The pharmacology and clinical uses of tamoxifen

Pancreatic cancer is the fifth leading cause of death from malignant disease in Western society. Apart from the fortunate few patients who present with a resectable small pancreatic adenocarcinoma, conventional treatment offers no hope of cure and has little palliative value. Over the past two decades major steps have been made in our understanding of the biology of pancreatic growth and neoplasia. This review sets out to explore these advances, firstly in the regulation of normal pancreatic growth, and secondly the mechanism which may be involved in malignant change of the exocrine pancreas. From an understanding of this new biology, new treatment strategies may be possible for patients with pancreatic cancer.

https://gut.bmj.com/content/gutjnl/32/7/800.full.pdf

Biology of pancreatic cancer.

In a prospective controlled clinical trial, 108 patients with pancreatic adenocarcinoma were randomly allocated to receive tamoxifen 20 mg b.d., cyproteron acetate 100 mg t.d.s. or no active treatment. The median survival of those receiving tamoxifen was longer than either of the other two groups (5.25 compared to 4.25 and 3 months, respectively) but this difference did not achieve statistical significance. Cox regression analysis of 12 clinical and biochemical features showed that, for the entire group of patients, survival was significantly longer in younger patients, those undergoing surgical bypass and those with better initial performance status. However, even when adjustment was made to allow for the distribution of these prognostic variables within the three groups, the difference in survival still did not achieve statistical significance. No side-effects attributable to treatment was observed.

A prospective randomised controlled trial of tamoxifen and cyproterone acetate in pancreatic carcinoma.

Between 1984 and 1987, 176 Norwegian patients with histologically verified unresectable pancreatic adenocarcinoma were randomized to double-blind treatment with oral tamoxifen (30 mg daily; 48 men and 44 women) or placebo (47 men and 37 women). Analysis of oestrogen receptor activity in the carcinomas was not performed. There were no statistically significant differences between the two groups according to age, Karnofsky performance index, tumour node metastasis (TNM) stage, operative treatment or other patient characteristics. The tamoxifen or placebo treatment continued to death or to 10 months after accrual into the trial was stopped. In the tamoxifen group, the mean and median survivals were 205 and 115 days, respectively. These values did not differ statistically from the 192 and 122 days, respectively, observed in the placebo group. Additional retrospective analyses of sex and stage revealed no beneficial effect of tamoxifen upon survival. For women in stage III (any T N1 M0), mean and median survivals were 255 and 191 days, respectively, compared with values of 84 and 45 days, respectively, in the placebo group (P = 0.011). After 2.5 years, three (7 per cent) women in the tamoxifen group were still alive compared with no survivors in the placebo group. No male patients survived beyond 2.5 years. This therapeutic result in a small subgroup of women is probably incidental and not an effect of tamoxifen.

Tamoxifen therapy in unresectable adenocarcinoma of the pancreas and the papilla of Vater.

The incidence of adenocarcinoma of the pancreas has risen steadily over the past 4 decades. Since pancreatic cancer is diagnosed at an advanced stage, and because of the lack of effective therapies, the prognosis of such patients is extremely poor. Despite advances in our understanding of the molecular biology of pancreatic cancer, the systemic treatment of this disease remains unsatisfactory. Conventional chemotherapy has not produced dramatic improvements in response rates or patient survival. New treatment strategies are clearly needed. This paper reviews emerging therapies for pancreatic carcinoma. A more profound understanding of the molecular biology of cell growth and proliferation, as well as of neoplastic cell transformation, has led to advances in several areas, including the use of somatostatin analogues and antiandrogens as adjuvant therapy; inhibition of tumour growth and metastasis by inhibitors of matrix metalloproteinases and angiogenesis, and by small molecules such as retinoids, which interfere with progression through the cell cycle; immunotherapy with monoclonal antibodies; disruption of intracellular signal transduction with farnesyltransferase inhibitors; and finally gene therapy with specifically designed vaccines.

K Satake

Papers

Estrogen receptors in 7,12-dimethylbenz (a) anthracene (DMBA) induced pancreatic carcinoma in rats and in human pancreatic carcinoma.

Experimental pancreatic carcinoma as a model of human pancreatic carcinoma.