A randomized trial comparing adjuvant fluorouracil, doxorubicin, and mitomycin with no treatment in operable gastric cancer. International Collaborative Cancer Group.

Three hundred fifteen patients with operable gastric cancer were randomized to receive fluorouracil, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and mitomycin (FAM) or no adjuvant treatment between September 1981 and July 1984. After excluding ineligible patients, 281 patients are included in this analysis. Treatment was moderately well tolerated by the majority of patients, the common side effects being nausea and vomiting (58%) and alopecia (57%). Three possible treatment-related deaths were seen, all due to cardiac failure. At median follow-up of 68 months, 164 patients have died, 73 in the treated arm and 91 in the control arm. There was no significant difference in disease-free or overall survival between the two arms of the study (P = 0.21). There is some evidence that patients with more advanced carcinoma (T3-T4) derived some benefit from treatment (P = 0.04). The interpretation of this finding must take into account that all subgroups were defined retrospectively, and this could, therefore, be a chance finding. We conclude that adjuvant chemotherapy as given in this trial is not indicated as routine treatment in operable gastric cancer, but that further evaluation in stage T3-T4 patients is warranted.

Adjuvant cyclophosphamide, methotrexate, and fluorouracil versus fluorouracil, epirubicin, and cyclophosphamide chemotherapy in premenopausal women with axillary node-positive operable breast cancer: results of a randomized trial. The International Collaborative Cancer Group.

PURPOSE: To determine whether a combination chemotherapy regimen that contains epirubicin (fluorouracil, epirubicin, and cyclophosphamide [FEC]) is superior to the standard cyclophosphamide, methotrexate, and fluorouracil (CMF) combination in premenopausal women with axillary node-positive operable breast cancer. PATIENTS AND METHODS: The International Collaborative Cancer Group (ICCG) conducted a large randomized trial in which two alternative schedules were used according to participating center: CMF1 versus FEC1 and CMF2 versus FEC2. RESULTS: Seven hundred fifty-nine patients were entered onto the trial. At a median follow-up time of 4.5 years, no significant benefit for the anthracycline-containing regimen was observed in terms of relapse-free (P = .61) or overall survival (P = .13). FEC1 and CMF1 appear to be of similar efficacy, but there is a suggestion that FEC2 may be superior to CMF2, since patients who received FEC2 had improved overall (P = .02) and relapse-free survival (P = .03) rates. Nausea and vomiting and alopecia were more common in the epirubicin-containing regimen (P = .001). CONCLUSION: We conclude that the FEC2 regimen, in which epirubicin replaced the methotrexate in CMF, is the preferable adjuvant chemotherapy regimen for premenopausal patients with operable axillary node-positive breast cancer.

Association between a family history of fractures and bone mineral density in early postmenopausal women.

The aim of this analysis was to measure the strength of the association between a family history of fractures and bone mineral density (BMD), and to determine what definition of family fracture history best predicts BMD. Five hundred and eighty postmenopausal women aged 45-59 at recruitment completed a risk factor questionnaire. Women were asked to recall details of fractures sustained by any female relative. BMD measurements taken at five sites were used. The data were analysed using linear regression, adjusting for age. Two hundred and ninety-seven (52.8%) women reported a family history of fractures, and they had a significantly lower BMD at two of the sites measured (p < 0.05). The associations with BMD were most significant when only counting fractures that occurred in the subject's mother or a sister as a result of low trauma, with no restrictions made on age at the time of fracture and site of fracture (p < 0.01 at three sites; 0.01 < p < 0.05 at two sites). Women with a family history according to this definition had a 4.6% reduction in BMD at the femoral neck. When T scores were used to categorize women as either osteopenic/osteoporotic (T < -1) or normal at the femoral neck, the sensitivity of using this definition was 39% and the specificity was 74%. The small group of women that reported a low-trauma hip fracture in a mother or sister (n = 23) had a mean femoral neck BMD which was 8.9% lower than that of the remainder of the sample, although this difference was less statistically significant than when low trauma fractures at any site were counted. Of these 23 women, 70% were osteopenic or osteoporotic, compared with 57% of those reporting a low-trauma fracture at any site and 47% of the sample as a whole. The sensitivity of this definition, however, was low (6%). From these analyses it can be concluded that the definition of family fracture history that best predicts BMD in postmenopausal women is a fracture at any age in a mother or sister resulting from low trauma, although the sensitivity and specificity of using a family history of fractures by itself to screen for low BMD were poor.

