Long-term chemotherapy in the treatment of chronic pulmonary tuberculosis with cavitation

Tubercle, Lond., (1962), 43,201

ORIGINAL

ARTICLES

LONG-TERM CHEMOTHERAPY IN THE TREATMENT OF CHRONIC PULMONARY TUBERCULOSIS WITH CAVITATION A REPORT TO THE MEDICAL RESEARCH COUNCIL

BY THEIR TUBERCULOSIS CHEMOTHERAPY TRIALS COMMITTEE*

SUMMARY

A total of 284 patients with chronic extensive pulmonary tuberculosis with cavitation was admitted to a co-operative study of long-term chemotherapy from 46 centres in Britain. The intake of patients began in January 1956 and ended in January 1958. This report presents results for three years for all the patients, with certain fourth-year results in an addendum. Four times as many men as women were admitted; about three-quarters of the men and just under half the women were aged 45 years or more (Table II). A standard regimen of isoniazid 200 mg. plus PAS (sodium) 10 g. a day given in the same oachet in two equal doses was prescribed for all the patients. In the first stage of the trial, streptomycin 1 g. daily in a single intramuscular injection was also prescribed for the first six weeks to half the patients, chosen at random. From July 1957, all patients received the standard regimen with the same streptomycin supplement until the results of initial drug sensiti vity tests indicated that the strains were sensitive to isoniazid and PAS (Table I). Nearly aU the patients were admitted to one of two main intakes; within each intake they were allocated at random to one of three durations of chemotherapy, as follows:(a) t/l/2-year intake: durations of six months, one year or two years. (b) 1/2/3-year intake: durations of one, two or three years. The effects of long-term chemotherapy have been assessed in the patients admitted to the 1/2/3-year intake. All the patients who continued on combined chemotherapy for the prescribed duration have been considered in the analysis whether or not there had been any departure from the prescribed regimen. All patients began treatment in hospital; half of them remained there for at least six months. Of the 187 patients assessed at one year, 91 % had bacteriologically quiescent disease, that is, had had negative cultures for at least the last three monthly examinations. The corresponding proportions of the smaller numbers who continued on chemotherapy by allocation were 86% of 86 patients at two years and 86 % of 35 patients at three years (Table VI). Thus, a high rate of bacteriological quiescence was achieved with chemotherapy alone by one year and this was maintained, but not improved upon, by the continuation of chemotherapy for a second or a third year, with the same drugs in the great majority of patients. The effects of stopping chemotherapy at various times were assessed by considering the incidence of bacteriological relapse (that is, the re-appearance oftubercle bacilli in at least two of four consecutive monthly cultures) in patients who had bacteriologically quiescent disease at the end of their prescribed duration of chemotherapy. For patients in the tl1/2-year intake, 8 (62 %) of the 13 patients who stopped chemo"'Members of the Committee: Sir Geoffrey Marshall (Chairman), Professor J. W. Crofton, Professor R. Cruickshank, Dr. A. J. Eley, Dr. Wallace Fox, Dr. J. E. Geddes, Professor F. R. G. Heaf, Professor Sir Austin Bradford Hill, Dr. J. V. Hurford, Dr. D. A. Mitchison, Professor W. D. M. Paton, Dr. J. G. Scadding, Dr. Ian Sutherland, Dr. D. Thomson (resigned in 1958), Dr. P. D'Arcy Hart (Secretary). Reprints of the report may be obtained from the Tuberculosis Research Unit, M.R.C. Laboratories, Holly Hill, Hampstead, London, N.W.3. D

202

TUBERCLE

therapy at six months relapsed and 1 further patient showed a clinically important radiographic deterioration in the two-and-a-half-year period of subsequent observation, whereas only 1 (9 %) of the 11 patients who continued chemotherapy for at least one year relapsed and none showed clinically important radiographic deterioration in the same period (Table IX). Thus, a period of chemotherapy of only six months was inadequate to prevent later relapse. Of the patients in the 1/2/3-year intake, 14 (19 %) of the 74 patients who stopped chemotherapy at one year had a bacteriological relapse in the second and third year compared with 3 (4 %) of the 82 patients who continued chemotherapy for a second or third year (Table XII). As the result of a fourth year of observation (see Addendum), these figures become 16 (22 %) and 3 (4 %), respectively. Thus, extending the period of chemotherapy from one to two or three years led to a considerable reduction in the relapse rate. Among the patients in the 1/2/3-year intake, the numbers of clinically important radiographic deteriorations in the second and third years were 2 of the 74 patients who stopped chemotherapy at one year compared with I of the 82 who continued fo r a second or third year. The results from the fourth year (see Addendum) bring the figures to 5 and I, respectively. One (2 %) of the 42 patients who stopped chemotherapy at two years had a bacteriological relapse in the third year compared with none of the 29 patients who continued chemotherapy for a third year (Table XII). There appeared to be little additional benefit from the extension of chemotherapy from two to three years. Considering these findings in another way, the bacteriological relapse rates in the first year after stopping chemotherapy were 14 % for the 74 patients in the one-year group (i.e. from the relapses in the second year) and 2 % for the 42 patients in the two-year group (i.e. from the relapse in the third year ). Thus, continuing chemotherapy for a second year led to a true reduction in the relapse rate; it did not simply postpone it. When the relapses are considered in a third way, according to the duration of bacteriological quiescence at the time of stopping chemotherapy, 21 % of the 73 patients who had had seven to twelve months of bacteriological quiescence before stopping chemotherapy relapsed, compared with 5 % of the 42 patients who had had quiescent disease for periods of nineteen to twenty-four months (Table XIV). There was a high incidence of persistent cavitation in the absence of positive bacteriological findings (the 'open-negative syndrome'); it was present in 108 (70 %) of the 155 patients with quiescent disease at one year. Of these 108 patients, 15 (14 %) relapsed subsequently, compared with 2 (4 %) of the 47 patients without residual cavitation at one year (Table XVIII), a non-significant difference. Of the se patients with residual cavitation, 24 % of the 50 who stopped ch emotherapy at one year relapsed subsequently, compared with 5 % of the 58 who continued on chemotherapy (Table XVIII); this difference is significant at the 5 % level. Thus, in patients with the 'open-negative syndrome' at one year, continuation of combined chemotherapy for a second year led to a substantial reduction in th e relapse rate. Factors of possible prognostic importance were studied. Failure to close cavities at one year was associated significantly with the multiplicity and size of the cavities and with the presence of cavities in the periphery of the lung field initially (Table XVI). A number of further bacteriological findings of interest emerged : (a) A small number of patients produced isolated positive cultures, some during and some after chemotherapy. (b) The development of isoniazid resistance during chemotherapy was usually an adverse prognostic sign.

LONG-TERM CHEMOTHERAPY

203

(c) Isoniazid-sensitive organisms were found persistently in a small number of patients for whom chemotherapy containing isoniazid was still being prescribed. Of the 24 patients who relapsed after stopping chemotherapy 20 relapsed with sensitive organisms compared with 3 of the 11 patients who relapsed while still on chemotherapy, a difference significant at the 1 % level. With further chemotherapy, mostly with the same drugs, 82 % of those who relapsed after stopping chemotherapy achieved quiescent disease at three years, compared with 30 % of those who relapsed while stilI on chemotherapy, a difference significant at the 5 % level. A comparison was made between the progress of two groups of patients allocated at random, one to treatment with isoniazid plus PAS (the PH series) and the other to treatment with isoniazid plus PAS with an initial supplement of streptomycin for six weeks (the SPH series). Assessments were made of 81 PH and 70 SPH patients according to their bacteriological status at twelve months (Table XXVI). An unfavourable response was found in 16% of the PH and 3 % of the SPH series, a difference significant at the 1 % level. Symptoms attributed to toxic or hypersensitivity reactions to the drugs occurred in 14 % of the PH and 27 % of the SPH series (Table XXVII). This difference was significant at the 5 %level and was attributed to the initial streptomycin supplement. Twenty-seven PH and 17 SPH patients remained on their allocated chemotherapy throughout the first year, had quiescent disease at one year and then stopped chemotherapy. There was little difference between the two series in the subsequent relapse rates, which were 22 %for the PH and 18% for the SPH patients. In the study as a whole , there was a high incidence during chemotherapy of specimens yielding positive smears but negative cultures (Table XXVIII) . These occurred particularly frequently in a small group of patients who had the most extensive disease and the largest cavities (Table XXIX). There was no conclusive evidence that such results indicated the presence of living organisms in the sputum. The ESR examination was found to be of limited value in assessing the progress of patients with chronic pulmonary tuberculosis. In conclusion, this study has shown that, even in patients with chronic disease and cavitation, a high rate of bacteriological quiescence was achieved by the end of one year with chemotherapy alone. The results obtained with isoniazid plus PAS, supplemented by daily streptomycin for the first six weeks, were better than those with isoniazid plus PAS throughout. However, stopping chemotherapy at one year led to a substantial relapse rate, especially among those patients who had persistent cavitation at one year. Continuance of combined chemotherapy for a second year substantially reduced the relapse rate.

The Medical Research Council's earlier trials of chemotherapy in pulmonary tuberculosis in Britain were concerned with the efficacy of short (usually three-month) courses of various combinations of isoniazid, p-aminosalicylic acid (PAS) and streptomycin in bringing about clinical and radiographic improvement , in rendering the sputum negative for tubercle bacilli and in preventing the emergence of drug-resistant bacilli, especially in patients with acute extensive disease. Between 1949 and 1953, when these trials were undertaken, longer courses of chemotherapy were not generally regarded as being desirable. Towards the end of this period, however, some clinicians were beginning to ad vocate courses of chemotherapy of six months, a year, or even longer. Accordingly, in 1955, the Tuberculosis Chemotherapy Trials Committee, at the suggestion of the British Tuberculosis Association's Research Committee, planned a trial of long-term chemotherapy in patients with chronic pulmonary tuberculosis with cavitation.

204

TUBERCLE

Patients with chronic cavitary disease were chosen for study because they are also frequently chronic excretors of tubercle bacilli in the absence of chemotherapy, and so constitute a serious public health risk. The chief objects of the trial were to determine how long a period of chemotherapy was necessary in such patients to render the sputum negative, how long they would remain sputum-negative under prolonged chemotherapy, how long they would remain sputum-negative after stopping courses of chemotherapy of different durations, and how extensive cavitation would behave during and after such courses. The prescribed durations of these courses ranged from six months to three (or four) years. The standard chemotherapeutic combination was isoniazid plus PAS; in a proportion of the patients this was supplemented with streptomycin in the early weeks. These forms oftreatment were customarily used at the time the trial was planned. Two hundred and eighty-four patients were admitted to the trial, the first on the 3rd January, 1956, and the last on 28th January, 1958. The present report contains results on the patients for three years after entry to the trial, together with an addendum giving a brief account of the progress in the fourth year. A list of the participating centres and the names of the co-operating clinicians, bacteriologists and pathologists arc given at the end of the report. The trial was co-ordinated successively by Dr. A. Wiener, Dr. J. Pepys , Dr. H. W. Bunje Dr. Joan F . Heffernan and Dr. J. H. Angel , of the Council's Tuberculosis Research Unit. Dr. D. A. Mitchison and Dr. J. B. Selkon, of the Council's Unit for Research on Drug Sensitivity in Tuberculosis, provided central labo ratory facilities for testing drug resistance. Drs. Angel and Bunje and Miss B. .T. Kinsley (of the Council's Statistical Research Unit) analysed the results and Drs. Angel and Bunje prepared the report. Radiographic assessments were made by Drs. J. R. Bignall, L. G. Blair, A. F. Foster-Carter and G. Simon. I. PLAN AND CONDUCT OF THE TRIAL Type of Case A patient was eligible for the trial if the disease appeared clinically and radiographically to be pulmonary tuberculosis, excluding only those patients in whom the disease was judged to be predominantly pneumonic and of recent origin. In addition, to qualify for acceptance the patient had to : (a) be aged between 20 and 70 years; (b) have bilateral disease (or unilateral in patients over 40 years of age); (c) have cavitation in one or both lungs, the cavities on a full-size postero-anterior radiograph having a minimal total diameter of 5 em.; (d) have sputum positive for acid-fast bacilli on two consecutive direct (or concentrated) smear examinations within one week; (e) have had no previous anti-tuberculosis chemotherapy; (f) beunlikely in the opinion of the physician in charge to require collapse therapy or resection; (g) be likely to remain in the district for several years. Recent apparent spread of tuberculosis, co-existent bronchitis or emphysema were not contraindications to admission to the trial. Patients with any of the following conditions were ineligible: (a) pleural effusion obscuring more than one-third of one lung field; (b) extra-pulmonary tuberculosis which required treatment; (c) pneumoconiosis (the Medical Research Council has undertaken a parallel trial in pulmonary tuberculosis with pneumoconiosis in collaboration with the United Cardiff Hospitals) ; (d) other chronic disease likely to affect the prognosis of the pulmonary tuberculosis, for example, cirrhosis of the liver, or a disease having , in itself, a poor prognosis, such as cerebral thrombosis; (e) pregnancy. Patients of non-European stock were also ineligible. Chest radiographs and clinical information for potentially suitable cases were submitted by

