Epidemiological reservations about risk assessment.
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Breast Neoplasms↗
Biomedical subjects
R Peto
Publications and source records attributed to R Peto.
Intravenous and intracoronary fibrinolytic therapy in acute myocardial infarction: overview of results on mortality, reinfarction and side-effects from 33 randomized controlled trials.
During the past 25 years, 24 randomized trials of intravenous (IV) fibrinolytic treatment have been reported, involving a total of some 6000 patients in the acute phase of myocardial infarction. Most tested IV streptokinase (SK), but a few tested IV urokinase (UK). In the past 2 or 3 years numerous small randomized trials of intracoronary (IC) SK have been started, 9 of which, involving a total of about 1000 such patients, have been reported. Because all of these IV and IC trials were small (the largest including only 747 patients), their separate results appear contradictory and unreliable. But, an overview of the data from these trials indicates that IV treatment produces a highly significant (22% +/- 5%, P less than 0.001) reduction in the odds of death, an even larger reduction in the odds of reinfarction, and an absolute frequency of serious adverse effects to set against this that is much smaller than the absolute mortality reduction. The apparent size of the mortality reduction in the IV trials was similar whether anticoagulants were compulsory or optional, whether treatment was in a coronary care unit or an ordinary ward and, surprisingly, whether treatment began early (less than 6 h from onset of symptoms) or late (generally 12-24 h). In addition, there was no evidence that UK was more effective than the less expensive SK, or that, despite their technical complexity, the new IC regimes were more effective than the old IV regimes. Even the IV schedules that have been studied in randomized trials were, however, quite complex, and the IC schedules were far more so. Perhaps partly because of this, none of them is widely used. If so, then some much simpler, and hence more widely practicable, IV SK regimes should be developed and tested. For example, a simple one hour high-dose IV SK infusion, without anticoagulation, will successfully convert virtually all of the available plasminogen into plasmin. But, it may be several years before the net effects on mortality of any more widely practicable IV SK regimes can be agreed unless many of the hospitals that do not wish routinely to use IC regimes or the complex previous IV regimes will collaborate in multicentre randomized trials that can, if necessary, continue rapid intake until some tens of thousands of patients have been randomized, and some thousands of deaths have been observed among the control and treated patients. The same, of course, may be true for any other fibrinolytic regimes (e.g. infusion of tissue plasminogen activator) if their net effects on mortality are comparable to those of IV SK.
Anticoagulants↗
There is no such thing as ageing, and cancer is not related to it.
Several separate cellular processes have to accumulate in a normal cell to alter it into the seed of a growing carcinoma. Even though cancer is much commoner in the old than in the young, there is no good evidence whatever that these separate processes have any systematic tendency to take place more readily among old than among young adults. (Indeed, there are some instances in which carcinogenic treatments actually elicit cancer less rapidly among the old!) There are obvious evolutionary reasons why substantial cancer risks should be delayed until the end of the usual lifespan, and it appears that this is achieved chiefly not by having the component processes of neoplastic transformation themselves particularly dependent on age, but simply by requiring not one, but several, of them en route from full normality to full malignancy, and by giving at least some of them an extraordinarily low daily probability. The daily probabilities of these separate events are, of course, under evolutionary influence, and some of them appear to have changed by orders of magnitude over the tens of millions of years of evolution that separate humanity from various short-lived animals.
Adult↗
UK prospective study of therapies of maturity-onset diabetes.
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Clinical Trials as Topic↗
A case-control study of oral contraceptive use and breast cancer.
Among 989 cases of breast cancer and 9,890 controls selected from a cohort of married, female registered nurses aged 30-55 years, the relative risk (RR) of breast cancer for women who had ever used oral contraceptives (OC) compared with those who had never used them was 1.0, with 95% confidence limits 0.9-1.2. Among OC users, there was no consistent pattern of excess risk with increasing duration; in fact, the few women who had used OC longest (greater than 10 yr) had a slightly lower risk than never-users. Moreover, there was no association between OC use and breast cancer among women with a positive history of breast cancer in the mother or sister or with OC use before their first pregnancy. The only subgroup of women among whom any adverse effect was apparent was current OC users aged 50-55 years (two onsets expected vs. seven observed). This finding is consistent with earlier reports of an increased risk of breast cancer among older OC users; however, it is also likely to reflect, at least to some extent, the play of chance, since at ages 45-49 and in each younger age group fewer cases than expected were observed among current OC users.