Tooth counts do not predict bone mineral density in early postmenopausal Caucasian women. EPIC study group.

BACKGROUND: It has been suggested that poor dental status may be a suitable criterion for bone densitometry referral in early postmenopausal women. We evaluated this hypothesis in a cohort of 1365 Caucasian women aged between 45 and 59 years, who were enrolled into an international multi-centre trial. METHODS: Subjects were recruited at four study centres, using population-based techniques. Bone mineral density (BMD) at the lumbar spine and proximal femur was measured by dual energy x-ray absorptiometry (DXA) (Hologic QDR 2000). A full physical examination was performed including a tooth count. RESULTS: Baseline tooth counts ranged from 0 to 32 (median 26): 84 (6%) subjects were edentulous. When classified according to the WHO criteria 445 (33%) of the subjects were osteoporotic at one or more of the skeletal sites analysed; 694 (51%) were osteopenic, and 226 (16%) were normal. Adjusting for confounding variables, there was no significant correlation between tooth count and BMD at any skeletal site. Subjects were divided into tertiles of tooth count, and chi2 tests used to compare the two 'extreme' groups against the WHO criteria for BMD. At each of the six BMD regions the proportion of subjects with normal, osteopenic or osteoporotic BMD was similar for both tertiles. CONCLUSIONS: We found no relationship between tooth count and BMD in early postmenopausal women. This may be because in younger women dental status is a reflection more of dietary habits and past dental surgery than of age-related bone loss. Tooth counts therefore cannot be used to identify individuals at risk of osteoporosis.

Habitual physical activity and bone mineral density in postmenopausal women in England.

BACKGROUND: Reduced levels of physical activity have been found to be associated with an increased risk of osteoporotic fracture in a number of epidemiological studies, and intervention studies have shown beneficial effects of exercise regimes on bone mineral density. It is not yet established, however, which specific forms of customary physical activity are most strongly associated with bone mineral density in postmenopausal women. METHODS: A cross-sectional study was conducted in 580 postmenopausal women, aged 45-61 years, resident in Nottingham, England. The participants completed a detailed interviewer-administered activity questionnaire. Physical activity was assessed as total hours of participation per week in activities including housework, walking, gardening and sports. Stair-climbing and self-reported walking pace were also reported. Bone mineral density measurements were made using dual energy x-ray absorptiometry, measurements at five sites were used in analysis. RESULTS: The strongest associations between the activity measures and bone mineral density were for stair-climbing and walking pace, which both gave statistically significant positive associations at the trochanter hip site and the whole body. In women reporting a fairly brisk or fast walking pace, bone mineral density at the proximal femur was also significantly and positively associated with the frequency of walking at least a mile. There were no significant associations with aggregate measures of total customary physical activity. CONCLUSIONS: This study has identified two forms of physical activity, namely stair-climbing and brisk walking which are associated with increased bone mineral density at the hip and whole body in postmenopausal women. Both are feasible forms of activity for promoting to middle-aged women.

Depot medroxyprogesterone acetate and breast cancer. A review of current knowledge.

Depot medroxyprogesterone acetate (DMPA) has been used worldwide since 1964 as a contraceptive and by 1993 was in use in more than 90 countries. It was licensed for contraceptive use in the US in 1992. One of the reasons for this delay in licensing in the US was the possibility of an increased risk of breast cancer associated with its use. A pooled analysis has recently been published, which brings together the data from 2 large studies of breast cancer risk associated with DMPA use. The overall results are reassuring, but there is some evidence of an increased risk of breast cancer associated with recent use of DMPA. There are substantial difficulties in interpreting this increase in risk. It is certainly possible that it may be the result of surveillance bias, although it could be a short term increase in risk that is not in fact sustained. The conclusion that DMPA should not be restricted as a contraceptive, provided that appropriate advice is given before use, is well-founded. However, further epidemiological work is needed on the long term effects of DMPA.