LONG-TERM CHEMOTHERAPY

205

participating centres to the Tuberculosis Research Unit. To ensure reasonable uniformity in the type of case admitted to the trial, each case was reviewed by members of a small group of clinical assessors" before acceptance. Allocation of Chemotherapy When a patient had been accepted for the trial, the duration and type of chemotherapy were allocated by the Tuberculosis Research Unit from confidentially held pre-arranged lists (one for each participating centre) based upon random sampling numbers and prepared by the Statistical Research Unit. They provided for the allocation both to one of three durations of chemotherapy and to one of two types of chemotherapy. The Chemotherapeutic Regimens It was decided to use as a standard drug combination, isoniazid plus PAS, which had been used in a previous Medical Research Council trial. The regimen, prescribed for all patients in the trial, was isoniazid 200 mg. daily plus PAS (sodium salt) 10 g. daily by mouth, given together in cachets. It was suggested that this should be given in the form of 'Pycamisan PH 10' (Smith and Nephew Pharmaceuticals), four cachets in each of two doses, twelve hours apart. (Each cachet contains 25 mg. isoniazid plus 1·25 g. of sodium PAS,) Apart from its efficacy as shown in the previous trial (Medical Research Council, 1955), there were two additional reasons for using this particular regimen as a standard. First, it was expected that many of the patients would be middle-aged or elderly and that a regimen involving the administration of a long course of streptomycin should therefore be avoided. Second, since PAS was to be administered for a period of at least several months, it was felt it should be given in a dose which would reduce the risk of producing toxic reactions, and yet would retain clinical efficacy, However, to assess the effects of giving three drugs at the very beginning of treatment, streptomycin sulphate 1 g. daily in a single intramuscular injection was prescribed for the first six weeks, in addition to the standard regimen, to half the patients chosen at random. In 1957, a national survey of drug-resistant tubercle bacilli (Fox and others, 1957) showed that there was an appreciable risk that previously untreated patients, if given a combination of only two drugs, might later be found to have been infected with organisms resistant to one of them. In July 1957, therefore, eighteen months after the start of the trial, it was agreed with the participating clinicians that all the patients admitted thereafter should start treatment with all three drugs, isoniazid, PAS and streptomycin. The streptomycin was to be stopped if, and when, the results of the sensitivity tests on pre-treatment cultures indicated that the strains were sensitive to isoniazid and PAS; these results were usually available six to nine weeks after the start of chemotherapy. Although it was hoped that clinicians would be able to continue chemotherapy with the standard regimen described, provision was made for a change to other forms of chemotherapy under certain circumstances. Duration of Chemotherapy To meet the wide range of views on the optimum duration of chemotherapy current at the start of the study, participating clinicians were offered a choice between submitting patients either for random allocation to periods of chemotherapy of six months, one year, or two years (i/1/2-year intake), or for random allocation to periods of one, two or three years (1/2/3-year intake) (Table I). One centre elected to submit patients for random allocation to courses of chemotherapy of two, three, or four years (the 2j3j4-year intake). At the end of their prescribed period of chemotherapy, the patients, excepting only those still excreting tubercle bacilli, were to stop all chemotherapy, their progress being followed until five years had elapsed from the start of the prescribed course. The allocation lists were so arranged that the shortest treatment period within each intake was allocated to about twice as many patients as to each of the two longer periods within the intake. This provision was to ensure that the number of patients stopping chemotherapy after a particular duration was approximately equal to the number ... Dr. J. R. Bignall, Dr. R. Grenville-Mathers, Dr. J. A. Keeping, Dr. H. Nicholson, Dr. J. G. Scadding, Dr. G. Shneerson, Dr. P. Stradling, Dr. H. J. Trenchard, Dr. C. H. C. Toussaint.

206

TUBERCLE TABLE I.-NUMBERS OF PATIENTS IN THE TRIAL (AFTER EXCLUSIONS) -_.,---".

Duration of standard chemotherapy prescribed concurrently (in years)

Intake

1!2!3-ye'Jr

2!3!4-ye'Jr

Admissions from 1st July, 1957 Streptomycin until initial sensitivity results available

Total

No streptomycin supplement

Streptomycin for the first 6 weeks

10 4 4

13 6 4

0 0 0

23

1 2 1 2 3

41 21 19

32 21 16

28 15 13

101 57 48

2 3 4

3

3 1

1 2 1

7 4 4

60

262

k !/I!2·year

Admissions before 1st July, 1957

All intakes

I 2

I

------- 105

97

10

8

continuing beyond that duration; this arrangement gave the best chance of detecting any disadvantages following cessation of chemotherapy. It is an indication of the views of chest physicians, late in 1955, on the optimum duration of chemotherapy, that 13 (28 %) of the 46 participating centres chose to submit patients for random allocation to the shorter periods of chemotherapy, namely, to the i!lf2-year intake. By the middle of 1957, an increasing number of clinicians had become doubtful of the efficacyof a six-month period of chemotherapy. Moreover, preliminary findings of the trial, presented to the participating clinicians at that time, indicated that bacteriological relapses were occurring more often in those who had stopped chemotherapy at the end of six months than in those who had continued. At the request of the participating clinicians, therefore, no further patients were admitted to a six-month treatment period and all patients admitted to the trial after July 1957 were allocated chemotherapy at random for one, two or three years (except for the one centre mentioned above). General Management of the Patients All patients entering the trial were to be admitted to hospital or sanatorium for at least three months. The amount of bed rest was left to the discretion of the physician in charge. After discharge from hospital the patient's treatment continued at home under regular clinic supervision. As far as possible, cases were admitted to the trial from chest clinics with access to hospital beds, to ensure continuity of supervision. Changes of Chemotherapy In a trial of a drug combination prescribed for a considerable length of time, it was inevitable that circumstances would arise in some patients which would necessitate a change either in the type or in the duration ofthe chemotherapy. To keep these changes to a minimum, clinicians were asked to observe certain principles and to discuss each problem with the staff of the Tuberculosis Research Unit before making any alteration. The clinician was permitted to change to another drug combination if the patient developed a toxic reaction to isoniazid or PAS to which he could not be desensitised, or if the patient was found at any time during chemotherapy to be excreting organisms resistant to isoniazid or PAS. Apart from these circumstances the clinician was expected to adhere to the standard combination, but when variations were introduced continuity of chemotherapy was regarded throughout as being of greater importance than the exact nature of the drug combination. The frequency of such variations is indicated later (page 210). The clinician was also permitted, and indeed encouraged, to continue some form of chemotherapy for a patient who was excreting tubercle bacilli at the end of the prescribed course, or to re-introduce it for a patient who showed a definite radiographic spread or a bacteriological relapse after the end of the prescribed course. However, clinicians often showed considerable reluctance to stop chemotherapy at the end of the prescribed course in patients who had achieved bacteriological quiescence, although the assessment of the efficacy of different durations of chemotherapy depended on this. The frequency and the consequences of such departures will be described later (pages 217 and 218).

207

LONG-TERM CHEMOTHERAPY

Investigations Before and During Treatment After admission to the trial and before the start of chemotherapy the clinician recorded the general condition of the patient, the amount of sputum produced in twenty-four hours, the character of the sputum, the ESR (Westergren, 200 mm. reading at one hour) and the weight; he also obtained a postero-anterior chest radiograph and sent one specimen of the patient's sputum to his 'local' laboratory and one to the central laboratory. In both laboratories direct smear and culture examinations and sensitivity tests were performed on these specimens, and all direct smear and culture results were graded. The bacteriological procedures are described in Appendix A. After the start of chemotherapy, direct smear and culture examinations and sensitivity tests were made in the local laboratory on one sputum specimen every calendar month from the date of starting chemotherapy up to four months. Direct and culture examinations of sputum (in the absence of sputum, examinations oflaryngeal swabs or gastric juice specimens) were made monthly in the local laboratories up to thirty months from the start of chemotherapy and then at three-monthly intervals. From four months onwards a sample of any positive culture obtained was sent to the central laboratory for sensitivity testing, and sensitivity testing locally became optional. The sensitivity test results used in the analysis, both for the pre-treatment specimen and the specimens from four months onwards, are those given by the central laboratory. (Patients allocated three or four years of chemotherapy continued to have monthly bacteriological examinations up to forty-two and fifty-four months respectively before changing to the three-month interval.) At six weeks, at three months and then at three-monthly intervals, the clinician obtained a chest radiograph and made the same observations on the patient as before the start of chemotherapy. In addition, he recorded the patient's physical activity, any drug toxicity, clinical and radiographic changes since the previous examination and the result of a ferric chloride test on a urine specimen obtained at the time of the examination. In addition, every six months, the clinician assessed the activity of the patient's disease, his working capacity, and the clinical and radiographic changes since the start of chemotherapy. NUMBER OF PATIENTS IN THE ANALYSIS

Of the 284 patients admitted to the trial, 22 have been excluded from the main analysis of the results. One patient died before chemotherapy could be started. One patient was admitted to another trial in error and 2 patients refusedadmission to hospital. For 5 patients (4 from one small centre) too few observations were provided after the start of chemotherapy to justify including them in the analysis. One patient was later found to have received previous anti-tuberculosis chemotherapy. The remaining 12 patients were excluded on bacteriological grounds; 2 were found to be infected with 'atypical' mycobacteria and 10 produced strains which were initially resistant to one of the three drugs (2 to isoniazid, 3 to PAS and 5 to streptomycin). Of these 22 patients, 5 (4 six-month, lone-year) had been admitted to the ill/2-year intake, 16 (8 one-year, 3 two-year, 5 three-year) to the 1J2J3-year intake and I (two-year) to the 2/3/4-year intake. After these exclusions there remain 262 patients in the analysis. Table I shows the distribution of these patients according to the duration and type of chemotherapy. The third and fourth columns show the admissions during the first period of the trial, when streptomycin was prescribed for the first six weeks to half the patients chosen at random. The fifth column shows the later admissions (from lst July, 1957) when streptomycin was prescribed to all the patients until the initial sensitivity results became available. The great majority of admissions (206) was to the IJ2J3-year intake. Table II shows the age and sex distribution of the 262 patients. It will be seen that nearly four times as many men as women were admitted. Moreover, 72 % of the 205 men were aged 45 years or more, whereas only 44 % of the 57 women were in this age-group. TABLE n.-AGE AND SEX DISTRIBUTION OF PATIENTS (AFTER EXCLUSIONS)

Age (in years) Sex 20-24

Men Women Total

I

I I

4 4 8

I

25-34 18 16 34

I I

II

All ages

35-44

45-54

55-64

62

70 10

\

36 12

\

14

,

48

I

65-69 15

\

I

1

I

I

76

80

\

205 57

16

262

208

TUBERCLE

Plan of the Present Report Because the trial gives information on a number of distinct problems, it is convenient to present the results in separate sections of this report. Section II is concerned with the progress of the patients during the time they received chemotherapy ('long-term chemotherapy' section). To simplify the presentation, the analysis has been made on the largest intake, namely the 1/2/3-year intake. Section III presents a comparison of the subsequent progress of patients with quiescent disease who stopped chemotherapy, with the progress of patients with quiescent disease who continued on chemotherapy ('relapse' section). Comparisons have been made between patients who stopped chemotherapy: (a) at six months (from the Vl/2-year intake); (b) at one year (from the 1/2/3-year intake); (c) at two years (from the 1/2/3-year intake); and those who continued chemotherapy beyond each of these times. Section IV considers the factors of prognostic importance both in relation to progress during chemotherapy and to subsequent bacteriological relapse ('prognostic' section). Section V contains further bacteriological information. Section VI presents a comparison of the effect of one year of treatment with isoniazid plus PAS, and that of one year of isoniazid plus PAS with an initial six-week course of streptomycin ('PH/SPH comparison' section). Section VII is concerned with the prevalence and interpretation of sputum specimens which were positive on direct smear examination but negative on culture ('smear-positive, culture-negative' section). Section VIII considers the value of the ESR in the management of patients with chronic pulmonary tuberculosis. Section IX contains a discussion of the results.

II. PROGRESS OF PATIENTS DURING LONG-TERM CHEMOTHERAPY To study progress during long-term chemotherapy, patients in the 1/2/3-year intake only have been considered. The pre-treatment condition of the patients allocated to the three different durations of chemotherapy was similar, and it is therefore justifiable to amalgamate the results for the three durations. Because the allocation of the durations of chemotherapy was made at random, no bias is introduced at one year nor at two years when the totals of patients are reduced. The corresponding results for patients in the MI/2-year and 2/3/4-year intakes are not presented here, because of the comparatively small numbers involved. In this section, therefore, the progress of all the 206 patients in the 1/2/3-year intake has been studied for the first year, the progress of 105 of them (i.e. the 57 allocated to two years and the 48 allocated to three years of chemotherapy) for a second year and the progress of 48 (allocated to three years of chemotherapy) for a third year. PRE-TREATMENT CONDITION OF THE PATIENTS

Clinical Condition The clinical condition of the 206 patients at the time of admission to treatment is shown in Table III. Ninety-two (45 %) were in poor general condition; the ESR was above 20 mm. in 87 % of the patients and was 51 mm. or more in 49 %; 36 % weighed less than 50 kg. (110 lbs.). Radiographic Condition The extent of the disease, as gauged by the number of lung zones involved and the extent of cavitation, was reported from a single full-size postero-anterior radiograph by an independent assessor (Dr. G. Simon), who was unaware of the treatment series of any patient (Table III). Nearly all the patients (96 %) had bilateral disease; in 74 % there was involvement of four or more lung zones. The assessor classified 16 % of the patients as having no cavities, 34 % as having single cavities, and 50 % as having multiple cavities. There were 74 patients (36 %) who had at least one cavity measuring 4 em. or more in diameter. (It will be noted that there is a discrepancy between the requirement that cases admitted to the study were to have cavitated disease and this classification by the independent assessor. However, the panel accepting the case often had access to several radiographs, including tomographs, while the independent assessor, for uniformity, reported only on a single postero-anterior radiograph.) Bacteriological Condition Of the 204 direct smear findings available, 47% were heavily positive and only 5 % were negative (Table III). All the 203 cultures available were positive and the great majority (87%) yielded confluent growth or innumerable colonies.

209

LONG-TERM CHEMOTHERAPY

TABLE IlL-CLINICAL, RADIOGRAPHIC AND BACTERIOLOGICAL CONDITION ONADMISSION

i No.

Assessment

Total patients

%

206 1

General condition

E.S.R.* (mm. in I hr. Westergren 200 mm.)

