Ruth Tall

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.

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.

The therapy of pulmonary tuberculosis in Kenya: A comparison of the results achieved in controlled clinical trials with those achieved by the routine treatment services

Abstract A comparison has been made of 311 patients in a Survey who were bacteriologically positive on smear and culture and treated by the routine treatment services of Kenya in 1964/1965 with thiacetazone plus isoniazid (TH) or the same regimen supplemented by streptomycin (STH) and the results for 283 comparable patients similarly treated in Kenya, but in two preceeding controlled clinical trials (the Trial ). There were no important differences in the pretreatment distributions of the Survey and Trial patients. Between 11 and 14 months, 50 % of the Survey and 88 % of the Trial patients had a follow-up assessment, all of the latter and 32 % of the former being assessed at 12 months. In the first year there were 19 (6 %) deaths in the Survey and seven (2 %) deaths in the Trial and 18 (6 %) and 12 (4 %) respectively were permanently lost from observation. At one year, 70 % of the 89 Survey patients and 78 % of the 172 Trial patients on the TH regimen who were assessed between 11 and 14 months were culture negative, the corresponding findings for the STH regimen being 76 % of 86 and 96 % of 85. A higher proportion of patients had shorter courses of chemotherapy in the Survey than in the Trial , 19 % and 4 % respectively on the TH regimen having less than a six-month course. In the Survey and the Trial both for the TH and the STH regimens there was an association between culture negativity and the duration of treatment with the TH regimen. A multiple regression analysis in the Survey population demonstrated that this duration was the most important factor affecting the response for both regimens and that the duration of streptomycin in the Survey was not of prognostic importance. It is concluded that the benefit conferred by an initial course of streptomycin in the conditions of a controlled clinical trial was not obtained by the Survey patients receiving streptomycin, because of an inadequacy of intake of the TH regimen in the continuation phase of chemotherapy.

Primary drug resistance in pulmonary tuberculosis in Great Britain second national survey, 1963.

Summary A second national survey in Great Britain was conducted in 1963 to determine the prevalence of primary drug resistance to isoniazid, streptomycin and PAS and to compare the results with the national survey of 1955–56. A sample of 125 chest clinics was selected by a random process. Specimens of sputum from 1,292 newly-diagnosed patients were cultured for tubercle bacilli at a central laboratory. Of the 911 positive cultures obtained, 894 were Myco. tuberculosis, 2 Myco. bovis and 15 anonymous mycobacteria. After excluding the patients with anonymous mycobacteria, the prevalence of primary drug resistance to isoniazid, streptomycin and PAS alone or in combination was 4·1%. Resistance to only 1 drug occurred in 3·0% of patients, to 2 drugs in 0·9% and to all 3 drugs in 0·2%. The total resistance to isoniazid was 1·7%, to streptomycin 3·0% and to PAS 0·8%. Most single drug resistance was to streptomycin. Most double drug resistance was to isoniazid and streptomycin. The prevalence of primary drug resistance was statistically significantly higher among immigrants than among the British and Irish patients. The prevalence was higher among the recently arrived immigrants than among immigrants who had been in Great Britain for 5 or more years. A comparison of the findings between the 2 national surveys shows that there has been no change in prevalence over the 7-year period. Patients from countries other than Britain and Ireland comprised 10·0% of the bacteriologically confirmed patients with tuberculosis in the survey. The significance of these findings has been discussed in relation to the problem of the origin of primary drug resistance and of its importance.

PHARMACOLOGY OF SOME SLOW-RELEASE PREPARATIONS OF ISONIAZID OF POTENTIAL USE IN INTERMITTENT TREATMENT OF TUBERCULOSIS

Abstract The pharmacology of three slow-release preparations of isoniazid (I.N.H.) have been studied for their potential use in the once-weekly treatment of tuberculosis. The I.N.H. in the matrix preparation was almost completely absorbed, yet the rate of absorption should allow a dose of at least 30 mg. per kg. body-weight to be given to slow and rapid inactivators of I.N.H. without acute toxicity. Such a dose should be therapeutically effective in once-weekly regimens. Effective and safe once-weekly chemotherapy might also be achieved in rapid inactivators by giving 15 mg. per kg. ordinary I.N.H. with 15 mg. per kg. of the enteric-coated preparation studied, but this regimen would not be safe in slow inactivators.