PIP: Although further epidemiological studies of the long-term effects of depot medroxyprogesterone acetate (DMPA) on breast cancer risk are needed, preliminary research results are reassuring. Pooled analysis of the results of two large case-control studies--the World Health Organization Study (involving women newly diagnosed with breast cancer in 1979-88 in Thailand, Kenya, and Mexico) and the New Zealand Study (comprised of women with breast cancer diagnosed in 1983-87)--has facilitated assessment of this association. Overall, 219 of the 1768 breast cancer cases and 1725 of the 13,905 controls had ever used DMPA (odds ratio, 1.1; 95% confidence interval, 0.97-1.4), with no increase in risk with increasing duration of use. Women under 35 years of age at diagnosis and those initiating DMPA use before 25 years of age had marginally statistically significant increases in breast cancer risk. The highest risks were recorded among women who had initiated DMPA use within 5 years of diagnosis. Risks declined with time since first use in all age categories. After 5 years since last use, DMPA use for more than 2 years was associated with a decreased risk of breast cancer. The raised relative risks in certain subgroups are difficult to interpret and may reflect surveillance bias. Enhanced understanding of the biology of breast cancer will aid interpretation of these results.

General practitioner notes as a source of information for case-control studies in young women. UK National Case-Control Study Group.

STUDY OBJECTIVE: The UK National Case-Control Study was carried out to investigate the relationship between oral contraceptive use and breast cancer risk. This study investigates whether general practitioner notes could be used as the sole data source for epidemiological studies of young women and what the effect would be on non-response and recall bias. DESIGN: Case-control study with data on gynaecological, obstetric, and contraceptive history collected at interview and from general practitioners' notes. Information from these two sources was compared. SETTING: This was a population-based study. PARTICIPANTS: Altogether 755 women with breast cancer aged under 36 years at diagnosis, each with an age-matched control, participated in the study. Response rates at interview were 72% and 89% for cases and controls but GP data were available for 90% of the 1049 case and first-selected control pairs. MAIN RESULTS: There was generally good agreement between the two data sources with respect to obstetric history and gynaecological procedures (hysterectomy, oophorectomy, and tubal ligation). The use of intra-uterine devices, or diaphragm, and partner's vasectomy were not reliably recorded in the GP's notes. The overall results of the UK study would have been qualitatively the same with respect to the relationship between oral contraceptive use and breast cancer risk if GP notes only had been used, in spite of the fact that only about half of all oral contraceptive usage was recorded in the notes. Response rates would have been higher, recall bias eliminated, and the cost of the study halved. CONCLUSIONS: When planning case-control studies in young women, the possibility of using GP notes as the primary data source should be considered. Lack of data on potential confounding factors is a possible drawback to such use. The practice of destroying GP's notes shortly after the death of patients seriously restricts the possibility of using these notes when studying rapidly fatal conditions.

Hormone replacement therapy and survival after surgery for ovarian cancer.