Weight (lb.)t

Number of lung zones involved

Good Fair Poor 1- 20 21- 50 51-100 101 or more Less than 110 110-139 140 or more Average

2 3 4

5

6 Extent of cavitation

No cavity Single {Less than 4 em. cavity 4 em. or more (diameter) Multiple cavities {Less than 4 em. (diameter 4 em. or more of largest)

Direct smear* examination

Negative Scanty Moderate Heavy

30 84 92

15 41 45

26 78 79 21

13 38 39

10

36 68 47 87 32 17 120 lb.

16 37 63 60 30

8 18 31 29 15

32

16

39 31

19 15

61 43

30 21

11

5

47

23 25 47

50

96

* No assessment was available for 2 patients. t Initial weights were not recorded for 19 patients. WITHDRAWALS FROM ANALYSIS BEFORE THE END OF THE ALLOCATED PERIOD

In a number of instances, the allocated chemotherapy was modified. Patients have been retained in the analysis throughout, provided that chemotherapy was both adequate and continuous for the prescribed duration. 'Adequate' chemotherapy was defined as any combination of two or more drugs given daily (except that, after the first nine months, one of the drugs could be given twice or three times a week). Chemotherapy was regarded as 'continuous' if the total interruptions did not exceed six weeks in the first year, three months in the first two years, and sixmonths in the first three years, an 'interruption' being any period with no chemotherapy or without adequate chemotherapy.

210

TUBERCLE TABLE IV.-PATIENTS WHO COULD NOT BE RETAINED IN THE ANALYSIS FOR THE WHOLE OF THEIR ALLOCATED PERIOD OF CHEMOTHERAPY

II

I

Treatment Group

I

Reasons for withdrawal Time of withdrawal

Total One-year

I

! I

i In the first year

I

Total patients admitted to study

Non-tuberculous deaths" Non-tuberculous disease Inadequate chemotherapy Excessive interruption of chemotherapy Self-discharge Surgery Total

Between 12 and 18 months

Non-tuberculous deaths Stopped chemotherapy Excessive interruption of chemotherapy Total

Between 18 and 24 months

Non-tuberculous deaths Self-discharge

206

101

57

48

4

2 I I

2

0

0 1 0

2 1

I

I

I I I

7 2 3

19

In the third year I

Stopped chemotherapy (at two years)

I

I

0

4

1

I

1

2 0

2

0

I

11

4

4

I

-

0

4

-

1

I 3

2

-

1

1

7

-

2

5

3 I

-

1

-

1

2 0

4

-

2

2

1

-

I Total

Two-year Three-year

-

1

'" See Appendix B. Thirty-one patients could not be retained in the analysis for the whole of the allocated period for various reasons, principally death from a cause other than tuberculosis, excessive interruption and early stopping of chemotherapy; the reasons are summarized in Table IV and full details are given in Appendix B. These reasons did not appear to be associated with the progress of the disease (with the possible exception of the 3 patients who had surgical treatment) and the patients have therefore been included in the assessments up to the time of their withdrawal. As a result of these withdrawals, the numbers of patients available for analysis are 187 at one year, 90 at eighteen months, 86 at two years, 36 at thirty months and 36at three years. MANAGEMENT OF PATIENTS

Duration ofStay in Hospital All 206 patients began their chemotherapy in hospital. The length of stay in hospital was less than three months in 38 (18 %), between three and six months in 59 (29 %), between six and nine months in 58 (28 %) and between nine and twelve months in 39 (19%). Of the 105 patients allocated to chemotherapy for two or three years, 12 (11 %) remained in hospital for more than a year. Nature of the Chemotherapy The chemotherapy which the 206 patients received in the first twelve months is summarized in Table V. Sixty-two (30 %) received only isoniazid plus PAS during the twelve-month period; 16 (8 %) received an initial supplement of streptomycin for less than six weeks, 57 (28 %) for six weeks, and 34 (17 %) for between seven and twelve weeks. The remaining 37 patients had chemotherapy which differed considerably from that prescribed by the protocol. In 12 of

211

LONG-TERM CHEMOTHERAPY TABLE V.-DETAILS OF CHEMOTHERAPY DURING THE FIRST YEAR

Chemotherapy

No.

%

6

3

PH for 12 months until withdrawal for 12 months with addition of streptomycin for periods of 4 to 18 weeks (after the first 6 weeks) changing to " " " " "

SH (at I, 9, 28 and 40 weeks) SP (at 31,40,43 and 46 weeks) SC (at 42 weeks) SHPz (at 8 weeks), then PH SPH (at 7 weeks), then SH ST (at 25 weeks), then SP before withdrawal

6

PH + initial streptomycin for less than 6 weeks, then PH for 6 weeks, then PH for 7-12 weeks, then PH for 13-26 weeks, then PH for 27, 31, 40, 40 and 50 weeks, then PH

16

8

57

28

34

17

;} 12

PH +initial streptomycin for between 5 to 8 weeks then PH, then SPH for periods of 14,17,24,25 and 29 weeks, then PH PH initial streptomycin for 5 weeks then PH, then SPH, then SH

:},

+

6

3

SH then PH, then SH Total S-Streptomycin P-PAS H-Isoniazid

206

101

._._-----

C-Cycloserine Pz-Pyrazinamide T-TetracycJine

them, the initial course of streptomycin was prolonged beyond twelve weeks for no specified reason. In the other 25 patients, chemotherapy was modified by the addition or re-introduction of streptomycin, or its substitution for isoniazid or PAS (in 3 of the patients another drug was also used). The reasons given by the clinician for these 25 modifications were reactions to drugs (6), the emergence of isoniazid-resistant organisms (8), bacteriological relapse (1), poor clinical progress (2), clinical and radiographic deterioration (5) and miscellaneous (3). Moreover, 14 of the 206 patients (including 9 of the 37 above) received adjuvant steroid therapy, usually in theform of prednisone or prednisolone; in 5 patients, this was given because of the acute nature of the disease and in the remaining 9, during desensitisation to drugs.

In summary, there were 37 patients in whom the anti-tuberculosis therapy was substantially modified and a further 5 patients who received adjuvant steroid therapy without any change in the chemotherapeutic regimen, representing 42 (20 %) departures from the originally prescribed regimen during the first year. In other words, the great majority (80 %) of the patients remained on the chemotherapy laid down by the protocol during the first year. Among the 105 patients allocated chemotherapy for a second year, 8 had their regimen modified in this period; 6 had streptomycin added to their regimen and 2 were treated with a combination of viomycin and cycloserine. One of these patients had had a spontaneous pneumothorax, I had remained persistently sputum-positive and had developed PAS-resistant organisms, and 6 had had a bacteriological relapse.

212

TUBERCLE

One of the 48 patients allocated chemotherapy for a third year received streptomycin for twentyfive weeks during that year. In view of the varied nature of the chemotherapy, the results will be described only briefly, and primarily in terms of the achievement of bacteriological quiescence. RESULTS

Deaths from or with Active Tuberculosis

Four patients died with active tuberculosis while on chemotherapy; 3 of them died as a direct consequence of the disease, the fourth from a non-tuberculous cause. Two patients (men, aged 58 and 65 years) with extensive disease and multiple cavities died of active tuberculosis on the fourth and thirteenth days respectively. Another patient, a man aged 50 years, died of a massive haemoptysis in the twenty-ninth month of chemotherapy. He had begun treatment with isoniazid plus PAS, had become negative on culture at four months but relapsed bacteriologically at nine months with organisms doubtfully resistant to isoniazid. Daily streptomycin was added to his treatment at eleven months and continued in combination with isoniazid plus PAS until twenty-three months, after which isoniazid plus PAS was maintained. During this period he had only one positive culture (at twelve months), but within a month of stopping streptomycin (at twenty-four months) he relapsed again, this time with organisms resistant to isoniazid, PAS and streptomycin. At post-mortem examination tubercle bacilli were found in the lungs both on smear and culture; they were resistant to all three drugs. The fourth patient, a man aged 52 years, died of renal failure secondary to chronic (non-tuberculous) pyelonephritis in the thirty-fourth month. He had begun treatment with isoniazid plus PAS (to which daily streptomycin was added for five weeks during the second and third month) and his sputum became negative on culture at eight months. At twelve months he relapsed with organisms sensitive to isoniazid and PAS but resistant to streptomycin. Although chemotherapy with isoniazid and PAS was continued, most of his subsequent cultures were positive; all these cultures were sensitive to isoniazid and PAS, and all but 2 of the 13 cultures tested were resistant to streptomycin. It is probable that he was not taking his drugs regularly in the second and third years since the ferric chloride test was negative on four of the five occasi.ons on which the urine was examined. At postmortem examination tubercle bacilli were found in the lungs both on smear and culture; the organisms were again sensitive to isoniazid and PAS, and resistant to streptomycin. Bacteriological Status of the Patients at Six-monthly Intervals

The results of treatment have been assessed on the basis of the cultures obtained during the period of chemotherapy. The bacteriological status of the patients one year after the start of treatment and at six-monthly intervals thereafter has therefore been defined as follows: Quiescent: If the cultures at the last three monthly examinations were negative (for example, at one year, if the cultures at ten, eleven and twelve months were negative). Doubtfully active: If one of the cultures at the last three monthly examinations was positive, unless criterion (b) applied (see 'Active'). Active: (a) If at least two of the cultures at the last three monthly examinations were positive, or (b) if the last culture only was positive and at least one culture at the three succeeding monthly examinations was positive, under continued chemotherapy. The classification of patients according to their bacteriological status has been set out in Table VI. The proportion of patients with bacteriologically quiescent disease was 91 % at one year, 88 % at eighteen months and 86 % at two years, at thirty months and at three years. The proportion of patients who had active disease or who had died of their tuberculosis was 7 % at one year, 11 % at eighteen months, 12 % at two years, and 14 %at thirty months and three years. These results show that, even in patients with chronic disease and cavitation, a high rate of bacteriological quiescence was achieved by the end of twelve months and that no increase in the percentage of patients achieving quiescence was obtained by continuing the chemotherapies used in

213

LONG-TERM CHEMOTHERAPY TABLE VI.-BACTERIOLOGICAL STATUS OF PATIENTS

---------_._----Classification of bacteriological status Total patients assessed

Months after start of chemotherapy

Doubtfully active

Quiescent

Deaths from or with active tuberculosis

Active

I

No.

!

12 18 24 30 36

170

187

90 86 35* 35*

79

II ,I

74

30 30

% i No. 91

I \

88 86 86 I 86

3 1

2 0 0

%

No.

%

No.

%

2 1 2 0 0

12 8 8 3 2

6 9 9 9 6

2 2 2 2 3

1 2 2 6 9

I

* Excluding 1 patient who produced no bacteriological specimens from twenty-eight months. TABLE VII.-DRUG REACTIONS

Total Drugis)

responsible

PAS

Streptomycin

number of

Nature of reactions

Gastro-intestinal disturbances Pyrexia Skin rash + pyrexia Skin rash + pyrexia +jaundice Purpura Acute circulatory collapse Vertigo Skin rash Acute circulatory collapse leading to myocardial infarct

PAS and streptomycin

Pyrexia Skin rash +pyrexia

PAS and isoniazid

Skin rash -l-pyrexia Skin rash-l-pyrexia-j-jaundice

PAS, streptomycin and isoniazid

Skin rash + pyrexia

patients with reactions

I

Interruption or stopping of Change of chemotherapy ; chemotherapy but without leading 10 withdrawal withdrawal from analysis from analysis

I

I

-1--1 35 3 9 1 1 1 8 5

4

o 1 1

o o I

o

2

o o o 1 1

o

o o

1

o

3

1

o o

o o

o

Uncertain 5 Skin rash o o --------'----------------------------Total

76

1t 5 ---_._--_ ..._--

214

TUBERCLE

this study. However, the findings presented so far give no inkling as to whether quiescence was maintained when chemotherapy was discontinued; this problem will be studied in Section III . Drug Toxicity Of the 206 patients admitted to the study, 76 (37 %) complained of symptoms attributable to one or other of the drugs. Details of these reactions are set out in Table VII. The most common complaint was of gastro-intestinal disturbance due to PAS, which occurred in 35 patients (17 %) ; nausea was the predominant symptom. In 6 of these patients, the complaint led to modification of the PAS-conta ining regimen and 4 of them were withdrawn from the analysis (for details, see Appendix B). Hypersensitivity reactions occurred in 33 patients (16%). The reaction was attributed to PAS in 15 patients, to streptomycin in 6, to both PAS and streptomycin in 4, to PAS and isoniazid in 2, and to all three drugs in 1 patient; thus, PAS was implicated in 22 patients, streptomycin in 11* and isoniazid in 3 patients. In the other 5 patients, it was not possible to attribute the hypersensitivity reaction to a particular drug. In 24 of the patients exhibiting hypersensitivity reactions, it was possible to contin ue the regimen either without interruption or after desensitisat ion, while 3 patients continued chemotherapy with a different regimen ; 6 patients, however, were withdrawn from the analysis (Appendix B). Vertigo due to streptomycin toxicity occurred in 7 (6 %) of the 125 patients receiving this drug initially for six to nine weeks, and in 1 further patient who received streptomycin for the first time at nine months. This last patient had his chemotherapy stopped on this account at fifteen months and was then withdrawn from the analysis (Appendix B).

Thus, of the 76 patients in whom drug reactions occurred, only 11 had so much interruption of chemotherapy that they could not be retain ed in the analysis for the whole of the alIocated period. Urine Tests At the time of each three-monthly clinical examination, a urine specimen was collected for a ferric chloride test for PAS (Simpson, 1956). Analysis of these results shows that the proportion of negative results rose throughout the first year and remained fairly constant thereafter. The proportions of patients with negative test results were 4 % at three months, 7 % at six months, 9 % at nine months, 14 % at one year, 10% at eighteen months, 13% at two years, 4 % at thirty months and 18 % at three years. There were , however , too few results for each patient reliably to separate patients into those who were regular, occasionally irregular, or persistently irregular in their drugtaking, or to correlate irregularity with clinical progress.