Adult↗
The TD50: a proposed general convention for the numerical description of the carcinogenic potency of chemicals in chronic-exposure animal experiments.
A generally accepted format for the numerical description of the carcinogenic potency of a particular chemical in a particular strain of animals is desirable so that statements from different sources about potency and attempts by different authors to correlate potency with particular laboratory measurements will be comparable. The choice of an appropriate standard format is to a certain extent arbitrary. In this paper we recommend that the TD50 (tumorigenic dose rate 50) be used. TD50 can be calculated for a single target site or combination of sites. The TD50, in analogy with the LD50, is defined as that chronic dose rate (in mg/kg body weight/day) which would halve the actuarially adjusted percentage of tumor-free animals at the end of a standard experiment time--the "standard lifespan" for the species. This paper consists of a brief discussion of the TD50, sufficient to make the general reader familiar with the properties of such an index, an appendix discussing methods for its estimation and certain conventions we have adopted for use in analyzing "nonstandard" experiments. A major problem in calculating any index of carcinogenic potency is that much published material gives only the final crude percentage of tumor-bearing animals at each dose, instead of percentages adjusted for the effects of intercurrent mortality or data from which these adjusted percentages can be derived. If the dose level administered to the animals is toxic, then premature death from nonneoplastic causes may prevent some dosed animals that would have developed tumors from actually doing so. This will particularly affect the high-dose group.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
A carcinogenic potency database of the standardized results of animal bioassays.
The preceding paper described our numerical index of carcinogenic potency, the TD50 and the statistical procedures adopted for estimating it from experimental data. This paper presents the Carcinogenic Potency Database, which includes results of about 3000 long-term, chronic experiments of 770 test compounds. Part II is a discussion of the sources of our data, the rationale for the inclusion of particular experiments and particular target sites, and the conventions adopted in summarizing the literature. Part III is a guide to the plot of results presented in Part IV. A number of appendices are provided to facilitate use of the database. The plot includes information about chronic cancer tests in mammals, such as dose and other aspects of experimental protocol, histopathology and tumor incidence, TD50 and its statistical significance, dose response, author's opinion and literature reference. The plot readily permits comparisons of carcinogenic potency and many other aspects of cancer tests; it also provides quantitative information about negative tests. The range of carcinogenic potency is over 10 million-fold.
Animals↗
Nitrosamine carcinogenesis in 5120 rodents: chronic administration of sixteen different concentrations of NDEA, NDMA, NPYR and NPIP in the water of 4440 inbred rats, with parallel studies on NDEA alone of the effect of age of starting (3, 6 or 20 weeks) and of species (rats, mice or hamsters).
A Weibull analysis is presented of the dose and time relationships for the effects on 4 080 inbred rats of chronic ingestion in the drinking water of 16 different doses of N-nitroso-dimethylamine (NDMA) and of N-nitrosodiethylamine (NDEA). The sites chiefly affected were the liver (by both agents) and the oesophagus (by NDEA only). Since the experiment continued into extreme old age, effects became clearly measurable even at a dose of only 0.01 mg/kg per day, which is an order of magnitude lower than previously achieved. (After only two years of treatment, however, the 'TD50' doses needed to halve the proportion of tumourless survivors would have been about 0.06 mg/kg per day of NDEA and about 0.12 mg/kg per day of NDMA.) The general pattern of response was that the log probability of remaining tumourless was given by the product of two terms, the first (the 'Weibull b-value') depending on the dose-rate but not on the duration of exposure, and the second depending not on dose at all but on (approximately the seventh power of) duration. For oesophageal tumours, the 'Weibull b-value' was approximately proportional to the cube of the dose-rate of NDEA (males 21 d3, females 11 d3, where d = dose-rate in mg/kg adult body weight/day, and the background incidence was unmeasurably low. For liver tumours induced by NDEA, the b-value was approximately proportional to the fourth power of dose-rate + 0.04 mg/kg per day (males, 19 (d + 0.04)4; females, 32 (d + 0.04)4), although the relationships were slightly different for the different subsites of liver tumour. This one formula implies both approximate linearity at low doses and an approximately cubic relationship within the higher range of doses that was studied. For liver tumours induced by NDMA, the Weibull b-value was approximately proportional to the sixth power of dose rate + 0.1 mg/kg per day (males, 37 (d + 0.1)6; females, 51 (d + 0.1)6), again with variation between liver subsites, and again implying approximate linearity at low doses. The difference between the latter two relationships may represent differences in the induction of particular DNA repair enzymes by NDMA and NDEA, or in the effects of those enzymes on methylated and on ethylated DNA. These formulae should, of course, be trusted only in the range of doses from which they were derived, and particularly not for those above it.(ABSTRACT TRUNCATED AT 400 WORDS)
Age Factors↗
Calculation of carcinogenic potency from long-term animal carcinogenesis experiments.
