S.C. Pang

Vitamin A and cancer prevention II: Comparison of the effects of retinol and β-carotene

Former blue asbestos workers known to be at high risk of asbestos‐related diseases, particularly malignant mesothelioma and lung cancer, were enrolled in a chemo‐prevention program using vitamin A. Our aims were to compare rates of disease and death in subjects randomly assigned to β‐carotene or retinol. Subjects were assigned randomly to take 30 mg/day β‐carotene (512 subjects) or 25,000 IU/day retinol (512 subjects) and followed up through death and cancer registries from the start of the study in June 1990 till May 1995. Comparison between groups was by Cox regression in both intention‐to‐treat analyses and efficacy analyses based on treatment actually taken. Median follow‐up time was 232 weeks. Four cases of lung cancer and 3 cases of mesothelioma were observed in subjects randomised to retinol and 6 cases of lung cancer and 12 cases of mesothelioma in subjects randomised to β‐carotene. The relative rate of mesothelioma (the most common single cause of death in our study) for those on retinol compared with those on β‐carotene was 0.24 (95% CI 0.07–0.86). In the retinol group, there was also a significantly lower rate for death from all causes but a higher rate of ischaemic heart disease mortality. Similar results were found with efficacy analyses. Our results confirm other findings of a lack of any benefit from administration of large doses of synthetic β‐carotene. The finding of significantly lower rates of mesothelioma among subjects assigned to retinol requires further investigation. Int. J. Cancer 75:362–367, 1998.

Vitamin A and cancer prevention I: Observations in workers previously exposed to asbestos at Wittenoom, Western Australia

Our aim was to describe a vitamin A‐based cancer prevention program for former asbestos workers and to check for possible harmful effects by comparing rates of disease and death in study subjects with subjects who chose not to join. All subjects had been occupationally exposed to crocidolite at Wittenoom Gorge between 1943 and 1966; 1,677 subjects indicated interest in the program and 1,203 joined between June 1990 and May 1995. Comparison subjects consisted of 996 former workers known to be alive in Western Australia in 1990 who did not join the program. Program subjects were provided with annual supplies of vitamin A (either synthetic β‐carotene or retinol), help in quitting smoking and dietary advice. The comparison group received only mail contact. Both groups were followed up to December 1994 for vital status and cancer information, and rates of cancer and death from various causes were compared. Mortality in both groups was higher than expected (standardised mortality ratio 1.23 in program subjects and 1.67 in comparison subjects). After adjustment for age, smoking and asbestos exposure, the relative rates in participants compared with non‐participants was below 1 for all examined cancers and causes of death. For mesothelioma and lung cancer, group differences increased with time from entry, whereas other differences dissipated with time. No significant side effects were reported. In conclusion, program participants had significantly lower mortality than non‐participants, but the rates of the 2 groups converged with time. Int. J. Cancer 75:355–361, 1998.

The additional risk of malignant mesothelioma in former workers and residents of Wittenoom with benign pleural disease or asbestosis.

Aims: To examine the hypothesis that people with benign pleural disease or asbestosis have an increased risk of malignant mesothelioma beyond that attributable to their degree of asbestos exposure. Methods: Former workers and residents of the crocidolite mining and milling town of Wittenoom are participating in a cancer prevention programme (n = 1988). The first plain chest radiograph taken at the time of recruitment into the cancer prevention programme was read for evidence of benign pleural disease and asbestosis, using the UICC classification. Crocidolite exposure of former workers was derived from employment records and records of dust measurements performed during the operation of the asbestos mine and mill between 1943 and 1966. Based on fibre counts, exposure for former residents was determined using duration of residence and period of residence (before and after a new mill was commissioned in 1957) and interpolation from periodic hygienic measures undertaken from personal monitors between 1966 and 1992. Cox proportional hazards modelling was used to relate benign pleural disease, asbestosis, asbestos exposure, and mesothelioma. Results: Between 1990 and 2002, there were 76 cases of mesothelioma (56 of the pleura and 20 of the peritoneum). Cases had more radiographic evidence of (all) benign pleural disease, pleural thickening, blunt/obliterated costophrenic angle, and asbestosis than non-cases. Adjusting for time since first exposure (log years), cumulative exposure (log f/ml-years), and age at the start of the programme, pleural thickening (OR = 3.1, 95% CI 1.2 to 7.6) and asbestosis (OR = 3.3, 95% CI 1.3 to 8.6) were associated with an increased risk of peritoneal mesothelioma. There was no increased risk for pleural mesothelioma. Conclusion: The presence of benign pleural disease, in particular pleural thickening, and asbestosis appears to increase the risk of mesothelioma of the peritoneum, but not of the pleura beyond that attributable to indices of asbestos exposure in this cohort of subjects exposed to crocidolite.