III. THE CONSEQUENCES OF STOPPING CHEMOTHERAPY OF DIFFERENT DURATIONS The adequacy of a course of chemotherapy of a particular duration must be judged not merely by its success in rendering the patient's disease bacteriologically quiescent and keeping it so until the end of the course, but also by the risk of relapse subsequent to stopping chemotherapy. To assess this risk, the later progress of the group of patients with quiescent disease at the end of a particular duration of chemotherapy, who then stopped chemotherapy, must be compared with the later progress of a similar group of patients with quiescent disease who continued to receive chemotherapy. The analysis below therefore relates to those patients who , having had continuous chemotherapy (see page 209) for the prescribed duration, had achieved bacteriologically quiescent disease at the end of it (see page 212). In accordance with the design of the trial the patients had been divided at random on admission into two groups, those who were due to stop their chemotherapy at a designated point of time and those who were due to continue with it for a further period. Patients who were due to stop chemotherapy at a particular time have been accepted for the comparisons, provided that they stopped: (a) for the six-month group, not more than one month before or after the due date; (b) for the one-year group, not more than six weeks before or two months after the due date; (c) for the two-year group, not more than three months before or after the due date; (d) for the three-year group, not more than four months before or after the due date . .. When considering the frequency of the reactions to streptomycin , it must be recalled that only a proportion of patients received streptomycin and those for a relatively short period .

215

LONG-TERM CHEMOTHERAPY

Assessments of Progress ofPatients In this section, the progress of the patients has been assessed in terms of:(a) The incidence of bacteriological relapse. (b) The incidence of clinically important radiographic deterioration. Definitions and Procedures (a) Bacteriological relapse. Any patient with bacteriologically quiescent disease was considered to have had a bacteriological relapse if he produced two or more positive cultures in any period of four months; the relapse has been dated from the first of these positive cultures." In this report, 'relapse' is used only in this bacteriological sense. An isolatedpositive culture has not been regarded as evidence ofrelapse if later cultures were all negative without re-introduction or change of chemotherapy. (b) Clinically important radiographic deterioration. An independent radiographic assessor (Dr. G. Simon) was shown the radiographs at three-monthly intervals from the start of treatment, and reported any extension of radiographic lesions or any new lesions, however slight. The radiographs of patients with such changes were then shown to an independent clinical assessor (Dr. J. R. Bignall) who reported clinically important radiographic deteriorations, that is, tuberculous deteriorations warranting a change or re-introduction of chemotherapy. Neither ofthe assessors knew whether or not the patient was receiving chemotherapy at the time of the deterioration.

* In addition, 1 patient who produced a single positive culture and whose chemotherapy was re-introduced before the (negative) specimen of sputum for the next month was obtained has also been regarded as having had a bacteriological relapse (for further details, see page 238). _

With chemotherapy

IWithout chemotherapy

I

~/I/2-YEAR INTAKE

1/2/3 YEAR INTAKE

o

I

2

YEARS AFTER THE START OF CHEMOTHERAPY FIG.

1

Diagram to show the design of the relapse study.

3

216

TUBERCLE

In this section the effects of stopping chemotherapy at six months (from the t.fI/2-year intake), at one year and at two years (both from the 1/2/3-year intake) will be studied in turn. The design of this part of the study is shown diagramatically in Figure 1. The Effect of Stopping Chemotherapy at Six Months The following definitions have been adopted for classifying the bacteriological status of patients at the end of six months: Quiescent: If the cultures at both five and six months were negative. Active: If one or both of the cultures at five and six months were positive. TABLE VIIl.-CONDITION ON ADMISSION, AND PROGRESS IN THE FIRST SIX MONTHS

FOR PATIENTS IN THE !j1/2-YEAR INTAKE (AFTER EXCl-USIONS)

Treatment group i

Assessment Six-month

No. Total patients Number of lung zones involved in disease

2 3

4 5 6

I

No cavity 2 em. or less More than 2 crn., less than 4 em. 4 em. or more

Diameter of largest cavity

I I

Direct smear examination I

Negative Scanty Moderate Heavy

Improvement: considerable moderate slight I No change

RadiOgraPhiCl change ,

I

I

Progress in first ' six months

Residual Absent cavitation at I Present six months

I

I 2 5

No.

8

15 38 31

I

8

I I

I

II I

I 1

8 8

5 6

46

0 2 I 10

0 8 3

2

I

I

I I

38

I

2 2 2

27 18 18 18 18

I 1

9 9

2 7

64

3 2

18

I I

I

0

0

5 2

45

77 I

4

18 36

2 2

18 18

0

15 8

0

62 23 15 31 69

2

0 4

3

2

31 15

4

6 1

46 8

5 "-----,,,--,

%

11

4 I

4 9

I

Month of sputum conversion

%

13

I Condition on admission

One-year and two-year

0

5

45

2

18

2 9

18 82

4 0 0 4 3

36 0 0 36

27

217

LONG-TERM CHEMOTHERAPY

It will be appreciated that it is difficult to assess quiescence with confidence as early as six months; and it will be noted that this definition is less stringent than that used for quiescence at one year or later (see page 212). A total of 41 patients was admitted to the comparison between six months, one year and two years of chemotherapy (the i/l/2-year intake) (Table I). Of these, 2 (lone-year, 1 two-year) died three weeks after starting chemotherapy, 3 (2 six-month, 1 two-year (interrupted chemotherapy for more than one month in the first six months and 1 (six-month) developed a bronchial carcinoma which first became visible at three months. Of the remaining patients, 2 (1 six-month, lone-year) could not be classified at six months as they produced no sputum specimens at five and six months, and 3 (1 six-month, lone-year, 1 two-year) had active disease at six months. There remain 30 patients (18 six-month, 7 one-year, 5 two-year) who had had continuous chemotherapy and who had bacteriologically quiescent disease at six months. Five of these 30 patients (all six-month) continued chemotherapy for more than one month beyond the allotted duration. For another patient (two-year), chemotherapy was stopped at six months in error. There were therefore 24 patients (13 six-month, 7 one-year, 4 two-year) who fulfilled the criteria for entry into the study of relapse. A comparison of the group of 13 patients who stopped chemotherapy at six months with the 11 patients who continued, shows that the groups were reasonably similar both on admission to chemotherapy (Table VIII-upper section)-although the six-month group had a greater degree of bacterial positivity on direct smear examination-and in their progress during the first six months (Table VIII-lower section). Patients Who Could Not be Retained in the Analysis for the Whole of the Subsequent Two-and-ahalf years Three of the 24 patients could not be retained in the analysis for the whole of the subsequent twoTABLE IX.-BACTERIOLOGICAL RELAPSES AND CLINICALLY IMPORTANT RADIOGRAPHIC DETERIORATlON IN PATIENTS FROM THE t/lj2-YEAR INTAKE (AFTER EXCLUSIONS)

I

! Period of observation

------I-----------! 6-12 months

Total patients at risk] Bacteriological relapse

Withdrawn from analysis" 12-24 months

I

I Total patients at risk] Bacteriological relapse Clinically important radiographic deterioration I

I I

Withdrawn from analysis" 24-36 months

Total patients at risk] Bacteriological relapse

* See text

Six-month

I

i-----I

------1----------

T~eatment gro~lp

!

13 5 0 8 3

il I.

I

One-:ear I Two-year 7 0 1

4

o

'

0

6 0

4 0

I

0

0

0

1

4

I

I

5

o

above.

t Patients with quiescent disease at beginning of period. Patients to the right of the heavy lines were receiving chemotherapy.

c

I

1

Ii

_.-3

o

218

TUBERCLE

and-a-half years. One patient (one-year) died of congestive heart failure in the tenth month of treatment; his sputum had been negative on culture from one month. One patient (one-year) developed a bronchial carcinoma which first became apparent on the radiograph at twelve months; his sputum had been negative on culture from four months. One patient (two-year) stopped chemotherapy of his own accord at twenty months, having had negative cultures from four months. These 3 patients were retained in the analysis until nine, twelve and twenty months respectively. RESULTS

Bacteriological Relapse Of the 13 six-month patients who stopped chemotherapy at six months, 5 (38 %) had a bacteriological relapse between six and twelve months and 3 (23 %) in the second year; none had a bacteriological relapse in the third year (Table IX). Of the 11 patients who continued on chemotherapy beyond six months, only 1 (one-year) relapsed, in the third year, when no longer on chemotherapy. The difference in the relapse rates between those who stopped chemotherapy at six months and those who continued is significant at the 2 %level. Details of the relapses are given in Table X; the patients are listed according to the month of relapse. Of the 8 relapses in the six-month group, 2 occurred at seven months , 2 at eight, 1 at ten, 2 at thirteen and I at twenty months. Seven of the 8 patients relapsed with organisms sensitive to all three drugs; the other relapsed at seven months with a culture which was resistant only to isoniazid, but the 10 later cultures all yielded sensitive strains. The one-year patient relapsed with organisms sensiti ve to all three drugs. Clinically Important Radiographic Deterioration One patient (six-month) showed a clinically importan t radiographic deterioration without a bacteriological relapse. T his patient showed a spread of his disease at eighteen mo nths, worse at twenty-one months ; this had cleared by two years without the re-introduction of chemotherapy. In summary, over the whole two-and-a-half year period of follow-up , 8 of the 13 who stopped chemotherapy at six months had a bacteriological relapse and 1 had a clinically important radiographic deterioration compared with only 1 relapse among the 11 patients who continued chemotherapy. Another way of looking at these findings is to consider them according to the inte rval from the time of stopping chemotherapy. In the six-month group, 7 relapses occurred within a year of stopping chemotherapy ; 1 relapse and 1 radiographic deterioration occurred in the second twelve months. In the one- and two-year groups combined, there was no relapse or radiographic deterioration within a year of stopping chemotherapy and 1 relapse in the second twelve months after stopping chemotherapy. The Effect of Stopping Chemotherapy at One Year Of the 206 patients originally admitted to the 1/2f3-year intake, 170 (86 one-year, 47 two-year, 37 three-year) had bacteriologically quiescent disease at one year (Table VI) . Fourteen of these patients (12 one-year, 1 two-ye ar , 1 three-year) have been excluded from the st udy of relapse for the following reasons:(1) Six patients (all one-year) continued chemotherapy beyond the allocated year because their sputum repeatedly contained acid-fast bacilli on direct smear, although the cultures were consistently negative (see Section VII). (2) Six patients (all one-year) continued chemotherapy contrary to protocol. All these patients had had negative cultures from two, three or four months onwards except for 1 patient who produced an isolated four-colony culture at nine months. (3) Two patients (1 two-year, 1 three-year) interrupted chemotherapy for four and five months, respectively, at the beginning of the second year, I of his own accord, the other in error.

TABLE X . -BACTERlOLOGICAL RELAPSES

AFTER

STOPPING CHEMOTHERAPY , FOR PATIENTS IN TH E ~/I !2-YEAR INTAKE

i

I I

Results of sensiti vity tests

Months of ! Chemotherapy positi ve Analysis number

Treatment group

111

in allocated

I

cultures .

period

i

I

(from time! Isoniazidt ofrelapse] I

PAS

Streptomycin

!

I All S

All S

PH 8-12 m. SH 12-18 m. PH 18-31 m.

-

Quiescent

iQuiescent

Six-mon th

7-17

I R at 7(50) I All S

All S

SP 13-16 m. SH 16-19 m. PH 19-23 m.

-

Active

IQuiescent

Quiescent

All S

SH 9-10 m. \ PH 10-11 m. Nil II-19m. SH 19-22m. PH 22-36 m,

-

Active

IQuiescent

Quiescent

PH 13-36m.

-

PH

I

II

I

I Six-month

SPH 6 weeks then PH

I

I I

/

8,9, II, 13, 14, . 16-19,· 1 20, 21

Six-month

I

All S

AilS

All S

All S

S 10-14 R 16-25

All S except 25

All S except 25

I SPH 6 weeks

I 10, 11,*

1 then PH

I 12-14

,I I

116-19: 21, (J) ! 25

'

I I - - - ----_._.

All S

i

179 Six-month ! SPH 6 weeks \ 8-14 __ _ __ 1 then PH I

I I

Al : At At one year two years three yea rs

i All S

i

215

I

7-9

All S 8-17 !

106

II

o the r detail s

Six-month SPH 6 weeks then PH I

127

Bacteriological status Further chemotherapy (by months)

I !

PH SPH SH SPH PH Nil

12-20 m. 20-26 m. 26-28 m. 28-30 m. 30-31 m. 31-36 m.

Quiescent

I

I Active

Right uppe r Active and middle lobectomy in 26th month

I

I I

Quiescent

Active

i

IQuiescent I

I

Quiescent

I

I (Co ntinued on next page

N

\0

IV IV "0

TABLE

I

i

I

Analysis I Treatment number

IMonths of;

Chemotherapy in allocated

group

II

period

Results of sensitivity tests , , i

I positive

cultures

I(from time: Isoniazids I I o/relapse) I I 113-17,23, I All S

ISix-month: PH

. " -- . - _ 1

I

I

I!

I

1

131

'1

Six-month PH

I'

I I

159

1

Six-month I SPH 6 weeks then PH

II

34,36

I One-year

I

I

I StreptoI mycin

All S

All S

I 20,21, ! 22, 25

All S except 22 (5)

All S

S

S

,

(by months)

I i

I

All S

I

PH IS-24m. SH 24-27m.

At

I

S4H 24-32m. Nil 32-36 rn,

At

I two years

I

I

I i

At

three years

I

i

I

Pregnancy- Quiescent Doubtfully I Active active i delivered in 27th month :

I

I 1-----, All S

Other details

one year

1-- - - - I

I

/13, 15, 19,21, 23 1. , 26

i

II

Quiescent Active

Quiescent

I SPH 6 weeks I 27 I then PH

.., c:::

C;l

rrl :;
All S

!

PH 22-28 m.) SPH 28-36

m'l

IQuiescent

I

_I

132

All S

except 17 I (1) I

I

Bacteriological status Further . chemotherapy

I

PAS

II

134

x.-Continued

I

S

I PH 27-36m.