INFLUENCE OF PRETREATMENT BACTERIAL RESISTANCE TO ISONIAZID, THIACETAZONE OR PAS ON THE RESPONSE TO CHEMOTHERAPY OF AFRICAN PATIENTS WITH PULMONARY TUBERCULOSIS.

Summary The relationship between pretreatment bacterial sensitivity to isoniazid, thiacetazone or PAS and the progress of East African patients with pulmonary tuberculosis treated with either isoniazid plus thiacetazone or isoniazid plus PAS has been studied in co-operative controlled trials. Patients were randomly allocated to treatment for one year, in-patients with isoniazid 200 mg. plus PAS (sodium salt) 10g daily, isoniazid 300 mg. plus thiacetazone 150 mg. daily, isoniazid 200 mg. plus thiacetazone 150 mg. daily or isoniazid 300 mg. plus thiacetazone 100 mg. daily and out-patients with isoniazid 200 mg. plus PAS (sodium salt) 10 g. daily or isoniazid 200 mg. plus thiacetazone 150 mg. daily. A total of 558 patients who complied with the clinical criteria for admission and who completed six months of treatment were divided into 497 patients with isoniazid-sensitive organisms initially (the INH-sensitive group) and 61 patients with isoniazid-resistant organisms in one or both of their pretreatment cultures (the INH-resistant group). All of the INH-resistant group denied, having received previous antituberculosis chemotherapy on admission, but when the 32 in-patients were requestioned later, six admitted to previous treatment with isoniazid. Moderate or greater radiographic improvement occurred during the first six months of treatment in 52% of the INH-sensitive group and in 36% of the INH-resistant group. Cavities became smaller or disappeared in 81% of the INH-sensitive group and in 69% of the INH-resistant group. The smear and culture results at three months were similar in the INH-sensitive and the INH-resistant groups receiving PAS plus isoniazid, but were more frequently negative in the INH-sensitive group than in the INH-resistant group treated with isoniazid plus thiacetazone. A negative culture at six months was obtained from 83% of 176 INH-sensitive patients and 52% of 21 INH-resistant patients treated with 10 PH and from 72% of 304 INH-sensitive patients and 38% of 39 INH-resistant patients treated with isoniazid plus thiacetazone. Cultures at six months were more often resistant to the second drug used in treatment (PAS or thiacetazone) in the INH-resistant group than in the INH-sensitive group. A negative culture at six months was obtained as often from the patients with pretreatment resistance to the two drugs used in treatment as from those with resistance only to isoniazid. The bacteriological progress of the patient was best associated with the proportion of the pretreatment strain growing on 0·2 μg./ml. isoniazid. less well associated with the proportion growing on 1.5 or 50μg./ml. and not associated with the minimal inhibitory concentration of isoniazid. Considerable variation was found between patients in the thiacetazone sensitivity of their pretreatment strains. The progress of 228 patients with initially isoniazid-sensitive organisms during treatment with isoniazid plus thiacetazone was studied in relation to pretreatment thiacetazone sensitivity. Moderate or greater radiographic improvement occurred during the first six months of treatment in 64% of 72 patients with pretreatment minimal inhibitory concentrations (MICs) of 1·0 μg./ml. thiacetazone or less, in 58% of 83 patients with MICs of 1·1–2·0 μg./ml. in 51% of 53 patients with MICs of 2·1–4·0 μg./ml., and in 22% of nine patients with MICs of more than 4·0 μg./ml. The corresponding proportions yielding a negative culture at six months were 79% of 75 patients, 75% of 87 patients, 68% of 53 patients and 50% of 10 patients, respectively. Similar associations were found between pretreatment sensitivity to thiacetazone and other measures of progress, namely, the emergence of isoniazid resistance at three months and at six months, and the classification of the bacteriological status of the patients at twelve months. Initial PAS sensitivity was investigated in 215 patients with initially isoniazid-sensitive organisms who were treated with PAS plus isoniazid in four chemotherapy studies in East Africa. PAS resistance was found in a pretreatment culture from 19 patients, but it was often not confirmed in further tests on the same culture in the same or in a different laboratory. The progress of the patients during treatment was similar in those with a PAS-resistant pretreatment culture and in those with sensitive cultures. Sporadic unconfirmed resistant results were obtained more often from East African than from British strains and it is suggested that strains of Indian origin which are known to have these characteristics, are sometimes present in East Africa.

