Wallace Fox

MEDICAL RESEARCH COUNCIL COMPARATIVE TRIAL OF SURGERY AND RADIOTHERAPY FOR PRIMARY TREATMENT OF SMALL-CELLED OR OAT-CELLED CARCINOMA OF BRONCHUS: Ten-year Follow-up

Abstract This report gives the 10-year results of controlled trial of a policy of surgery and a policy of radical radiotherapy in the treatment of patients with small-celled or oat-celled carcinoma of the bronchus diagnosed preoperatively on bronchial biopsy and thought likely to be operable. The analysis included 144 patients, 71 allocated at random to the surgery series and 73 to the radical-radiotherapy series. There were no 10-year survivors in the surgery series, but in the radiotherapy series 3 remained alive and well. The mean survival for the surgery series was 199 days and for the radical-radiotherapy series 300 days—a statistically significant difference (P=0·04). This reinforces the conclusion of the 5-year report that in this trial radical radiotherapy has given, in terms of survival, a somewhat better result than surgery in the treatment of patients with small-celled or oat-celled carcinoma of the bronchus diagnosed preoperatively on bronchial biopsy and judged to be operable.

Whither short-course chemotherapy?

Our understanding of the mechanisms of short-course chemotherapy has largely, though not exclusively, been based on the Pasteur Institute (Paris) group’s experimental work in mice, the in vivo and in vi&o laboratory experimental work of Professor Mitchison’s unit and a number of large cooperative controlled clinical trials in several countries with which the Medical Research Council (MRC) has been closely involved. Each clinical trial, in addition to comparing the effectiveness of short-course regimens, was designed with the aim of measuring the contribution of individual drugs. The interfacing of all three groups’ activities has also been an important feature. The evidence from the mouse experiments has been summarized by Grosset (1978), the main points being: 1. Pyrazinamide and rifampicin are very potent sterilizing drugs in experimentally infected mice.

FIVE-YEAR FOLLOW-UP OF THE MEDICAL RESEARCH COUNCIL COMPARATIVE TRIAL OF SURGERY AND RADIOTHERAPY FOR THE PRIMARY TREATMENT OF SMALL-CELLED OR OAT-CELLED CARCINOMA OF THE BRONCHUS: A REPORT TO THE MEDICAL RESEARCH COUNCIL WORKING PARTY ON THE EVALUATION OF DIFFERENT METHODS OF THERAPY IN CARCINOMA OF THE BRONCHUS

Abstract This report gives the 5-year results of a controlled trial of a policy of surgery and a policy of radical radiotherapy in the treatment of patients with small-celled or oat-celled carcinoma of the bronchus diagnosed preoperatively on bronchial biopsy and thought likely to be operable. The analysis included 144 patients, 71 allocated at random to the surgery series and 73 to the radical-radiotherapy series. A complete resection of the tumour was performed in 48% of the 71 patients in the surgery series, a thoracotomy in 34%, and no surgery in 18%. Radical radiotherapy was received by 85% of the 73 patients in the radiotherapy series, palliative radiotherapy by 11%, and no radiotherapy by 4%. Additional treatment was received by 62% of the patients in the surgery series and 30% of the patients in the radiotherapy series. The additional treatment for the majority was radiotherapy. The survival-rates for the 71 patients in the surgery series and the 73 patients in the radical-radiotherapy series were 4% and 10% at 24 months, 3% and 7% at 48 months, and 1% and 4% at 60 months, respectively. The one 5-year survivor in the surgery series was a patient too breathless for surgery who was treated by radiotherapy. The three 5-year survivors in the radiotherapy series had all received radical radiotherapy. They remain alive and well with no evidence of recurrence after more than 6 years. The mean survival for the surgery series was 199 days and for the radical-radiotherapy series 284 days, a statistically significant difference (P=0.05). It is concluded that in this trial radical radiotherapy has given, in terms of survival, a somewhat better result than surgery in the treatment of patients with small-celled or oat-celled carcinoma of the bronchus diagnosed preoperatively on bronchial biopsy and judged to be operable.