!

Quiescent

* No sensitivity results available for these cultures. t The figures in brackets denote the highest concentration of isoniazid (in (.Lg.jml.) on which growth occurred (for the first resistant culture). CHEMOTHERAPY S - Streptomycin daily S4 - Streptomycin on alternate days P -PAS daily H -Isoniazid daily

SENSITIVITY TESTS .. S -sensitive}r . ror de finitions, see Appen d'IX A R -resIstant

o

t""

m

221

LONG-TERM CHEMOTHERAPY T ABLE X L-AGE, RADIOGRAPHIC AND BACTERIOLOGICAL CONDmON ON ADMISSION

FOR P ATIENTS IN THE I j2/3'YEAR INTAKE

Trea tment group

,

Assessment

One-year

I No. I

I

74

Total patients

I

%

Two-year No.

-

46

% ~

I

Age (in years)

I Less than 35

I I Number of lung zones involved

35-44 45-54 55 or more

5 6

Direct smear examination*

14

9

20

16 38 32

10

22 24

I

No.

%

36

-

4 7 12 13

11 19

11 16

35

32

3 9 8

7 20 17

27 7

18 8

39 17

11 9 9

33 36

I

2 3

4

Diameter of larges t cavity

10 12 28 I I 24

Three-year

I

I

5 20 24 20

5

7 27

I

I

i

I

2 5

6 14 31 25 25

No cav ity 2 em. or less More than 2 cm., less than 4 em. 4 em. or more

II

15

19

9 4

20 9

6 2

17

14 25 24

34 32

16 17

35 37

13 15

36 42

Negative Scanty Moderate Heavy

6 16 14 36

8 22

1

2

II

11 23

50

1 8 13 14

3 22

19 50

24 24

6

36 39

* No assessment was available for 2 patients in the one-year group.

There remain in the comparison 74 patients who stopped chemotherapy at one year and 82 (46 two-year, 36 three -year) who continued chemotherapy for a second year. COMPARABILlTY OF THE THREE GROUPS OF PATIENTS

Clinical, R adiographic and Ba cteriological Condition at the Beginning of the First Yea r of Chemotherapy

In common with all the patients originally admitted to the 1/2/3-year intake a large proportion of those whose d isease attained quiescence at one year a nd who are eligible for the study of relapse were older persons and had extensive bilateral disease initially (Table XI). There was involvement of four or more lung zones in 66 % of the oneyear group, 74 %of the two-year group and 81 %of the three -year group. The corresponding proportions with cavitation were 85 :Yo, 80 % and 83% ; the proportions with cavities 4 em. or more in diame ter were 32 %, 37 % and 42 % respectively. Direct smear examination was heavily or moderately positive in 69 % of the one -year, 74 % of the twoyear and 75 % of the thre e-year patients. The three groups of patients were closely similar on admission. Clinical and Radiographic Cond ition at the End of the First Yea r

It is important to compare th e three groups at the end of the first year, that is, at the beginning of the relapse study, as well as at the start of chemotherapy. At one year, the distributions of the ESR 's were clo sely similar in the three groups; the ESR was 20 mm. or less in 69 % of the one-year, 70 %of the two-year and 69 % of the three-year patients. The corresponding figures for residual cavitat ion were 68 %, 74 %and 65 %, respectively. The three groups of patients were thus also closely similar at the end of the first year.

222

TUBERCLE

WITHDRAWALS FROM THE ANALYSIS

In the Second Year Twelve patients (4 one-year, 3 two-year, 5 three-year) could not be observed for the whole of the second year. Six patients died from causes other than tuberculosis; I (one year) committed suicide in the fourteenth month, 1 (three-year) died in the fourteenth month of a cerebral haemorrhage, I (one-year) of a bronchial carcinoma in the seventeenth month, 1 (three-year) in the nineteenth month of an alveolar-cell carcinoma of the lung, 1 (two-year) in the twentieth month of a myocardial infarct and 1 (three-year) in the twenty-fourth month from influenzal bronchopneumonia. One patient (two-year) discharged himself from observation in the nineteenth month. Three patients (I two-year, 2 three-year) stopped chemotherapy before the end of their allocated period, all at fifteen months. All these 10 patients had negative cultures until the time of their withdrawal. Two further patients (both one-year) resumed chemotherapy without having had a bacteriological relapse or a clinically important radiographic deterioration, 1 because of the persistence of positive sputum smears with negative cultures and I because of the development of a fluid level in a pre-existing cavity, which later proved to be due to aspergillosis. In the Third Year Thirteen patients (7 one-year, 4 two-year, 2 three-year) could not be retained in the analysis for the whole of the third year. Three patients died of causes other than tuberculosis, I (one-year) in the twenty-seventh month of chronic bronchitis and emphysema, 1 (one-year) in the thirty-third month of renal failure, and 1 (two-year) in the twenty-ninth month of gastric carcinoma. Two patients (lone-year, I two-year) discharged themselves from observation in the twenty-fifth and twenty-sixth months, respectively. One patient (three-year) continued to attend for clinical and radiographic examination, but produced no sputum specimens after twenty-eight months. One patient (three-year) had his chemotherapy stopped in error at two years and I patient (two-year) had his chemotherapy prolonged beyond two years because he had produced an isolated positive culture at nineteen months. All except the last-mentioned patient had negative cultures until the time of their withdrawal. Five patients (4 one-year, I two-year) resumed chemotherapy in the third year without having had a bacteriological relapse or a clinically important radiographic deterioration. Two of them (both one-year) had had an isolated positive culture. One patient (one-year) developed a severe pneumonia, suspected of being tuberculous, but later proved to be staphylococcal. In 1 patient (one-year) a cavity re-opened, and in another (two-year) a previously existing cavity filled up.

RESULTS IN THE SECOND YEAR Bacteriological Relapse Among the 74 patients who stopped chemotherapy at one year, 10 (14 %) had a bacteriological relapse in the second year (Table XII, middle section). Full details of these patients are given in Table XIlI, the patients being listed according to the month of relapse; 2 of these relapses occurred at thirteen months, 1 at fourteen, 2 at fifteen, 2 at seventeen, 1 at eighteen, I at nineteen and 1 at twenty-three months. In all but 1 of these patients the organisms obtained at the time of relapse were sensitive to all three drugs. The exception relapsed at thirteen months, with organisms sensitive to isoniazid and PAS but resistant to streptomycin. Among the 82 patients who continued chemotherapy, there were 2 (2 %) bacteriological relapses (Table XII, middle section). Full details of these relapses are given in Table XXI, middle section. One of these patients (Case No. 304) produced a two-colony culture at thirteen months (with organisms resistant to isoniazid but sensitive to PAS and streptomycin); subsequent cultures yielded organisms resistant also to PAS and then to streptomycin. The other patient (Case No. 180) produced positive cultures at twenty-one and twenty-three months; the organisms were sensitive to isoniazid and PAS but resistant to streptomycin. Clinically Important Radiographic Deterioration Two patients (one-year) who had stopped and 1 (three-year) who continued chemotherapy showed a clinically important radiographic deterioration, all without bacteriological relapse. One patient (one-year) developed a new lesion between twelve and fifteen months; the lesion cavitated between eighteen and twenty-one months and the cavity was still visible at two years. One patient (one-year) developed a spread at twenty-one months. The three-year patient developed a new lesion at two years.

223

LONG-TERM CHEMOTHERAPY TABLE XI I.-BACTERIOLOGICAL RELAPSES AND CLINICALLY IMPORTANT RADIOGRAPHIC DUTERIORAATIONS IN THE THREE-YEAR PERIOD, FOR PATIENTS IN THE

Period of observation

lj2/3-YEAR

INTAKE (AFTER EXCLUSIONS)

Treatment group

I

Two-year

IThree-year

101

57

48

0 I 1

2 2 4

74

46

I

36

5 3 I I 10

I

0 0 0

!

0 0 I 0 1

One-year Total patients admitted to chemotherapy

I 9 months or before

111 the first year

Relapses

I

I

I

10-12 months Total

Total patients at riskf (see page 22 J)

Relapses

13-15 months 16-18 months 19-21 months 22-24 months Total

I

I

In the second year

I I

I I

I

I

!

2 1 3

Clinically important radiographic deteriorations (without bacteriological relapse)

2

0

i

1

Withdrawn from analysis"

4

3

I

5

58

42

29

2 2 0 4

0

0 0 0 0

7

4

Total patients at risk t

Relapses In the third year

I

I

25-27 months 28-30 months 31-36 months Total

Withdrawn from analysis"

I

I 0 I

0-

2

....

-----_._-~"

~--

See text, page 222. :!: Patients with quiescent disease at beginning of period. Patients to the right of the heavy lines were receiving chemotherapy. >I<

IN THE THIRD YEAR

The numbers of patients at risk of relapse in the third year were 58 of the one-year group, 42 of the two-year group and 29 of the three-year group. Bacteriological Relapse

During the third year there were 4 (7 %) relapses in the one-year group, I (2 %) in the two-year group and none in the three-year group (Table XII, lower section). Details are given in the lower part of Table XIII. The 4 patients in the one-year group relapsed at twenty-six, twenty-seven, twenty-eight and twentynine months, respectively. Three of these patients had produced sputum negative on both smear and culture since stopping chemotherapy; the patient who relapsed at twenty-six months had previously produced an isolated one-colony culture, at seventeen months. In 3 of the patients the organisms were sensitive to all three drugs; in the patient who relapsed at twenty-seven months the organisms were resistant to isoniazid, but sensitive to PAS and streptomycin.

TABLE XIII.-BACTERIOLOGICAL RELAPSES AFTER STOPPING CHEMOTHERAPY FOR PATIENTS IN THE 1/2/3-YEAR INTAKE

.

i

I

i Months ofpositive cultures (from time of

Chemotherapy in allocated period

Analysis Treatment number! group

158 332

I

,

One-year

I

One-year

PH

13-16

SPH 5 weeks* then PH

13,16

I SPH 2 weeks"

I

I

I

(by months)

PAS

Streptomycin

:

One-year

I

II i

:

then PH

All S

\

AllS

All S

----:---S,S

S,R

R,R

(02)

II

I I

At two years

:

At three years :

_

I,

S, S

PH

15-17

All S

PH 15-36 m.

Quiescent

Quiescent

I

Ca.B-PAS plus

Quiescent

Quiescent

Quiescent

Quiescent

I H 500 mg I

!

14§,15§, 16, 18

I

!

I

S, S

S,

s

daily

19-24 m. Ni124-36m.

i !

I

I

PH 16-36 m.

I

t

321

I I

1

296

Isoniazids :

1

One-year

I

Bacteriological status '-----'-----'------'1'i Further chemotherapy !, - - - - - , - - - - -

relapse)

_ _1

i

•

Results of sensitivity tests

All S

All S

SPH Pz 16-17 m. PH 17-36 m.

Quiescent

!

Quiescent

I I

201

202

SPH 6 weeks then PH

One-year

PH

! One-year

IS, 17-21

I I

I 163

One-year

I

i

torny 25 m.)

17, 18

S,R (0'2)

S,S

S, S

S3PH 18-20 m, SPH 20-23 m. S2PH 23-36 rn,

17-19

All S

All S

All S

PH 19-23 m. S3PH 23-36 m.

AIlS

SPH 19-21 m. PH 21-36 m.

i!

136

351

i One-year I\ One-year

:

PH 0-6 months SPH 6-9 months

I

i

I Quiescent !, Quiescent SPH 18-23 m. PH 23-25 m. 1 (right upper lobecI

I I

SH 25-21lm. PH 28-36 m.

1

PH

All S

All S

All S

18-22

19-21

I

AlIS

An s

I

All S

All S

I

AIlS

PH 21-36 m.

Quiescent

Quiescent

Quiescent

Quiescent

II Quiescent

Quiescent

Quiescent

Quiescent

I I i

(Continued on next page

TABLE

I ' Months ofpositive cultures Analysis ITreatment I Chemotherapy in number i group allocated period (from time of I

XIII.-Continued Bacteriological status

Results of sensitivity tests Further chemotherapy (by months)

'I

I 370

260

SPH 6 weeks then PH

l One-year

i One-year

26-32

!

148

276

137

One-year

\ One-year

27-30, 32, 33

!

I SPH 6 weeks then PH

28-31, 33

PH

* Not in PH/SPH comparison

s

PAS

I

I S,S

I

St reptomycin

I

S,S

PH 24-36 m,

All S

SPH 30-32 m, PH 32-36 m.

29,31 ,33

I

28, 33, 36

(Section VI)

I !

! , i I I

At two years

At three y ears

Active

Quiescent

Quiescent

Quiescent

i AIlS

r-

'I All S

I

PH

Two-year I PH

S,

I

--

I

li

i -

! 'soniazidt

1I- - - -

lOne-year : SPH 8 weeks* 1 23,24 then PH 1

II

185

relapse)

All R except (50) All S

I

AlIS

jjl

I II All S i

All S

j I

All S

iI

!

I I II

,

I All S

i

!

1

AIlS

1

SliP 35-36 rn,

J

...,

tTl

:>:l

o

i

:I: tTl

Active

I

Quiescent , Active

I

Quiescent

!

!

Z

c

;;::

,

! Quiescent

II SPH 30-35 m. PH 35-36 m.

Active

Quiescent

I

PH 30-36 m.

