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Most women with "early" breast cancer have distant metastases by the time the primary growth comes to diagnosis. This observation is based upon the fact that these frequently appear despite successful removal of the primary growth, and given that they originate from the now no longer present tumour, the inescapable conclusion is that dissemination must have taken place prior to initial treatment. Failure to appreciate this rather obvious point results from shortcomings in available diagnostic technology, and inadequate usage of that which is available. Whether detected early or late, treatment of this disseminated cancer poses a common problem, and the various systemic methods are reviewed. Androgens, oestrogens, progestogens and single drug chemotherapy can, from time to time, produce useful results. By careful selection of patients with appropriate metastatic patterns, these methods may yield improved response rates up to 50% but, by and large, experience remains disappointing with across the board representative figures of perhaps 25% response being commonplace. Additionally, these methods are not without their side effects which can be distressing, and indeed on occasion life-threatening. Their short-comings have led to the development of cyclical combination chemotherapy as here reported. Cyclophosphamide, vincristine, 5-fluorouracil and methotrexate are administered for five consecutive days per month. The results obtained in 100 patients treated with this technique are compared with the authors' previous experience with norethisterone acetate and hypophysectomy. Whether the results are considered in total or broken down into prognostic categories such as predominant metastatic pattern, disease-free interval, or age, combination chemotherapy has a clear advantage over other techniques. Whilst this experience does not constitute a randomised trial, it is considered that the results are so superior to previous treatment techniques as to render such a study unnecessary or even unethical. It is proposed that combination chemotherapy should constitute the first line of treatment for overt advanced breast cancer. It is further proposed that its role should be explored at an earlier stage in the treatment of breast cancer. Before this can take place however, treatment must be made less demanding and less toxic. Further research is underway with these aims in mind.

This article considers the distinction between "explanatory" and "pragmatic" aims in clinical trials--the distinction between testing a biological hypothesis and providing evidence to permit a choice between alternative treatment policies. The choice of treatments to compare, the selection of patients for the trial, the study size, and how the treatment comparison should be made are among the matters discussed. In general, where explanatory and pragmatic aims conflict, the pragmatic aim will often take priority.

This prospective study has established the effectiveness and safety of two courses of a combination of vincristine, bleomycin, methotrexate, 5-FU, and hydrocortisone with a folinic acid "rescue" given over 24 hours on Days 1 and 14 prior to surgery and/or radiotherapy in 93 patients with advanced (stage III and IV) untreated epidermoid cancer of the head and neck. Of 91 patients evaluated on Day 28 for chemotherapy response, 58 (64%) had a partial remission and 33 (36%) were classified as nonresponders, although 12 had a minimal response of 20%-30%. After completion of local therapy, 73% of the chemotherapy responders achieved complete remission compared with only 48% of the nonresponders (P = 0.005). Forty-seven percent of the patients achieving complete remission were alive at 5 years compared with only 4% of those with residual disease after local therapy. Response to chemotherapy is a good prognostic sign. Side effects were minimal and there was 100% patient compliance.

Twenty patients with previously untreated nasopharyngeal tumors received, as initial treatment, two courses of Schedule A chemotherapy including vincristine, 5-fluorouracil, bleomycin, hydrocortisone, methotrexate, and a folinic acid rescue, prior to definitive radiotherapy. Thirteen patients had Stage IV and seven had Stage III tumors, with nodal involvement in 18 patients (90%). Response to two courses of Schedule A chemotherapy was assessed on day 28, and overall, 18 patients responded. Side effects were minimal. Following radiotherapy 17 patients achieved a clinical complete remission. Durations of response ranged from 6 to 95+ months (median 40 months) and of survival from 8 to 95+ months (median 53 months). This chemotherapy protocol should be more widely evaluated as initial treatment in nasopharyngeal carcinomas since the 90% chemotherapy response rate and, after radiotherapy, 85% clinical complete remission rate was accomplished with minimal toxicity and interference with patients' quality of life and resulted in median overall survival figures of approximately four years.

To assess whether the use of large stents is justified, we have retrospectively reviewed the results of 8 French gauge (FG) stents with pigtails and 10 FG straight stents in the palliation of biliary obstruction due to malignancy. The incidence of cholangitis following stent insertion was significantly lower with 10 FG stents, 3 (5%), compared with 8 FG stents, 13 (34%), p less than 0.001, chi 2. Stent survival until blockage was significantly longer for 10 FG (median 32 weeks) compared with 8 FG (median 12 weeks), p less than 0.001, log-rank. The superior performance of the 10 FG stents was due to their larger diameter which gives them a flow capacity much greater than the physiological bile flow. We recommend that stents of at least 10 FG diameter are used for the endoscopic palliation of biliary obstruction due to malignancy.