Compliance of patients and physicians : experience and lessons from tuberculosis?II

The already obvious clinical need to try to overcome the prob? lems of self administration of medicaments,16 supported by a scientific basis,42 led us to explore the efficacy and acceptability of intermittent regimens based on twice weekly or once weekly treatment with isoniazid and streptomycin in Madras.6 7 Subsequently Mitchison and Dickinson43 showed that single pulses of bactericidal drugs could inhibit all division of bacilli for several days. A key community study, which began in 1967 in the central Bohemian region of Czechoslovakia, surrounding Prague, compared in outpatients twice weekly streptomycin plus isoniazid and daily isoniazid plus PAS, both after an initial daily phase of three drugs in hospital. The supervised inter? mittent regimen proved to be as effective therapeutically as the widely used unsupervised daily regimen.44 46 This conclusion was confirmed in a controlled trial in Britain,47 and in Singapore the intermittent regimen was rather better than the oral combination.48 Supervised intermittent chemotherapy was therefore shown to be an effective alternative system to self administered oral regimens. Moreover, it improves the control of chemotherapy, reduces the risk of drug toxicity, and sub? stantially lowers the cost of the drugs.41 An integral part of the organisation of the supervised inter? mittent regimens in Czechoslovakia was to make the arrange? ments as flexible as possible, our aim being to suit the conveni? ence of the patients so that there would be as little disruption as possible of their normal lives.44 Thus patients could choose to

The Problem of Self-Administration of Drugs; with particular reference to Pulmonary Tuberculosis.

There has been much discussion recently on the most suitable form of tuberculosis chemotherapy for mass application. The discussion has centered largely on oral medicaments, and particularly on the relative merits of isoniazid alone and two-drug therapy with isoniazid and PAS. Although this is a very important issue it is less fundamental than the regularity with which patients will administer such medicamerits to themselves for long periods of time. This is a major problem of long-term Chemotherapy in the treatment of any disease. In the field of tuberculosis it has tended to become overlooked in general discussion concerning the use of particular drugs. The issue to be settled is whether patients will take any form of medicine by self-administration regularly for a period of many months or possibly even years, and, if not, how regularity may be achieved. Before specifically considering Chemotherapy for pulmonary tuberculosis it is of interest to review the experience of workers in some other fields.

Deaths occurring in newly notified patients with pulmonary tuberculosis in England and Wales

In a survey of the chemotherapy prescribed for 1312 adult patients of white or Indian subcontinent ethnic origin with pulmonary tuberculosis only, notified in the 6 months from October 1978 to March 1979, it was found that 163 (12%) patients died before they had completed chemotherapy. Of the 163 patients who died 96% were of white ethnic origin; 15% of the 1022 white patients died compared with 2% of the 290 Indian subcontinent patients. According to the death certificate, approximately half the white patients died from tuberculosis, and in a further 31% tuberculosis was a contributory factor. Death from tuberculosis most frequently occurred in the older age groups, accounting in part for the different findings in these two ethnic groups, because of the excess of older white patients. In a step-wise multivariate discriminant analysis death from tuberculosis was found to be significantly associated in the white patients with the radiographic extent of disease before treatment, and with age, extent of cavitation and a positive sputum smear result, but not sex. Most of the deaths from tuberculosis occurred early, 38% before the end of the first week of chemotherapy and 69% by the end of 4 weeks. There was a further group of 51 adult patients with pulmonary tuberculosis notified in the same 6-month period in whom the diagnosis was not made until after death, 25 of them dying from tuberculosis. It is concluded that there is still a substantial risk of death from tuberculosis in patients with extensive disease in the older age groups.

The Prevalence of Drug-resistant Tubercle Bacilli in Untreated Patients with Pulmonary Tuberculosis: a National Survey, 1955-56.