All S

I

All R(50)! S, R , S 1

SP 30-33 m. S.P 33-36

All S except j 3

o

I

s:: o

..,

:r: m :a > "C -<

Active

§ No sensitivity results available for these cultures.

t The figures in brackets denote the highest concentration of isoniazid (in v.g./ml.) on which growth occurred (for the firs t resistant culture) S S2 Sa S5 -

CHEMOTHERAPY Streptomycin daily P - PAS Strep tomycin twice weekly H - Isoniazid Streptomycin thrice weekly Pz - Pyrazinamide Streptomycin five times a week

SENSITIVITY TESTS S -sensitive .. see AppendiIX A . t t }.,ror definitions, R -reslS an

~

VI

226

TUBERCLE

The patient in the two-year group who relapsed did so at twenty-eight months, with organisms resistant to isoniazid but sensitive to PAS and streptomycin. Clinically Important Radiographic Deterioration No patient showed a clinically important radiographic deterioration in the third year. BACTERIOLOGICAL RELAPSE lN RELATlON TO TH E STOPPING OF CHEMOTHERAPY AT ONE YEAR

In order to interpret the above differences in the bacteriological relapse rates, it is first necessary to consider the bacteriological relapses in the first year, which occurred in 1 of the 101,4 of tile 57 and 3 of the 48 patients in the three groups respectively (Table XII, upper section). Thus, of the patients due to stop chemotherapy at one year, I had shown bacteriological relapse before the end of the year, whereas no less than 7 of a similar total of patients treated in the same way, but due to continue chemotherapy beyond one year, had relapsed bacteriologically before the end of the year. It is therefore possible that the group of patients with quiescent disease who stopped chemotherapy at one year (and have been studied in this section) may , by chance, have included some who were on the verge of bacteriological relapse and would have relapsed shortly after the end of the year even if their chemotherapy had been continued. In other words, the larger number of relapses in the second year among those stopping chemotherapy at one year may be attributable at least in part to the shortcomings of chemotherapy in the first year and not solely to the fact that it was not prolonged into the second year. The relapses in the second year have therefore been divided according to the period in which they occurred (Table XII, middle section). The numbers of relapses among those who stopped chemotherapy at one year and among those who continued were 5 and 1, respectively, from thirteen to fifteen months and 5 and 1, respectively, from sixteen to twenty-four months; in the whole of the third year there were 4 and I , respectively. The contrast between the two groups of patients was thus the same in the early months as it was later in the second year, and both were similar to that in the third year; for this reason the numbers of relapses in the second and third years do not appear to have been affected by the differences between the groups in the first year . It may therefore be accepted that there was a substantially increased risk of bacteriological relapse in the second and third years associated with stopping chemotherapy at one year. The Effect of Stopping Chemotherapy at Two Years For consideration in this section, patients were to have received continuous chemotherapy for two years and to have bacteriologically quiescent disease at two years. There were 42 patients who stopped chemotherapy at two years and 29 who continued chemotherapy for a third year (see Table XII, lower section). Six patients (4 two-year, 2 three-year) were not observed for the whole of the third year ; the reasons for their withdrawal have already been given on page 222. RESULTS

Bacteriological Relapse One (2 %) of the 42 patients who stopped chemotherapy at two years had a bacteriological relapse in the third year, compared with none of the 29 who continued chemotherapy. This patient relapsed at twenty-eight months, with organisms resistant to isoniazid but sensitive to PAS and streptomycin. Clinically Important Radiographic Deterioration No patient in either group showed a clinically important radiographic deterioration in the third year. Other Ways of Considering Bacteriological Relapse In this section, so far, comparisons of relapse rates have been made between patients stopping chemotherapy at different times and those continuing chemotherapy beyond those times. It is also possible to consider these relapse rates in two other ways.

LONG-TERM CHEMOTHERAPY

227

BACTERIOLOGICAL RELAPSE IN THE FIRST TWELVE MONTHS AFTER STOPPING CHEMOTHERAPY It is desirable to compare the relapse rates in the first year after stopping chemotherapy, that is, in the second year for the one-year group and in the third year for the two-year group. Ten (14 %) of the 74 one-year patients relapsed in the second year compared with 1 (2 %) of the 42 two-year patients who relapsed in the third year. This difference between these relapse rates is significant at the 5 % level. It may be concluded that the continuation of chemotherapy for a second year not only maintains the position achieved at the end of one year (see page 212 and Table VI), but reduces the likelihood of relapse after chemotherapy has been stopped. It is not yet possible to determine the effect of a third year of chemotherapy on the later relapse rate (but see Addendum). BACTERIOLOGICAL RELAPSE IN RELATION TO THE LENGTH OF BACTERIOLOGICAL QUIESCENCE WHILE STILL RECEIVING CHEMOTHERAPY The incidence of relapse in patients in the 1j2j3-year intake has also been related to the number of months of bacteriological quiescence at the time that chemotherapy was stopped. For this purpose, only patients allotted to one and two years of chemotherapy have been considered; however, patients previously excluded from this section because they had received shorter or longer periods of chemotherapy than that allocated (for example, the 14 patients described on page 218) have also been considered, provided that they did not receive more than two years of chemotherapy. The results are set out in Table XIV. It will be seen that even among the 39 patients who had had ten to twelve months of bacteriological quiescence before stopping chemotherapy, 21 % relapsed compared with only 5 %of the 42 who had had quiescent disease for periods of nineteen to twentyfour months. These results show that stopping chemotherapy when a patient had been bacteriologically quiescent for a year or less led to a considerable relapse rate subsequently, whereas when chemotherapy was continued for a period of quiescence of more than eighteen months the subsequent relapse rate was at a much lower level. Unfortunately, the number of patients who stopped chemotherapy after periods of quiescent disease of between thirteen and eighteen months is too small to decide whether these intermediate periods of quiescence were sufficiently long to prevent relapse. IV. PROGNOSTIC VALUE OF VARIOUS FACTORS ON ADMISSION, AND DURING TREATMENT, IN RELATION TO THE BACTERIOLOGICAL STATUS AND CAVITY CLOSURE AT ONE YEAR AND TO SUBSEQUENT RELAPSE

Analyses were performed to assess, for patients in the 1/2j3-year intake, the prognostic importance of various factors in relation to the bacteriological status and to cavity closure at one year, and to

subsequent relapse. Most of the factors investigated have already been mentioned; there were, in addition, further assessments of initial cavitation by the independent radiographic assessor, namely, the thickness of the cavity wall, whether or not it was located peripherally in the lung field*, and whether or not it lay in an atelectatic area of the lung. BACTERIOLOGlCAL STATUS AT ONE YEAR IN RELATION TO INITIAL CONDITION The attainment of quiescence was not apparently associated with the ESR, the number of lung zones involved in disease, the thickness of the cavity wall, or with the location of the cavity (these findings have not been tabulated here). There was evidence of some association with age and sex, the bacterial content of the sputum, the extent of cavitation and the presence of a cavity in an atelectatic area; however, none of these associations was statistically significant (Table XV). All the 29 patients aged less than 35 years old had quiescent disease at one year, compared with 55 (83 %) of the 66 patients aged 55 years or more. Since the majority of the women were in the younger age groups, this association is also

* A 'peripheral' cavity was defined as a cavity lying against the lateral edge of the lung field in the axillary region or below (i.e, below the level of the anterior end of the 2nd rib).

228

TUBERCLE TABLE XIV.-RELAPSE AFTER STOPPING CHEMOTHERAPY

IN RELATION TO NUMBER OF MONTHS OF BACTERIOLOGICAL QUIESCENCE AT TIME OF STOPPING

Number of months of bacteriological quiescence before stopping chemotherapy

Total patients \ R elapses with bacteriolog ical I quiescence I No . % I I

3-6 7-9 10-12 13-18

J9-24

5

2

34

7

39

I

8 42

II

40 21

8 0

21

2*

5

a

I

I

128

Total

19

15

* One pa tient had had bacteriological quiescence for twenty months and the other for twenty-four months. TABLE XV .-BACTERIOLOGICAL Q UIES CENC E AT O NE YEAR, ACCORDING TO THE INITIAL CONDmON, FOR THE PATIENTS IN THE Ij2/3-YEAR I NT AK E .. .. .... - -- --_ _.". _. . ..

__

_ - -- -~

~_

~

Total patients assessed

Condition all admission

187

170

91

Less than 35

13

35-54 55 or more

74

13 68

60

49

100 92 82

Less than 35

16

35-54 55 or more

18 6

16 18 6

100 100 100

11

11

100

41 47 86

39

95

43 75

91 87

27 7

96

8

Jess than 4 em. 4 em. or more

27 27

25 25

2 em . or less More than 2 crn ., less than 4 em. 4 em . or more

19

17

38

Total

M ale

Quiescent at one year No . %

Sex and age (years) Female

Negative Scanty Moderate Heavy

D irect smear examination"

I

I ! No cavity

!

Extent of c a v it a t ion

S ingle cavity (diameter) Multiple cavities (diameter of largest)

Position of cavity

[2 om. or less Mo re than 2 em. ,

1.

J

L

In atelectatic area Not in atelecta tic are a

I I

28

88}

92

33

8"}

89

40

36

90

17 142

17 126

100 89

.. Results of smear examinations were not available for 2 patients .

-- -

93 93

87

229

LON G -TERM CHEM OTHERAPY TABLE XVI.-CAVlTY CLOSURE AT O NE YEAR, ACCORDING TO INITIAL CAVITA TION, FOR THE PATIENTS IN THE 1/2/3-YEAR INTAKE

Total patients assessed

Cavitation on admission

Total

41

8

4

less than 4 em. 4 em . or more

27 27

13 9

or less More than 2 cm., less than 4 em. 4 em . or more

19

6

38 40

9 0

27

9

33

60 70

16 16

27 23

Periphera l'[ Non-peripheral

52 107

4

8

37

35

atelectatic area Not in atelect atic area

17 142

3 38

18 27

Single cavity (diameter) Multiple cavities (diameter of largest)

Locat ion of cavity

Position of cavity

26

159

Extent of cavitation

Thickness of cavity wall"

Cavity closed at one yea r No . %

Mo re than 2 cm., rmOd~'

rem.

Hairline More th an hairline, less than 0·5 em. 0·5 em. or more

I

50}

48 42

33

3] 2

6

15

.. No assessment of the thi ckness of the cavi ty wall was made for 2 patients.

t A cavity lying against the later al edge of the lung field in the axilla ry region or below (i.e. below the level of the anterior end of the 2nd rib).

reflected in a relationship between sex and the achievement of quiescence; all the 40 women had quiescent disease at one year, compared with 130 (88 %) of the 147 men. All the p atients wit h a negative smear result, 95 % of those with scanty bacilli, 91 % of those with moderately positive and 87 % of those with heavily positive sputum, achieved quiescent disease . Of the patients without initial cavitation, 96 %achieved quiescence compared with 92 % of those with single cavities and 89 % of those with multiple cavities. All the 17 patients with cavities in an atelectatic area of the lung achieved quiescence, compared with 89 % of the 142 patients with cavities in normally-expanded areas of the lung. (Table XVI) The attainment of cavity closure at one year showed some association with the thickness of the cavity wall and the presence of a cavity in an atelectatic area; h owever, neither association was statistically significant. There were statistically significant associations (at the 1 % level) with the extent of initial cavitation and the location of the cavity within the lung field. Thus, 26 (42 %) of the 62 patients with single cavities achieved cavity closure compared with 15 (IS %) of97 patients with multiple cavities. Of92 patients with cavities less than 4 em. in diameter, 32 (35 %) achieved cavity closure compared with 9 (13 %) of 67 patients with cavities 4 ern, or more in diameter. Only 8 % of 52 patients whose cavities were located peripherally achieved cavity closure, compared with 35 % of 107 with cavities in other situations. CAVITY CLOSURE AT ONE YEAR lN RELATION TO INITIAL CAVITATION

230

TUBERCLE TABLE XVll.-BACTERIOLOGICAL RELAPSES AFTER STOPPING

CHEMOTHERAPY AT ONE YEAR,

ACCORDING TO THE INITIAL CONDITION AND EARLY PROGRESS

One-year group Condition

0/1

admission Total assessed

Total 2 3 4 5 6

Number of lung zones involved

Extent of cavitation

Relapses No. %

74

14

19

5

1 2

20 10

20 24 20

4

17

5

6 I

30 20

No cavity

11

I

2 em. or Jess Diameter More than 2 cm., of largest less than 4 em. { cavity 4 em. or more

14

3

9 2/

25

2 8

8 33

24 13

Hairline More than hairline, less than 0 ·5 em. 0 '5 em. or more

23 27

Location of cavity

Non-peripheral Peripheral"

45 18

Position of cavity

Not in atelectatic area I' In a telectatic area,

Thickness of cavity wall For patients with cavitation

8

.

1----: I

57 6

I

4 8

30

/7

8 5

18 28

9 4

/6 67

-----------------------1---------1,2 3, 4 5, 6 7,8

Month of sputum conversion in the fi rst year

* See

i I

'

18 I 35 ! 17 ! 4!

3 6 3 2

17 17 /8 5J

definition in Table XVI.