AN ASSESSMENT OF THE WORLD HEALTH ORGANIZATION CLASSIFICATION OF THE HISTOLOGIC TYPING OF LUNG TUMORS APPLIED TO BIOPSY AND RESECTED MATERIAL

In a study of the World Health Organization classification of the histologic typing of lung tumors.6 sections from a total of 740 patients in the Medical Research Council Study of Cytotoxic Chemotherapy, 182 of whom also had positive preoperative bronchial biopsies and 231 involved lymph nodes in the resected specimens, and from 30 patients in the Medical Research Council Trial of Surgery and Radiotherapy in Small or Oat‐celled Carcinoma of the Bronchus have been assessed. Of the 740 primary tumors from the Study of Cytotoxic Chemotherapy, 71% were placed in Type I, 12% in Type II, 9% in Type III, and 7% in Type IV. Only 2 primary tumors could not be typed. A blind comparison of the type of primary tumor and bronchial biopsy showed that the biopsy was a good indicator of the type of the primary tumor. A bind comparison of the primary tumor and involved lymph node also showed a close degree of agreement. However, when the type of the primary tumor was assessed in the presence of the involved node. tumors were placed in Type IV far less frequently than when assessed blind. It is concluded that the World Health Organization classification is applicable to primary tumor, bronchial biopsy, and involved node, that the biopsy is a valuable indicator of the type of the primary tumor, and that the apparent type of the involved node should not be allowed to over‐influence the pathologist in deciding on the type of the primary tumor when both are assessed together.

A second international co-operative investigation into thiacetazone side-effects Rashes on two thiacetazone containing regimens

Abstract This report describes the rashes occurring in an international co-operative investigation into thiacetazone side-effects. The regimens studied were : •STH Streptomycin 1 g intramuscularly daily together with thiacetazone 150 mg and isoniazid 300 mg in a single tablet daily. •SH Steptomycin 1 g intramuscularly daily together with isoniazid 300 mg in a single tablet daily. •TH Thiacetazone 150 mg together with isoniazid 300 mg in a single tablet daily. Patients were allocated for 12 weeks to all 3 regimens in Algeria, Ethiopia, India, Malaysia, Mongolia, Pakistan, Singapore and Trinidad but only to the streptomycin-containing regimens in Czechoslovakia and Morocco. All the tablets were identical in appearance. Rashes occurred in 17·6 per cent of the 1,396 STH patients, 7·7 per cent of the 1,407 SH patients and 16·1 per cent of the 1,165 TH patients. Of the patients with rashes, 70 per cent of 246 STH, 61 per cent of 109 SH and 70 per cent of 188 TH developed them in the first 6 weeks and 12 per cent, 16 per cent and 11 per cent respectively in the last 3 weeks. The rashes were severe in 20 per cent of the STH, 6 per cent of the SH and 20 per cent of the TH patients, the duration was less than 30 days in 73 per cent, 68 per cent and 72 per cent respectively. The rashes led to the discontinuation of the chemotherapy in 15 per cent, 6 per cent and 13 per cent respectively. Exfoliative dermatitis was rare and occurred only in 7 (3 STH, 4 TH) patients. One (TH) patient had the Stevens-Johnson syndrome. Hypersensitivity was demonstrated to streptomycin in 35 per cent of the STH and 50 per cent of the SH patients tested, to thiacetazone in 41 per cent of the STH, 20 per cent of the SH and 60 per cent of the TH patients and to isoniazid in 2 per cent, 10 per cent and 7 per cent respectively. Hypersensitivity was to 1 drug in the majority of patients. No additional treatment was given to 51 per cent of the STH, 72 per cent of the SH and 51 per cent of the TH patients. Antihistamines were given to 39 per cent, 24 per cent and 43 per cent respectively and steroids to 11 per cent, 1 per cent and 7 per cent respectively. Desensitization was successful in 19 per cent, 7 per cent and 22 per cent of the patients with rashes and unsuccessful in 6 per cent, 3 per cent and 2 per cent respectively. The frequency of rashes on all 3 regimens varied considerably from country to country but was nearly always greater in the thiacetazone-containing regimens than the SH regimen. The frequency was high in Singapore and Trinidad and low in Czechoslovakia, Morocco and Pakistan. No rashes were reported from Ethiopia. In Trinidad the frequency of rashes was significantly higher in patients of Indian than of African descent but the differences between the Chinese, Malays and Indians in Malaysia and Singapore were smaller and non-significant.