Summary The findings of a survey to assess the prevalence in England, Wales and Scotland of bacillary resistance to streptomycin, PAS and isoniazid among newly diagnosed and previously untreated cases of pulmonary tuberculosis are reported. A representative sample of 80 chest clinics, selected by a random process, participated in the survey, and with the co-operation of their chest physicians 1,404 sputum specimens, from the same number of patients, were cultured at a central laboratory. The collection of specimens started on June 15, 1955, and ended on March 8, 1956. Sensitivity tests to streptomycin, PAS and isoniazid were undertaken on all positive cultures. Of the 974 positive cultures obtained, 50 (5·1 per cent) were resistant to one or more of the three anti-tuberculosis drugs; 44 (4·5 per cent) yielded Myco. tuberculosis; and 6 (0·6 per cent) yielded resistant atypical mycobacteria. Of the 44 resistant strains of Myco. tuberculosis, 22 (2·3 per cent) were resistant to streptomycin, 21 (2·2 per cent) to PAS and 7 (0·7 per cent) to isoniazid; 5 of the strains showed resistance to more than one of the drugs. Those patients found to be infected with resistant organisms were further investigated; their contact histories were compared with those of a similar group of patients derived from those patients infected with sensitive organisms. For each drug separately more of the resistant group than of the sensitive group were known to have been in contact with cases treated with the drug. Definite evidence of contact with organisms resistant to the relevant drug was obtained for 3 of the 22 patients infected with streptomycin-resistant organisms, for 5 of the 21 patients with PAS-resistant strains and for 2 of the 7 patients with isoniazid-resistant strains. No evidence of contact with resistant organisms was found in the matched sensitive group. The clinical, radiographic and bacteriological progress in the two groups of patients are at present being compared and the findings will be reported later.

An International Co-Operative Investigation into Thiacetazone (Thioacetazone) Side-Effects.

Summary In view of conflicting reports from different parts of the world, a study has been under-taken to determine the incidence of side-effects to thiacetazone in combined chemotherapy. It was conducted as a ‘double-blind’ controlled comparison of two regimens, streptomycin 1 g. daily with a daily tablet containing isoniazid 300 mg. plus thiacetazone 150 mg. (the STH regimen) and streptomycin 1 g. daily with a daily tablet of identical appearance containing isoniazid 300 mg. only (the SH regimen). In the main comparison the patients were treated for 8 weeks (8-week series) in 13 countries, Czechoslovakia, Cyprus, Turkey, Ghana, Kenya, Malawi, Nigeria, Rhodesia, South Africa, India, East and West Pakistan, Fiji and Hong Kong. In-patients were studied in all the countries, and in five of them, out-patients were also studied. In eight countries patients were treated for 16 weeks (16-week series). A total of 2,077 (1,045 STH, 1,032 SH) patients were admitted. After exclusions there were 1,002 STH and 987 SH patients for analysis in the 8-week series. Pre-treatment comparisons showed that, with few exceptions, in each country the distributions for sex, age, haemoglobin and weight were similar for the patients on the 2 regimens. During the 8-week period 21 (13 STH, 8 SH) patients died, 16 (10 STH, 6 SH) of tuberculosis. One (STH) patient died of hepatitis in the sixth week and an additional 2 (1 STH, 1 SH) patients died after 8 weeks with jaundice. Side-effects occurred in 214 (21·4%) of the STH patients compared with 77 (7·8%) of the SH patients, a statistically highly significant difference. The incidence of side-effects ranged from 0% on each regimen in Cyprus to 69% for the STH and 25% for the SH patients in Hong Kong. Treatment was not interrupted in 11·5% STH and 5·3% SH patients, was interrupted in 6·5% and 1·6%, and stopped in 3·4% and 0·9% respectively. Nausea or abdominal discomfort occurred in 4·0% STH and 1·6% SH patients, vomiting in 4·3% and 0·5%, and jaundice or hepatitis in 0·2% and 0·3% respectively. Flushing or itching occurred in 1·3% STH and 0·5% SH patients and rashes in 3·9% and 1·0% respectively. Dizziness or giddiness occurred in 9·6% STH and 2·9% SH patients, vertigo and ataxia in 2·3% and 0·7% and tinnitus and deafness in 1·1% and 0·0% respectively. Agranulocytosis occurred in 2 (STH) patients (both in Czechoslovakia; both recovered rapidly). Of the episodes of side-effects, 50% in the STH and 61% in the SH patients, commenced in the first 4 weeks, 45% and 60% respectively, lasted 6 days or less and 50% and 63% respectively, were mild. Of the 18 STH and 2 SH patients with cutaneous hypersensitivity leading to a major departure from treatment, there was confirmation that 9 (8 STH, 1 SH) had hypersensitivity to streptomycin, and 4 (3 STH, 1 SH) had hypersensitivity to the oral medicament. The incidence of side-effects in in-patients and out-patients was the same in Cyprus and Ghana, whereas in Turkey and Kenya there were more side-effects in in-patients and in Nigeria more in out-patients. There were 299 STH and 310 SH patients in the 16-week series (all were in the 8-week series also). During the 16-week period 8 (4 STH, 4 SH) patients died, 7 (3 STH, 4 SH) of tuberculosis and 1 (STH) with jaundice. Side-effects developed in the first 8 weeks in 25·1% STH and 11·0% SH patients compared with 7·0% and 5·5% respectively, in the second 8 weeks. Thus, the main differences between the regimens occurred in the first 8 weeks. The reasons for the differences between the countries in the reported incidence of side-effects have been discussed.