BACTERIOLOGICAL RELAPSE RATES AFfER STOPPING CHEMOTHERAPY IN RELATION TO INITIAL CONDITION AND EARLY PROGRESS (Table XVII)

An analysis was undertaken to assess factors of possible prognostic importance in bacteriological relapse after stopping chemotherapy at one year. There appeared to be little relationship between relapse and age, sex or the bacterial content of the sputum (not tabulated here). There were some associations, none of which was significant, between relapse and the initial ESR, the number of lung zones involved in disease, the extent of cavitation and various characteristics of the cavity. Thus, of the 25 patients with involvement of two or three lung zones 12 % had a relapse compared with 22 % of the 49 patients with involvement of four or more lung zones. Only 1 (9 %) of the patients without initial cavitation relapsed compared with 5 (21 %) of the patients with single cavities and 8 (21 %) of the patients with multiple cavities (not tabulated). Five (13 %) of

231

LONG-TERM CHEMOTHERAPY TABLE XVIII.-BACTERIOLOGlCAL RELAPSES IN THE THREE TREATMENT GROUPS IN RELATION TO CAVITY CLOSURE AT ONE YEAR _._-~

...._._------=---:----

~---:---------_._-

Total patients with quiescent disease at one year Treatment group

Patients with residual cavitation at aile year

Total assessed

One-year Two-year Three-year"

50

All groups

108

34}58 24

* Cavitation at

I

Patients without residual cavitation at olle year

Relapses No. %

12

~} 15

24 5

14

Total assessed

Relapses No. %

24

2

8

12}23 J1

~}

0

47

2

4

one year was not assessed for 1 patient.

the 39 patients with cavities of diameter less than 4 ern. relapsed compared with 8 (33 %) of the 24 with at least one cavity 4 cm. or more in diameter. There was evidence of some association between relapse and both the thickness of the cavity wall and the position of the cavity. Only 8 %of the 13 patients with cavity walls of hairline thickness relapsed compared with 30 % of the 27 patients with cavity walls 0·5 cm. or more in thickness; 18 % of the 45 patients, whose cavity did not lie peripherally, relapsed compared with 28 %of the 18 patients with peripheral cavities. There was an association (significant at the 5 % level) between relapse and the presence of cavities in atelectatic areas of the lung. Four (67 %) of the 6 patients whose cavity lay in an atelectatic area relapsed compared with 9 (16 %) of the 57 patients whose cavity lay elsewhere. However, because atelectasis was not reported unless cavitation was also present, it is not possible to determine whether the presence of a cavity within an atelectatic area, or simply the presence of atelectasis, was responsible for this difference. There was little difference in the month of sputum conversion in the first year between the patients who relapsed and those who had quiescent disease throughout. BACTERIOLOGICAL RELAPSE RATES IN RELATION TO PERSISTENCE OF CAVITATION AT ONE YEAR

The bacteriological relapse rates have been examined in relation to the persistence of cavitation at one year, both in the patients who stopped chemotherapy at that time and in those who continued on chemotherapy for a second and a third year (Table XVIII). In both groups, the relapse rates were higher in the patients with persistent cavitation (the 'open-negative syndrome') than in those without residual cavitation. Of a total of 108 patients with persistent cavitation at one year, 15 (14%) relapsed during the second or third year, compared with 2 (4%) of the 47 patients without residual cavitation. The difference between the two relapse rates does not, however, attain statistical significance. Fifty of the patients with residual cavitation stopped chemotherapy at one year and 12 (24 %) relapsed; of the 58 patients who continued chemotherapy, 3 (5 %) relapsed, the difference being significant at the 5 % level. BACTERIOLOGICAL RELAPSE RATES IN RELATION TO PERSISTENCE OF CAVITATION AND TO THE DURATION OF QUIESCENCE DURING CHEMOTHERAPY

The incidence of bacteriological relapse after stopping chemotherapy has also been related to the number of months of bacteriological quiescence at the time that chemotherapy was stopped, separately for those with and for those without residual cavitation at one year. For this purpose, the same patients have been studied as those described in Section III, namely, those allocated to one and two years of chemotherapy, supplemented with those patients otherwise excluded from

232

TUBERCLE TABLE XIX.-BACTERIOLOGICAL RELAPSES AFTER STOPPING CHEMOTHERAPY ACCORDING TO RESIDUAL CAVITATION AT ONE YEAR AND PERIOD OF BACTERIOLOGICAL QUIESCENCE UP TO THE TIME OF STOPPING CHEMOTHERAPY

Total patients with quiescent disease at one year Number of months of bacteriological quiescence before stopping chemotherapy

Patients with residual cavitation at one year

Patients without residual cavitation at one year

I

Relapses )'Total assessed I No.Relapses% rotala:u," I No. % 100 2 o 0 I ,i 21 1 17 6

1-

1

_

1

3-6 7-9 10-12 13-18 19-24 Total

-

23 6

31

I

6 0 2

90

I

16

-

1~

26 0 , 6 18 •..

!

2

2 11

0 0

38

3

_--

12 0 0

8

Section III because they had received shorter or longer periods of chemotherapy than those originally allocated (page 227). The results are set out in Table XIX. It will be seen that the relapse rates were higher in those with persistent cavitation, whatever the length of quiescence during chemotherapy. Furthermore, considering the patients who had quiescent disease for more than twelve months when chemotherapy was stopped, there were no relapses among the 13 patients without residual cavitation, whereas there were 2 (5 %) relapses among the 37 patients with residual cavitation; these 2 patients had had quiescent disease for twenty and twenty-four months, respectively, before stopping chemotherapy. In other words, for some patients with persistent cavitation, the continuation of chemotherapy for a period of twelve months after attaining quiescence was not sufficient to prevent relapse. SUMMARY OF PROGNOSTIC FACTORS

In summary, the bacteriological status at one year was not significantly associated with any of the factors considered, although age, a large bacterial population, multiplicity of cavities and the presence of cavities in non-atelectatic areas of the lung apparently diminished the proportion achieving bacteriological quiescence. Failure of cavities to close at one year was associated to a significant degree with the multiplicity and size of the cavities and with the presence of peripheral cavities initially. Among those patients who achieved quiescent disease at one year, relapse occurred to a slightly greater extent in those who had extensive disease initially, as gauged by the number of lung zones involved, the size of the cavities and the thickness of the cavity wall. Patients with cavities in an atelectatic area of the lung relapsed to a significantly greater extent. There was no significant association between relapse and the persistence of cavitation at one year, although the relapse rates were higher in the patients with residual cavitation, whether they stopped chemotherapy at one year or continued. There was also a suggestion that a longer period of quiescence under chemotherapy was necessary to prevent relapse in those with, than in those without, residual cavitation. V. FURTHER BACTERIOLOGICAL FINDINGS AND INFORMATION ON BACTERIOLOGICAL RELAPSE This section gives further information on a number of bacteriological findings which are separate from the main exposition of the results. They relate to the progress of patients from the IJ2J3-year

LONG-TERM CHEMOTHERAPY

233

intake during long-term chemotherapy (see Section II) and of patients from the MIJl-year and IJ2j3-year intakes after stopping chemotherapy (see Section III). The section also contrasts bacteriological relapses occurring during chemotherapy (to be described below) with those which occurred after chemotherapy had been stopped (see Section III). FURTHER BACTERIOLOGICAL FINDINGS DURING LONG-TERM CHEMOTHERAPY

These are considered under the following headings :(1) Occurrence of isolated positive cultures. (2) Results of drug sensitivity tests. (3) Emergence of isoniazid resistance. (4) Persistence of isoniazid-sensitive organisms. ISOLATED POSITIVE CULTURES DURING CHEMOTHERAPY

Ten patients produced one isolated positive culture after achiev.ing quiescence and while still on chemotherapy, and 2 more produced two such cultures, separated by ten months and thirty-one months, respectively. There were 8 such cultures in the first year among the 206 patients admitted to treatment, 4 during the second year among the 86 patients continuing on chemotherapy and 2 among the 36 patients continuing chemotherapy for a third year. Eight of the cultures produced only a small number of colonies, ranging from one to eight. Ten of the cultures yielded organisms sensitive to all three drugs; of the remaining 4, 1 was resistant to isoniazid, I to isoniazid and streptomycin, 1 to PAS and streptomycin and 1 to all three drugs. Only 1 of these patients had a bacteriological relapse subsequently. This patient produced a two-colony culture at nineteen months and relapsed bacteriologically at thirty months, while he was still on chemotherapy. * It thus appears that a few patients were still capable of occasionally producing bacilli in the sputum over a long period of time, even when by any other criterion they were making satisfactory progress. However, in the majority of such patients, the bacterial content of the sputum was not very high since the cultures produced only small numbers of colonies. In view of the generally favourable experience of these patients, the appearance of such an isolated positive culture has not been regarded in the present report as indicating bacteriological relapse. RESULTS OF SENSITIVITY TESTS AT INTERVALS DURING CHEMOTHERAPY

The incidence of drug resistance at six-monthly intervals after the start of chemotherapy is set out in Table XX. At six months isoniazid-resistant strains were found in 5 (38 %) of the 13 positive cultures, that is in 3 %of the 182 culture results available. One of these strains was also resistant to PAS and I to streptomycin']. Eight patients were still excreting strains sensitive to all three drugs. At one year, there were 7 isoniazid-resistant strains among the 12 positive cultures, that is 4 % ofthe 176 culture results available; 1 of these was also resistant to PAS. One other culture (from a patient who had received streptomycin for five weeks) yielded a strain resistant only to streptomycin. The numbers of isoniazid-resistant strains at later assessments were 6 of 7 positive cultures at eighteen months, 4 of 5 at two years, 2 of 3 at thirty months and none of 2 at three years. EMERGENCE OF ISONIAZID RESISTANCE DURING CHEMOTHERAPY

The development of resistance to isoniazid has been studied in individual patients and will be described for each year separately. Since the sensitivity test results used in this report are those from the central laboratory the findings are available only from four months onwards.

* This patient was allocated two years of chemotherapy but was excluded from Section III because he continued chemotherapy into the third year (see page 222). t This patient's organisms were sensitive to streptomycin pre-treatment and he had not received the drug during the six months. D

TABLE XX.-RESULTS OF SENSITIVITY TESTS TO ISONIAZID, PAS AND STREPTOMYCIN

Patients with positive cultures i

Months afte r start of chemotherapy

I

Total I I patients with specimen Total cultured

Resistant to: Sensitive to all three drugs

I 182

6 I2

I

176

I

18

84

24

79

30

31

36

I I

13

27

I i

I

I

No.

%t

Isoniazid only

8

62

3

4

12

'1--1'

33

Isoniazid and PAS

I

6

1

I

I

Isoniazid

I I

\

1

I

0

7

0

0

2

1

I

2

5*

0

0

0

1

I

1

0

0

0

0

3 2

I I

2

100

I

j

0

I I

0

i

and PASand streptomycin streptomycin

i

1

I Isoniazid, I

I

I

1

I !

I I

i,

Total isoniazid

II No, I I,

%t

38 I

II

7§

58

I

6

86

4§

80

1

2

67

0

0

0

0 1 2

I

Streptomycin only

0

I

1-· I' 0 i I_-

I

I"

Ii

1

1-11

I-o-!

Ji-i II 0 i

t Percentage of positive cultures.

* Excluding 3 patients for

I

I

5§

0

I

0

I PAS I only,

whom sensitivity tests are not available. § For 1 of these patients, the highest concentration of isoniazid on which growth occurred was 0,2 !Lg./ml.

0

1 0 0

1

0

LONG-TERM CHEMOTHERAPY

235

In the First Year During the first year, 17 (8 %) of the 206 patients yielded one or more isoniazid-resistant cultures; 2 produced resistant cultures before achieving quiescence, 3 produced isolated resistant cultures after achieving quiescence, 5 developed isoniazid resistance during the course of a relapse and 7 produced persistently or intermittently positive (and mainly resistant) cultures for most of the year. Of the 2 patients who produced resistant cultures before achieving quiescence, 1 pr oduced a resistant culture at four months and had only negative cultures thereafter, while the second produced a resistant culture at six months, followed by a sensitive culture at seven months and then only negative cultures. The 3 patients who attained quiescence and subsequently produced an isolated isoniazid-resistant culture did so at five, eight and nine months, respectively. The 5 patients considered in this paragraph all had quiescent disease at one year; the appearance of isoniazid resistance did not herald an unfavourable response to chemotherapy . Of the 5 patients who developed isoniazid resistance in connection with a relapse, 4 had resistant organisms at the beginning of the relapse; in 3 of these (Table XXI, Cases No. 208, 246, 327) all the positive cultu res up to the end of the first year were resistant, while the fourth (Table XXI , Case No. 322), who relapsed at nine months with organisms of doubtful resistance to isoniazid, produced one further culture at twelve months which wassens itive. These 4 patients all had positive ferric chloride tests at the time of the relapse. The fifth patient (Table XXI, Case No. 258) relapsed at six months with isoniazid-sensitive bacilli; the organisms remained sensitive for the next five months but became resistant at twelve months. H is ferric chloride tests were negative at six and nine months and positive at twelve months. Seven patients yielded intermittently positive cultures for most oi the year ; of these, 4 produced three resistant cultures, 1 produced four, 1 produced five and 1 produced six resistant cultures. Once resistance to isoniazid had emerged, 4 of these patients produced only resistant cultures; the other 3 each produced one sensitive result interspersed among the later resistant cultures. Thus, in the 12 patients considered in this and the preceding paragraph, the development of isoniazid resistance was associated with an unfavourable response to the original chemotherapy. However, 2 of these patients achieved quiescenceat one year as the result of a change of chemotherapy.

In summary, the development of isoniazid resistance was associated with a favourable response to the original chemotherapy in 5 pat ients and with an unfavourable response in 12 patients. The emergence ofisoniazid resistance during chemotherapy was thus usually an adverse sign, particularly if such a result was obtained on more than one occasion. In the Second Year Three (3 %) of the 86 patients continuing on chemotherapy excreted isoniazid-resistant strains for the first time during the second year. One patient (Table XXI, Case No. 353), whose disease had relapsed in the first year, produced a single resistant strain at twenty-two months among otherwise sensitive cultures. Two patients (Table XXI, Cases No. 304, 172) relapsed with isoniazid-resistant organisms at thirteen and fifteen months, respectively ; both produced only resistant strains thereafter. The ferric chloride test was positive for 1 of these 2 patients and not available for the other. In the Third Year None of the 36 patients continuing on chemotherapy produced isoniazid-resistant cultures for the first time in the third year. PERSISTENCE OF ISONIA ZID-SENSITIVE ORGANISMS DURING CHEMOTHERAPY

It became evident during the course of the analysis that a small number of patients were continuing to excrete isoniazid-sensitive bacilli for periods of six months and even longer. In the following paragraphs, full details are presented of those patients who were still excreting isoniazid-sensitive bacilli at or after six months , while continuing to receive chemotherapy which included isoniazid. There were 10 patient s who were later to achieve bacteriological quiescence but who were still excreting isoniazidsensitive organisms at or after six mont hs. Eight of them became negative on culture while con tinuing on ison iazid plus PAS, 7 of them at seven months a nd I at eight months. The remaining 2 patients only achie ved negative cultures at twelve and twenty-two months , after a change of chemotherapy ; until these times, both intermittently produced positive cultures containing isoniazid-sensitive organisms. For the first patient, ferric chloride tests were available at nine and twelve months, and both were negative; for the other, ferric chloride tests were available only at nine and fifteen months and both were positive. Four of the 206 patients admitted to the study produced isolated sensitive cultures in the first year, after achieving quiescence (at seven, eight, nine and eleven months, respectively). Similarly, 4 of the 86 patients continuing on chemotherapy produced isolated sensitive cultures in (he second year (at fourteen, seventeen, nineteen and twenty months.

tv w

0\

TABLE XXl.-PATIENTS WHO RELApSED WmLE ON LoNG-TERM CHEMOTHERAPY

Analysis Allocated number chemotherapy

!