OBJECTIVE: To evaluate whether hormone replacement therapy affects survival in women who have undergone bilateral salphingo-oophorectomy because of epithelial ovarian cancer. DESIGN: Retrospective analysis by review of patients' notes and questionnaires completed by general practitioners to compare the overall survival and disease free survival in patients with ovarian cancer who did or did not receive hormone replacement therapy after diagnosis. Data were analysed by Cox regression, with hormone replacement therapy as a time dependent covariate because patients who received hormone replacement did so at different times after diagnosis. SETTING: Gynaecological oncology unit of Royal Marsden Hospital. PATIENTS: 373 patients aged 50 years or younger who attended the hospital from 1972 to 1988. All of the women had undergone bilateral salpingoophorectomy for epithelial ovarian cancer. In all, 78 had received hormone replacement therapy, starting at a median of four months after diagnosis. INTERVENTION: A questionnaire was sent to the general practitioners of all patients who were not recorded as having received hormone replacement therapy. MAIN OUTCOME MEASURES: Overall survival and disease free survival. RESULTS: There was no significant difference in survival between women receiving hormone replacement therapy and those not receiving it after accounting for the effects of other known prognostic factors (stage of cancer, differentiation of tumour, histological results, and time to relapse). The relative risk of dying in those who received hormone replacement therapy was 0.73 (95% confidence interval 0.44 to 1.20). In addition, there was no significant difference in disease free survival (relative risk in those receiving hormone replacement therapy was 0.90; 95% confidence interval 0.52 to 1.54). CONCLUSIONS: This study shows that hormone replacement therapy is unlikely to have a detrimental effect on the prognosis of patients with ovarian cancer, but this would be shown conclusively only by a randomised controlled trial.

Controversies in cancer epidemiology.

The histories of three controversies are described: fluoridation of water supplies and the risk of cancer; whether oral contraceptives cause breast cancer; and the role of self-examination in the prevention of cancer. For the future, some new controversies are already predictable. As well as the scientific debate around these topics, the roles of politics, the media, and pressure groups are discussed. The epidemiologist's responsibility to ensure that the correct interpretation of data is made clear to the public is considered.

The effect of patterns of oral contraceptive use on breast cancer risk in young women. The UK National Case-Control Study Group.

The effect of the duration and pattern of oral contraceptive use on breast cancer risk in young women (aged under 36 at diagnosis) has been investigated. Oral contraceptive users were divided into three groups: group 1, continuous users; group 2, interrupted only by pregnancy users; and group 3, intermittent users. There was a clear trend with duration of oral contraceptive use in all three groups of users (P < 0.001 for each category of use) and the relative risks per year of use were similar (1.07, 1.07 and 1.05 in continuous, interrupted and intermittent users respectively). The relative risks for intermittent users and for women who had used oral contraceptives except when pregnant were very similar, but the relative risk for users for more than 8 years was highest for continuous users. The results suggest that the relationship between oral contraceptive use and breast cancer risk is dependent upon the total duration of use and is not modified by the pattern of use.

Alcohol, smoking, passive smoking and caffeine in relation to breast cancer risk in young women. UK National Case-Control Study Group.

The UK National Case-Control Study Group has examined the relationship between smoking (both own smoking and passive), alcohol consumption and caffeine consumption and the risk of breast cancer. A total of 755 women with breast cancer diagnosed before the age of 36, each with an age-matched general population control, were interviewed, and detailed information on reproductive, contraceptive and medical history, personal attributes and habits were obtained. Additional data on passive smoking were obtained from a subgroup of women. There was no evidence of a statistically significant difference in breast cancer risk between subjects who had ever smoked as much as one cigarette per day and those who had not [relative risk (RR) = 1.01, 95% confidence interval (CI) 0.81-1.26]. Most relative risks for passive smoking exceeded unity, but there was little evidence of significant trends with increasing exposure. The lack of effect of own smoking, and the fact that such smokers are also themselves exposed to the effects of passive smoking, makes any relationship between exposure to others' smoking and breast cancer risk implausible. Alcohol consumption during the year prior to diagnosis and at ages 18 and 25 was examined. Consumers of 0.1-4.9 and 5.0-14.9 g per day generally had non-significantly increased risks compared with never drinkers, but consumers of more than 15 g per day had reduced risks.

Prognostic factors in a T3 bladder cancer trial. Co-operative Urological Cancer Group.

