific reactivity of the host. 3% of control subjects had a false-positive LAI response. The leucocytes from most of these positive patients did not react to the panel of antigens, and hence the false positives appeared to result from experimental error. In-hospital patients with benign breast disease had a 12% positivity rate when initially assayed, and 63% of these patients reacted to the panel of breast-cancer antigens. Those patients with benign breast disease who reacted to the panel of breast-cancer antigens had cytophilic anti-breast-cancer antibody in their serum; their leucocyte LAI reactivity was blocked in an immunologically specific manner by serum from advanced Stage IV breast-cancer patients; their leucocytes reacted to extracts of breast cancer and not fibrocystic breast tissue; their leucocyte reactivity was blocked by isolated breast-cancer TSA that was linked to beta 2 microglobulin, but not by normal breast-tissue proteins; and the kinetics of the LAI response after excision of the breast mass was identical to that observed with breast-cancer patients after mastectomy. In these patients, the breast tissue within the breast lump expressed breast TSA similar to unequivocal breast cancer.

A series of 300 patients presenting consecutively with primary operable breast cancer has been studied. A significant correlation was found between oestrogen-receptor (ER) content and histological grade: the better-differentiated tumours rarely lacked receptor. This correlation was significant only in women defined as post-menopausal. Data on early recurrence of disease indicate a worse prognosis for women in whom primary tumours are ER-.