An index of carcinogenic potency for chemicals tested in chronic animal experiments is described. By analogy with the well-known 'lethal dose 50' (LD50) of quantal bioassay, a 'tumorigenic dose 50' (TD50) may be defined (in the absence both of tumors in the control group and of intercurrent deaths) as that (daily) dose of chemical which gives 50% of the test animals tumors by some fixed age. Tumors in the control (zero-dose) group are handled exactly as for the LD50, and intercurrent deaths are handled by life-table methods. Nonparametric procedures are developed for estimating the TD50 and for constructing confidence intervals. These are based on likelihoods which assume that the tumor hazard is linear in dose.
Aniline Compounds↗
Trends in mortality from carcinoma of the liver and the use of oral contraceptives.
There is increasing concern that contraceptive pill usage may increase the risk of hepatocellular carcinoma. As primary malignant liver cancer is very rare in this country, any effect due to oral contraceptives should be apparent in national mortality statistics. An analysis of mortality rates over the last 24 years shows a small but consistent increase for young women starting to occur during the end of the last decade. However no such trend is apparent in data from other countries where pill usage is comparable to that in the U.K. Overall liver cancer remains an extremely uncommon cause of death in developed countries, but it will be particularly important to monitor trends in this disease in the future.
Adult↗
Genital warts and cervical neoplasia: an epidemiological study.
Cervical carcinoma and cervical intra-epithelial neoplasia (CIN) are likely to be associated with all sexually transmitted diseases (STDs). To help discover which (if any) of the recognised STDs might actually cause these conditions, a key question is whether one particular such association is much stronger than the others. The present study is therefore only of women newly attending an STD clinic, and compares the prevalences of cytological abnormalities of the cervix among 415 women attending with genital warts, 135 with genital herpes, and 458 with trichomoniasis or gonorrhoea. Significantly more genital wart patients (8.1%) than trichomoniasis or gonorrhoea patients (1.9%) showed dyskaryotic changes (adjusted relative risk (RR) = 5.8 with 95% limits 2.5-13.5) at, or a few months before, first attendance, while no excess whatever was seen in women with genital herpes. Moreover, half the women had a subsequent smear (at an average of 3-4 years after first attendance) and, although the diagnosis at first attendance was not related to the onset rate of dyskaryotic changes observed in these subsequent smears, it was related to the onset rate of grade III cervical intra-epithelial neoplasia (CIN III), which was found in 7 previous genital wart patients, in 2 previous trichomonas patients, but in 0 previous genital herpes patients. Thus, our findings suggest that herpes is not directly relevant to dyskaryotic change, but that one or more of the human papilloma viruses that cause genital warts may be.
Adult↗
What treatments for rheumatoid arthritis can best be assessed by large, simple, long-term trials?
If the really important questions in the long-term management of rheumatoid arthritis are to be answered reliably, then clinical trials may have to be undertaken that are very much larger and simpler than has previously been the case. For sufficient numbers of busy clinicians to collaborate wholeheartedly with such trials, the extra work per patient should be very slight. In addition, the collaborators should be more than recompensed for even that slight extra trouble by pro-rata secretarial and/or locum assistance, so that it will actually be less work for them to collaborate wholeheartedly in such a trial than not to do so. Two particular trials are discussed to illustrate these general principles.
Arthritis, Rheumatoid↗
Medical research council trial of antilymphocyte globulin in renal transplantation. A multicenter randomized double-blind placebo controlled clinical investigation.