Information on primary tumour size, status of the pelvic lymph nodes, histological type and macroscopic tumour appearance, as well as age and sex, was available at presentation for 394 patients in the Co-operative Urological Cancer Group's prospective randomised trial for T3 cancer of the urinary bladder. An apparently significant prognostic effect of age and sex was shown to be entirely consistent with the effect of natural mortality. Primary tumour size was found to be the single most powerful prognostic factor (P = 0.002), followed by nodal status (P = 0.02). These factors do not act independently. Multivariate analysis showed that 75% of the effect of all the six variables and their first order interactions could be explained by a single prognostic grouping based on tumour size and nodal status only. Three levels for this grouping are proposed: node-negative small tumour, node-negative moderate tumour and either node-positive or large tumour. The 3-year survival probabilities for the three prognostic groups were 85.7% (95% CI 57.2 and 96.4%), 60.3% (48.0 and 71.5%) and 33.3% (23.5 and 44.8%) respectively.

Generating social class data in primary care.

The objective of this study was to compare three methods of collecting social class data in general practice. The setting was a rural dispensing practice on the Nottinghamshire/Lincolnshire border. The methods examined were: (a) a self-administered questionnaire to 200 patients to determine their social class based on the occupation of the head of household; (b) members of the practice staff were asked to assign a social class to these households based on their local knowledge; and (c) use of small area statistics from the 1991 census data using modal and weighted methods. It was found that the practice staff were unable reliably to assign a social class to the households. The modal method of using small area statistics to assign social class to households through their postcode and its link to the census data was also inaccurate. While a personal questionnaire will remain the only method for assigning a social class to individual patients for clinical care or most research, the weighted method of small area statistics is shown to be a cost-effective and sufficiently accurate method for health needs assessment in general practice.

The contribution of bone densitometry to the diagnosis and treatment of osteoporosis.

OBJECTIVE: It has recently been proposed that a specialist osteoporosis service, including bone densitometry, should be made available to those most at risk in the UK population. The aim of this study was to evaluate such a service, and in particular the role of bone densitometry, in terms of its effect on the diagnosis of osteoporosis and clinical management of the disease. METHODS: A retrospective data abstraction study was performed to investigate the diagnosis and management of patients referred to the Metabolic Clinic, City Hospital Nottingham, with a potential diagnosis of osteoporosis. Hospital records were available for 117 patients, aged between 45 and 59, who had attended the Clinic in a given time period and undergone bone mineral density measurement. RESULTS: Forty-eight patients (41.0%) had osteoporosis of the lumbar spine. The final diagnosis of osteoporosis after attending the clinic was different from that on referral in a substantial proportion (62.6%) of cases. Only 48.9% of patients with spinal osteoporosis were identified by their referring doctor. The percentage of patients receiving treatment for osteoporosis increased from 34.2% to 72.6% after attending the clinic. CONCLUSIONS: Measurement of bone mineral density identifies cases of osteoporosis who would not otherwise be detected and as a consequence contributes to the proportion of patients receiving treatment after referral. The osteoporosis service provided by the Metabolic Clinic including measurement of bone mineral density was thus found to have a considerable impact on the diagnosis and treatment of patients with osteoporosis.

A case-control study of congenital hip dislocation.

In this study we have investigated various epidemiological factors which may be related to congenital dislocation of the hip (CDH). Eighty-one cases born during the period 1st January 1988 to 31st August 1990, with four matched controls per case, were identified from consultants' records held at the Queen's Medical Centre and City Hospital, Nottingham. One hundred and twenty-four subjects who were referred to a new Hip Instability Clinic with suspected CDH, but not diagnosed or treated for CDH, were also included as a third group. Information about the mother's pregnancy, previous medical history and family history was collected from obstetric records kept at the two hospitals. Multigravidae and similarly multiparous women had a statistically significantly reduced risk of having a baby with CDH. The relative risks were 0.55 (95% confidence interval 0.33, 0.93) and 0.53 (95% confidence interval 0.31, 0.91) respectively. The method of delivery was also of importance. Babies born by Caesarean section or in breech position had an increased risk of CDH which was statistically significant. Using addition clinical information obtained from subjects attending the Hip Instability Clinic we also found that cases were more likely to have a family history of CDH than subjects who were screened for CDH but found to be normal.