The effect of asbestosis on lung cancer risk beyond the dose related effect of asbestos alone

Aims: To determine if the presence of asbestosis is a prerequisite for lung cancer in subjects with known exposure to blue asbestos (crocidolite). Methods: Former workers and residents of Wittenoom with known amounts of asbestos exposure (duration, intensity, and time since first exposure), current chest x ray and smoking information, participating in a cancer prevention programme (n = 1988) were studied. The first plain chest radiograph taken at the time of recruitment into the cancer prevention programme was examined for radiographic evidence of asbestosis according to the UICC (ILO) classification. Cox proportional hazards modelling was used to relate asbestosis, asbestos exposure, and lung cancer. Results: Between 1990 and 2002 there were 58 cases of lung cancer. Thirty six per cent of cases had radiographic evidence of asbestosis compared to 12% of study participants. Smoking status was the strongest predictor of lung cancer, with current smokers (OR = 26.5, 95% CI 3.5 to 198) having the greatest risk. Radiographic asbestosis (OR = 1.94, 95% CI 1.09 to 3.46) and asbestos exposure (OR = 1.21 per f/ml-year, 95% CI 1.02 to 1.42) were significantly associated with an increased risk of lung cancer. There was an increased risk of lung cancer with increasing exposure in those without asbestosis. Conclusion: In this cohort of former workers and residents of Wittenoom, asbestosis is not a mandatory precursor for asbestos related lung cancer. These findings support the hypothesis that it is the asbestos fibres per se that cause lung cancer, which can develop with or without the presence of asbestosis.

Increased body mass index is related to apparent circumscribed pleural thickening on plain chest radiographs

BACKGROUND Diffuse pleural thickening and pleural plaques are the commonest radiological manifestations of asbestos exposure. Differentiation between subpleural fat and non-calcified pleural plaques is important clinically and medico-legally. This study aims to determine if apparent circumscribed pleural thickening on chest radiographs is related with obesity. METHODS Surveillance chest x-rays of 693 former asbestos workers were read with the ILO classification. Subjects with costophrenic angle obliteration (n = 57) were analyzed separately. The remaining subjects were subdivided according to their body mass index (BMI): Group 1 < 26 kg/m(2); Group 2 26-30 kg/m(2); Group 3 > 30 kg/m(2). RESULTS Baseline characteristics, asbestos exposure, and profusion scores were evenly distributed. BMI of > 30 kg/m(2) was associated with a higher prevalence of pleural thickening on CXR (Gp1 = 8.5%; Gp2 = 9.3%; Gp3 = 18.3%). This relationship was strongest in the subgroups with 25-50% of the lateral chest wall involved and pleural thickness of < 10 mm. CONCLUSIONS Obesity (BMI > 30 kg/m(2)) is related to apparent circumscribed pleural thickening on CXR, especially thin (< 1 cm) shadows covering 25-50% of the lateral chest wall.

Radiographic (ILO) readings predict arterial oxygen desaturation during exercise in subjects with asbestosis.

Background: Exercise impairment is common in subjects with asbestosis. Arterial oxygen desaturation during exercise is an important contributor to exercise limitation. The International Labour Office (ILO) classification of plain chest radiographs correlates with resting pulmonary function, but its value in predicting abnormal ventilatory responses to exercise, including desaturation, has not been explored. Aims: To determine in subjects with asbestosis (1) if radiographic profusion scores and the extent of small irregular shadows on plain chest radiographs correlate with resting lung function and abnormal ventilatory responses to exercise; and (2) if radiographic scores add value to resting lung function tests in predicting abnormal ventilatory responses to exercise. Methods: Thirty eight male subjects with asbestosis were included. Plain chest radiographs were read according to the ILO classification independently by three observers. All subjects underwent assessment of lung function and an incremental exercise test. Results: Profusion scores and number of affected zones correlated significantly with the percentage predicted values of single breath diffusing capacity (DLCO), forced vital capacity (FVC), and total lung capacity (TLC). Arterial oxygen desaturation occurred in 29% of the subjects. The severity of desaturation correlated significantly with profusion and the number of affected zones. The combined use of number of affected zones, FEV1/FVC ratio and DLCO predicted desaturation during exercise with an explained variance of 41%. VO2max was significantly related only to DLCO but was not predicted by the ILO score. Conclusion: Arterial oxygen desaturation correlated with the profusion and extent of parenchymal abnormality on chest radiographs. The addition of morphological indices to physiological measurements is valuable for predicting oxygen desaturation during exercise but not for VO2max. Refinement of the radiographic scoring system and the addition of more sophisticated imaging techniques may further improve the predictive power.