A total of 173 patients who received live donor or cadaveric primary or secondary renal transplants at five British hospitals were entered into a randomized double-blind controlled clinical trial of equine antilymphocyte globulin (ALG) administered prophylactically to prevent rejection. The ALG was prepared in the early 1970s and used cultured human lymphoblasts as antigen. Following transplantation all patients were treated with a standard immunosuppressant regimen of steroids and azathioprine and, in addition, were given either 30 mg/kg ALG or placebo daily for 10 days by intravenous infusion. In comparison with more recently produced materials, the ALG employed in this study was of moderate potency in prolonging skin graft survival in monkeys. Primary graft failure occurred in 27 patients (15/86 ALG and 12/87 placebo). At three to five years after transplantation 50 of the remaining patients had died, almost all from diseases relating to their renal condition, and 25 more had suffered complete graft failure. No significant differences were found between patients treated with ALG and placebo in the numbers with functioning grafts during the 3 years following transplantation, in the time between transplantation and the first rejection episode, or in the number of episodes during the first six months after transplantation. This applied whether live or cadaveric grafts were employed. Within the first 6 months of operation, infection was given as a major contributory cause of death in 12 patients treated with ALG and in 5 who received placebo (P greater than 0.1). Infections were also slightly more common during the two weeks following transplantation in those receiving ALG (13/86 ALG, 10/87 placebo). As expected, graft survival was significantly better in patients who received live donor grafts (P = 0.001) and in patients with the least donor-recipient histocompatibility mismatches (P = 0.008). The results of this multicenter trial show no therapeutic benefit to renal graft recipients from the administration of ALG, and suggest that the risks of fatal infection may have been aggravated. Use of such equine ALG in similar dose regimens is therefore, not, justified in renal transplantation, especially if some part of the apparent effects on fatal infections is real. It is stressed that these findings are relevant only to the equine ALG used in this study, which was raised with cultured human lymphoblasts as the antigen, and to ALG prepared in a similar way and of similar potency. It should not be inferred that these results are applicable to ALG prepared in other ways.
Adolescent↗
The relevance in adults of air-flow obstruction, but not of mucus hypersecretion, to mortality from chronic lung disease. Results from 20 years of prospective observation.
From 1954 to 1961, pulmonary function was assessed in 2,718 British men by forced expiratory maneuvers, and mucus hypersecretion and smoking habits were assessed by questionnaires. In 20 to 25 yr of follow-up, 104 men (all of whom had smoked) died of chronic obstructive pulmonary disease (COPD). The risk of death from COPD was strongly correlated with the initial degree of air-flow obstruction. Among men with similar initial air-flow obstruction, however, age-specific COPD death rates were not significantly related to initial mucus hypersecretion, supporting the concept that air-flow obstruction and mucus hypersecretion are largely independent disease processes. A moderate relationship existed between initial mucus hypersecretion and subsequent lung cancer mortality, but it is not known whether this was due solely to a common correlation of both conditions with the effective degree of exposure of the large bronchi to causative factors such as tobacco smoke.
Adult↗
Reduction in infarct size, arrhythmias and chest pain by early intravenous beta blockade in suspected acute myocardial infarction.
Four hundred seventy-seven patients suspected of having had acute myocardial infarction within less than 12 hours were randomized to receive i.v. atenolol followed by oral treatment for 10 days or to a control group. In patients with ECG changes indicative of infarction at entry, i.v. atenolol significantly reduced enzyme release by one-third and enhanced R-wave preservation. In patients without such ECG changes, treatment significantly prevented the development of infarction in a proportion of patients. There was also a significant reduction in R-on-T ectopics, repetitive ventricular arrhythmias and supraventricular arrhythmias. Treated patients had significantly greater pain relief and required fewer opiate analgesics. Significantly fewer atenolol-treated patients died by 10 days (the treatment period), had nonfatal cardiac arrests, developed heart failure, or suffered reinfarction.
Administration, Oral↗
Effect of intravenous streptokinase on acute myocardial infarction: pooled results from randomized trials.
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Clinical Trials as Topic↗
Cigarette consumption and biochemical measures of smoke intake.
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Carboxyhemoglobin↗
Survival and desferrioxamine in thalassaemia major.
A small randomised trial and observation of all patients homozygous for beta-thalassaemia in Britain born in or before 1963 indicated that those patients who had received average weekly doses of more than 4 g of desferrioxamine over the previous few years were less likely to die in the near future than were patients of similar ages who had received less, or no, desferrioxamine.
Adolescent↗