Oral contraceptive use and histopathology of cancerous breasts in young women. Members of the U.K. National Case-Control Study Group.

A retrospective histopathological study of 300 women under 36 years of age was carried out to determine whether breast cancers occurring in oral contraceptive users showed any differences in pathological features compared with non-users. The patients belong to an age group in which an increased risk of cancer development has been reported following oral contraceptive usage. The incidence of non-neoplastic conditions in the residual breast was also studied in the two groups. There was little difference between breast cancers arising in pill users and non-users but in the residual non-neoplastic breast a decreased incidence of cysts and blunt duct adenosis was found in current users of the contraceptive pill. In contrast, lactational foci were found only in the breasts of pill users. The incidence of intraductal hyperplasia was not significantly different in the two groups.

Attitudes and impressions of participants in a study of the causes of childhood cancer.

Researchers and ethics committees are increasingly concerned about the perceived emotional impact on individuals following participation in epidemiologic studies. This attitudinal survey was designed to investigate this issue among 751 of the parents who had already given an interview in the UK Childhood Cancer Study (UKCCS), one of the largest case-control studies ever undertaken to investigate the aetiology of cancer in children. Information was collected by postal questionnaire on their reasons for agreeing to take part in the UKCCS, on whether questions had caused distress or difficulty and what their feelings were immediately after the interview and at the time of this survey. Parents were asked if they felt they had benefited in any way by taking part and control parents were asked if they would have taken part without prior consent of their doctor. 90% of both cases and controls felt glad to have taken part immediately after the interview and few reported any anxiety at having done so; 95% of both cases and controls felt satisfied that they had made a worthwhile contribution. Although 18% of cases felt tense and 14% felt unhappy after the interview, over 90% of them felt glad that they had taken part a few weeks later. Of particular interest is that 38% of cases and 24% of controls said they had positively benefited from taking part in the UKCCS and 96% of control mothers did not mind their family doctor giving permission for them to be contacted.

A double-blind controlled crossover trial of an antigen-avoidance diet in atopic eczema.

20 out of 36 children (aged two to eight years) with atopic eczema completed a twelve-week, double-blind, controlled, crossover trial of an egg and cows' milk exclusion diet. During the first and third four-week periods, patients on an egg and cows' milk exclusion diet received a soya-based milk substitute (trial period) or an egg and cows' milk preparation (control period). Response was assessed in terms of eczema activity, number of areas affected, pruritus, sleeplessness, and antihistamine usage while on the two diets. During the middle period patients resumed their normal diet to minimise any carry-over effect. 14 patients responded more favourably to the antigen-avoidance diet than to the control diet, whereas only 1 responded more favourably to the control diet than the trial diet. Patients experienced more benefit during the first diet period than the second, whatever the nature of the diet. There was no correlation between a positive prick test to egg and cows' milk antigen and response to the trial diet.

Survival of patients with breast cancer attending Bristol Cancer Help Centre.

The Bristol Cancer Help Centre (BCHC) was set up in 1979 to offer various alternative therapies and treatments for patients with cancer. It attracted much public interest and a high demand for its services--and profound medical scepticism. In a study beginning in 1986 of 334 women with breast cancer attending the centre for the first time between June, 1986, and October, 1987, information about the diagnosis was obtained from case notes. Controls were a sample of 461 women with breast cancer attending a specialist cancer hospital or two district general hospitals. The same information was obtained for the control group as for the BCHC group. All patients have been followed up to June, 1988. 85% of patients with breast cancer attending the BCHC were aged under 55 at diagnosis. More than half had experienced recurrence of their disease before entry. For patients metastasis-free at entry, metastasis-free survival in the BCHC group was significantly poorer than in the controls (relapse rate ratio 2.85). Survival in relapsed cases was significantly inferior to that in the control group (hazard ratio 1.81). For cases metastasis-free at entry to the BCHC there was a significant difference in survival between cases and controls, confirming the difference in metastasis-free survival. There was no significant difference in survival or disease-free survival between the cancer hospital controls and other controls.