248 patients with locally radically treated early breast cancer (196 node-positive) were randomized post-operatively between 6 courses of a 'CMF like' chemotherapy and no further treatment. Results (with a minimum of 5 years follow-up on every patient) favour chemotherapy with a significant increase in the median time to recurrence from 31 to 50 months for all patients (P = 0.04) and from 26 to 49 months for node-positive patients (P = 0.023). No significant effect on survival is seen although there is a trend towards longer survival in the treated group. The regimen used was relatively non-toxic when compared to the traditional CMF with 34% of patients experiencing mild nausea and vomiting immediately post-injection and only 11% complaining of more severe nausea and vomiting. Because of this lower toxicity the treatment was found to be amenable to administration in both regional hospitals and specialized centres.

In a randomized controlled trial 50 patients with duodenal ulcer treated by proximal gastric vagotomy (P.G.V.) without drainage were compared with 50 who underwent selective vagotomy and gastrojejunostomy. The clinical results were assessed in 99 patients one to four years after operation. Patients who had undergone P.G.V. had significantly less dumping, nausea, and bile vomiting and fared better in their overall clinical grading. The postoperative Visick grading of the 50 patients with P.G.V. was similar to that of 56 controls with no known gastrointestinal disease who had not undergone operation. The results obtained in the patients who had had P.G.V. without drainage were compared with those of a further group of 24 patients subjected of P.G.V. with gastrojejunostomy, and the better results obtained in the former group were thought to be due to elimination of the drainage procedure. The average follow-up period of the trial was just over two years, but there were no indications that the recurrent ulceration rate after P.G.V. would be any higher than after other types of vagotomy and drainage.

The carbohydrate and nitrogen content of the gastric juice was assessed in 18 persons whose diagnosis were unknown to the investigators and the data compared by discriminant function analysis with similar measurements from 42 patients with proven duodenal ulceration and 22 normal controls. It was possible to assess correctly 14 of the 18 patients (77.8%) of the unknown group as having a duodenal ulcer. The results of three patients (16.7%) were equivocal, and one person (5.5%) was wrongly classified. The investigation confirms that the carbohydrate and nitrogen content of gastric secretion in duodenal ulcer patients is abnormal.

A prospective randomized clinical trial of treatment with vincristine, cyclophosphamide, methotrexate and 5-fluorouracil after conventional curative treatment for stage II breast cancer is described. The results at 2 years are recorded together with details of toxicity. Future plans are discussed briefly.

The sugar and nitrogen content of the gastric juice was assessed in 27 patients with duodenal ulceration, 17 patients with dyspepsia, and 27 normal volunteers. Comparing the data for each constituent for each patient using a discriminant function analysis, it was shown that the normal group differed significantly from both the duodenal ulcer group and the dyspeptic group, but that there was only a degree of variation between the two groups of patients.

Many publications have claimed that oral contraceptives (OCs) are associated with an increased risk of circulatory disease, yet between the years 1962 and 1976, when OCs became widely used in the United Kingdom, death rates from circulatory disease in women of reproductive age fell steadily. This decreased mortality was greater in young women than in men of comparable age, and did not occur in older women. These data tend strongly to refute the belief that OCs are causative of circulatory disease. The possibility that the decreased mortality rate is due to a protective effect of OCs was examined. It was concluded that they could not be completely responsible, although a partial effect could not be ruled out with certainty. It is suggested that, when mortality trends are opposed to the results of case-control or cohort studies, serious doubts are cast on the conclusions about causal relationships.

Patients with biliary obstruction due to malignant disease, and judged unfit for open operation, were randomised to have a biliary stent inserted either endoscopically via the papilla of Vater or percutaneously. Analysis after 75 patients had been entered showed that the endoscopic method had a significantly higher success rate for relief of jaundice (81% versus 61%, p = 0.017) and a significantly lower 30-day mortality (15% versus 33%, p = 0.016). The higher mortality after percutaneous stents was due to complications associated with liver puncture (haemorrhage and bile leaks). When stenting is indicated in elderly and frail patients the endoscopic method should be tried first.