Streptomycin plus thiacetazone (thioacetazone*) compared with streptomycin plus pas and with isoniazid plus thiacetazone in the treatment of pulmonary tuberculosis in rhodesia

Summary Between September 1964 and July 1965, 220 patients were allocated at random to three treatment regimens. TH: thiacetazone 150 mg. plus isoniazid 300 mg. daily in a single tablet. SP: streptomycin sulphate 1 g. intramuscularly daily plus sodium PAS 15 g. daily in three doses. ST: streptomycin sulphate 1 g. intramuscularly daily plus thiacetazone 150 mg. daily in a single tablet. All patients were treated in hospital for six months. There were 171 (58 TH, 55 SP, 58 ST) patients who complied with the clinical criteria for admission and who had strains of tubercle bacilli sensitive to isoniazid and streptomycin. The condition of the three series on admission to treatment was broadly similar. The great majority of patients had severe disease pretreatment. The 168 pretreatment Rhodesian cultures were less sensitive on average to thiacetazone than a control series of cultures examined concurrently from 76 previously untreated British patients, the geometric means of the MICs being 1·56 μg./ml. and 0·59 μg./ml. respectively (P Ten patients died. five (two TH, two SP, one ST) from active tuberculosis, three (one SP, two ST) from non-tuberculous causes but with active tuberculosis and two (both TH) from possible drug toxicity with active tuberculosis. The sputum was negative on both cultures at six months in 72% of the TH, 82% of the SP and 33% of the ST patients. At three months none (0%) of the 53 SP and 20 (37%) of the 54 ST patients were excreting streptomycin-resistant organisms (P At six months 72% of 58 TH, 76% of 55 SP and 26% of 57 ST patients had a favourable response classified mainly on bacteriological grounds. The differences between the ST and each of the other two regimens were statistically highly significant (P Cutaneous hypersensitivity occurred in 9% of the TH, 10% of the SP and 10% of the ST patients. It was most severe in the TH patients. Jaundice occurred in one patient in each of the three series. Gastric side effects were almost confined to the SP series and dizziness was recorded only in the ST patients, occurring in 11%. It is concluded that the ST regimen was markedly inferior. The SP and TH regimens wereof similar effectiveness, the latter being an effective oral regimen under Rhodesian conditions.

Bacteriological aspects of the second national survey of primary drug resistance in pulmonary tuberculosis, 1963.

Summary The bacteriological methods employed in the second national survey of the prevalence of primary drug resistance to streptomycin, PAS and isoniazid among adults with newly-diagnosed and previously untreated pulmonary tuberculosis have been described. Duplicate cultures were tested from a sample of patients. From the results, estimates were made of variation between duplicate cultures from the same patient, variation, between patients, and variation between the tests set up in different batches. For patients with sensitive strains there was significant variation between patients in the level of sensitivity to each of the 3 drugs. As a result of these statistical estimations, definitions of resistance based on a critical resistance ratio or minimal inhibitory concentration have been adopted; these are simpler to apply than those of the first survey (in 1955–56) and are more soundly based. Comparability between the 2 surveys was examined in tests on sensitive strains in each survey. The critical resistance ratios for streptomycin and PAS appeared equivalent, but the critical minimal inhibitory concentration for isoniazid was not quite equivalent in the 2 surveys, suggesting that the use of resistance ratios would have been advisable. Identification tests were undertaken on all strains. Of 911 patients with positive cultures, anonymous mycobacteria were isolated in 15 (1·6%). Ten of these were Myco. kansasii . Only 2 patients had strains of Myco. bovis .