A fourth study of case-finding methods for pulmonary tuberculosis in Kenya

Abstract This investigation is the fourth of a series of case-finding studies in Kenya. It explored in a new area (the Baragwi location of Kirinyaga), five methods of case-finding involving the examination of the sputum by smear and culture of symptomatic tuberculosis suspects in the community identified (i) by interrogation of the Elders, (ii) by interrogation of household heads, (iii) by tracing all patients registered during the previous 10 years in the District Tuberculosis Register, (iv) by the examination of all their close contacts and (v) from outpatients attending peripheral health units. The initial interrogation of the Elders yielded 123 suspects with bacteriological results, of whom seven were culture-positive, including four smear-positive. A second interrogation three to six months later produced a further 66 suspects and four more culture-positive cases (all smear-negative). The examination of a second sputum specimen after three to six months from all the suspects from both interrogations produced a further culture-positive smear-negative case. A single interrogation of household heads in a house-to-house survey yielded 867 suspects and 15 culture-positive cases, including eight smear-positive. Of 862 suspects with no history of tuberculosis, 778 (90%) claimed they had attended a medical facility for their respiratory symptoms during the previous year, the most recent visit being within the previous month in 24%. All except 1% of the total had attended on more than one occasion, the average number of attendances being 5·3. 83% said they had attended the peripheral health units and 37% had attended the Central District Hospital, yet 65% of the suspects had had neither a chest radiograph nor their sputum examined bacteriologically. Of the 114 cases of tuberculosis registered in the District Tuberculosis Register during the previous 10 years, nine were currently culture-positive, seven being smear-positive. The examination of a second sputum specimen from 105 yielded one more culture-positive case. Of 577 household contacts of the registered cases, seven were culture-positive, three being smear-positive. The examination of a second sputum specimen from 568 yielded two more culture-positive cases. During a full year, only 45 suspects were registered among out-patients attending seven health units serving the area (population 27,500), of whom four were smear-positive. This indicates a failure of the staff to take appropriate actions.

An assessment of the carcinogenicity of isoniazid in patients with pulmonary tuberculosis.

In an assessment of the carcinogenicity of isoniazid, 3,842 adult tuberculous patients admitted to 2 sanatoria in the period 1950 to 1957 (that is, in the years immediately before and after the introduction of isoniazid) have been followed up for a mean period of over 19 years. Their mortality has been compared with that expected during the same calendar period in a general population group in England and Wales with the same age and sex distribution. The relative risk of death (the observed divided by the expected number of deaths) from all malignant neoplasms in patients first starting chemotherapy in 1950 to 1952, before the general introduction of isoniazid, was 0.8 for those who received isoniazid at some time, compared with 0.5 for those who never received it; for those first starting chemotherapy in 1953 to 1957, after the general introduction of the drug, the respective risks were 1.4 and 1.8. The relative risk of death from malignant neoplasms was 2.1 in the first 4 years after starting the treatment with isoniazid; this high relative risk is unlikely to be attributable to isoniazid and largely disappears subsequently, for in successive 4-year periods it was 1.3, 0.9, 1.2 and 1.4. The relative risks of death from all malignant neoplasms for patients receiving a total dosage of less than 50, 50-99, 100-199 and 200 g or more were 1.5, 1.5, 1.0 and 1.3, respectively. For patients receiving a maximum daily dose of less than 250 g the relative risk was 1.3, and for those receiving 250 g or more it was 1.2. There was a curious and unexplained difference in the mortality from malignant neoplasms in patients first starting chemotherapy in 1950 to 1952 (relative risk 0.6) and those first starting in 1953 to 1957 (relative risk 1.5). This is being studied further. This study has provided no evidence of a carcinogenic effect of isoniazid in a period of follow-up averaging nearly 20 years. The follow-up is being continued.