258

PH

Months of positive cultures (from time of relapse)

i 6-15 (and subsequently)

i

Months at

I

I

I which no I Results of sensitivity tests C lange of I sensitivity i chemotherapy I tests are I I I' I available lsaniazidt ! PAS : Streptomycin !

I

S 6-11

R12-J5 (0'2)

I

L : IAII S

PH

9,12,24, 27,28

i

l

9*

DR, S, R (0'2)

i'

I All S 1- -

'NT, S, R, R, R

208

246

SPH 6 weeks

9, 11-18,

then PH

21,24-36

PH

9-23, 25-36

22

I All R

!

(1)

AlIS

Active

-

-

- ,1- -

NT, S, R, R, R

-

-

-

- 1--

-

-

-

- -1- -

I

I

, All S to 21, then all R except 26, 36

. SP 13-24 m. None 24-29 m, SP 29-31 m.

SPH 3 weeks then PH

_ _ _1

353

SPH 7 weeks

.1

10-13,15-17, I I, 15, 22, 24-26, 29-33 29-33,36

SPH 6 weeks I 12,13 then PH

I 23

]8,23,24 .1

then PH

372

10,12,14,15,

- 1- -

-

-

Doubt-

fully active

fully active

I Active

Active

1

I Active

S 9-10 S 9-14 All R 11-36 R 15-36 except 26

All R All S except 15 except 24

1_(_50_)_ _ 1.

Thoracoplasty in 25th month

-

All S S 10-22, 25\ All S except 22 R24,26,36 except 16 (R) (0'2) and 36 and 36 (DR)

is,s i

j

A,ti~

I

All S

I

S,S

-

Doubt-

Died in 29th month

,'SPH 11-23 m. PH 23-27 m.

I

327

p

-

at 15 months -

i

AlIR (50)

Stopped

chemotherapy

R, S

- - I - - -- I - - - i

I

At At At one year two yrs. uhree yrs.

I

iN one

-

- - - 1· - - - - - - \ - - - - -1 - - - - ; - - - - -

322

Bacteriological status Furt ter details

I

I~ 1

;

SPH 17-20 m. PH 20-27 m. CPR 27-30 m, SCPH 30-36 m.

Active

IStop ped chemoitherapy at 12m. ISPH 13-15 m. I I PH 15-36 m. I

1-

-

-

1

Active

C

1-

---'- -

Active

I

Act",

. ~ Quiescent

I

Active

Active

Active

1Doubt- i Quies-

Quiescent

I

full.y

] active

I'

I

cent

(Continued on next page

TABLE

Analysis number

191

I

JvJonths of positive Allocated j cultures chemotherapy! (from time I of relapse)

1----1 PH

-------

I

I..

i

which no sensitivity tests are available

I I

Results of sensitivity tests

IIsoniazidt II !

I All S

I SPH 6 weeks

i then PH

I SPH 6 weeks ! then PH

21,23

23

--

IAil S

IS

All R excep t13 and 34

IS

I SPH 2-3 m~ I PH 3-15 m.

Iexcept All R 13 I

;

/22,24,25,1 All R 27, 32, 331 (50) \ 1 :1·

i

Change of chemotherapy

Further details

At

Ilone year

Streptomycin

PAS

:

I

13, 16-25, 27, 28, 31-36

Bacteriological status

1----------.------

i l l I I ====c -

i ___I

172

I

i

12-17, 19 , 24-30

---3M-i--PH

180

I Months at I

XXl.-Continued

i S 13-21

Resection in 36th month

ve 18-20 m. SHe 20-28 m. VTh· 28-34 m.

! R 23, 28-36 iI

--

I

II

,

'

I Quies-

24

: AlI R

I

(5)

Is 15, 16, 18-26 R 27-35

S 15 R 16, 18-35

ISH 9-12 m. BaH 12-18 m.

i

ISePH 19-21 rn, lea.B.-PAS plus H 21-24 m. ICPH 24-36 m.

I

Cycloserine Ethionamide Terramycin Viomycin

S R _ DR _ NT -

-

1

Active

cent

I Active

..., rn

:;:,:

;

Active

o z o,

::c

I

I t

r-

I

1 1

:

-

I

cent 15,16, 18-35

I

At At two yrs. ithree yrs,

.Died of renal . I Ifailure in I Active Active

,SPH 15-17 m. I; 34th month II PH to 33 m. '

and 15

'[

Quies-

o ::r:

rn

i fulI.y

I

1 actIve

I

...,o

I Active

rn

Active

cent

~

;r: :;d

»-"'d

>-(

* The culture at 9 months was contaminated; there was growth on 0·2 !lg. of isoniazid

t The figures in brackets denote the highest concentration of Isoniazid (in fLg./ml.) on which growth occurred (for the first resistant culture)

S S3 P H

-

CHEMOTHERAPY Streptomycin daily C Streptomycin thrice weekly Th PAS T Isoniazid V

-

SENSITIVITY TESTS sensitive } resistant For definitions. doubtfully resistant see Appendix A not tested

IV

w

--.l

238

TUBERCLE

respectively) and 2 of the 36 continuing on chemotherapy in the third year produced sensitive strains (both at thirty-six months). Five patients relapsed with isoniazid-sensitive strains , 4 of them in the first year (Table XXI, Cases No . 258, 353, 372, 191) and 1 in the second year (Table XXI, Case No. 180). The ferric chloride test at the time of relapse was negative in 2 of these patients (Cases No. 258, 372), positive in 1 patient (Case No . 180) and not performed for the rem aining 2. Two of the patients excreted only isoniazid-sensitive organisms after the beginning of the relapse (Cases No. 372, 191), 1 (Case No . 353) produced one resistant and one doubtfully resistant strain interspersed among eight sensitive strains, and I (Case No . 258) produced sensitive strains from six to eleven months, and resistant strains from twelve months onwards. For the remaining patient (Case No. 180), no further sensitivity tests were available . BACTERIOLOGICAL FINDINGS AFTER STOPPING CHEMOTHERAPY

Isolated Positive Cultures After Stopping Chemotherapy The occurrence of isolated positive cultures during chemotherapy has already been described (page 233). Such isolated cultures also occurred in patients after stopping chemotherapy. Among the patients in the !/I/2-year intake only I produced an isolated positive culture after stopping chemotherapy, at twenty-seven months. Among patients in the 1/2/3-year intake, 4 (all one-year) produced isolated positive cultures after stopping chemotherapy. Two of them had received an initial supplement of streptomycin. One of these 2 patients produced an isolated two-colony culture at fifteen months which was sensitive to all three drugs; the other produced a one-colony culture at seventeen months with organisms resistant only to isoniazid and subsequently had a bacteriological relapse in the third year (see page Z23). Of the 2 patients who received no streptomycin supplement initially, 1 produced a one-colony culture at twenty-four months with organisms sensitive to all three drugs and the other a heavily positive culture at twenty-seven months, resistant only to isoniazid, folJowed by a positive smear with negative culture at twenty-eight months. As previously explained (page 233), isolated positive cultures have not, in this report, been regarded as indicating bacteriological relapse. However, an exception was made for the patient in the J;;/1/2-year intake who produced a single positive culture after stopping chemotherapy. Since the specimen was also positive on smear and since chemotherapy was re-introduced before the next month's specimen of sputum was obta ined, he has been regarded as having had a bacterio logical relapse. FURTHER INFORMATION ON BACTERIOLOGICAL RELAPSE

It is of interest to contrast the bacteriological relapses which occurred during long-term chemotherapy with those which occurred after chemotherapy had been stopped. Before doing this, a brief description of those patients from the 1/2/3-year intake who relapsed during chemotherapy will be given. Eleven patients relapsed bacteriologically while receiving chemotherapy. Details of these patients are set out in Table XXI. Eight of the relapses (4 % of the 206 patients admitted to the study) occurred in the first year. Of the 86 pat ients from the two-year and three-year group who cont inued on chemotherapy, 3* (3 %) had a bacteriological relapse in the second year. There were no relapses among the 36 patients continuing on chemotherapy in the third year . One of the relapses occurred at six months, 3 at nine months, 2 at ten months , 2 at twelve months, 1 at thirteen months, 1 at fifteen months and 1 at twenty-one months. The period of culture negativity before the relapse ranged from three to seventeen months. Of the 11relapses, 6 of the patients had received an initial supplement of streptomycin and 5 had received no supplement (seeTable XXI) ; 3 (27 %) relapsed with organisms sensitive to isoniazid, PAS and streptomycin, 2 with organisms resistant only to streptomycin and 6 with organisms resistant only to isoniazid (in 1 of these patients (fable XXI , Case No. 322), the organisms were classified as doubtfully resistant to isoniazid; because of contamination, the isoniazid sensitivity test could not be repeated nor could sensitivity tests for PAS and streptomycin be performed). Returning now to the 24 patients who relapsed after chemotherapy had been stopped, 9 (8 six-month, lone-year) were from the Ml/2-year intake and 15 (14 one-year, 1 two-year) from the 1/2/3-year intake (see Section III). Thirteen patients had received an initial supplement of streptomycin and 11 had received no supplement. Further details of the patients have already been given on pages 218, 222 and 223 and in Tables X and XIII. At the time of the relapse, the organisms were sensitive to all three drugs in 20t (83 %) of the patients, resistant only to isoniazid in 2, and resistant to streptomycin in 1 patient. The 7t pat ients who relapsed after having received six months of chemo-

* This includes 1 patient who had active disease at one year (and was therefore excluded from Section III) but later had three consecutive negative cultures before relapse. t In 1 further patient (six-month), the culture at the time of relapse was resistant to isoniazid, but all later cultures were sensitive (page 218). This patient has been om itted from the paragraphs which follow.

LONG-TERM CHEMOTHERAPY

239

therapy all relapsed with sensitive organisms. Of the 15 patients who relapsed after achieving quiescence with one year of chemotherapy, 13 had sensitive organisms, 1 isoniazid-resistant and 1 streptomycin-resistant organisms. Only 1 patient relapsed after achieving quiescence with two years of chemotherapy and he had isoniazid-resistant organisms. Thus it appears possible that, for patients who relapsed, sensitive organisms were more likely to be found at the time of relapse if they had received the shorter periods rather than the longer periods of chemotherapy. It is of interest to contrast drug sensitivity in relapses occurring during and after chemotherapy; 27 % of those relapsing during chemotherapy relapsed with sensitive organisms compared with 83 %of those relapsing after chemotherapy was stopped, a difference significant at the 1% leve1. Study of the later progress of the two groups of patients reveals that this difference was of clinical importance. Considering first those who relapsed while still on chemotherapy, of the 3 patients who relapsed with sensitive organisms 1 refused further treatment after fifteen months and continued to have active disease, while of the remaining 2 (both of whom received combinations of isoniazid, PAS and streptomycin), I had quiescent and I had active disease at three years. The 2 patients who relapsed with organisms resistant only to streptomycin were treated with isoniazid and PAS; 1 failed to respond and-died in the thirty-fourth month, with active tuberculosis, while the other had quiescent disease at three years. The 6 patients who relapsed with isoniazid-resistant organisms were treated with streptomycin plus PAS (sometimes combined with cycloserine and viomycin). One patient achieved quiescence after a thoracoplasty, 1 died from active tuberculosis and 4 still had active disease at three years. In other words, of the total of 10 patients who continued chemotherapy for the whole three-year period, 3 (30%) achieved quiescence (I of them after a thoracoplasty), 2 died with active tuberculosis and 5 had active disease at three years. Among the patients who relapsed after stopping chemotherapy, 20 relapsed with sensitive organisms. Twelve of these resumed treatment with the standard combination of isoniazid plus PAS, while the other 8 patients received various combinations of isoniazid, PAS and streptomycin. At three years, 17 of these 20 patients had quiescent disease (2 of them having undergone lobar resections) and 3 had active disease. Of the 3 patients who relapsed with drugresistant organisms, 1 who had streptomycin-resistant bacilli was treated with isoniazid plus calcium benzoyl PAS and had quiescent disease at three years, and 2 with isoniazid-resistant bacilli resumed treatment with streptomycin plus PAS. One of these patients had active disease at three years; the other patient resumed chemotherapy only at thirty-five months and it is therefore too early to assess its effect at three years. Thus, 18 (82 %) of 22 patients who relapsed after stopping chemotherapy achieved quiescent disease at three years compared with 3 (30%) of 10 who relapsed while still on chemotherapy; this difference is significant at the 5 % level.

In summary, patients who relapsed while on chemotherapy were likely to relapse with drugresistant organisms and to respond less well to further chemotherapy while those who relapsed after stopping chemotherapy were more likely to have drug-sensitive organisms and to respond well to further chemotherapy. In interpreting these findings, it must however be borne in mind that the chemotherapy exhibited in this study consisted in the main part of the three standard drugs; if 'reserve' drugs had been used more extensively for patients with drug-resistant organisms, it is possible that chemotherapy might have also yielded good results for them. VI. COMPARISON OF THE EFFECTS OF STANDARD CHEMOTHERAPY WITH THOSE OF THE STANDARD CHEMOTHERAPY PLUS AN INITIAL SIX WEEKS' SUPPLEMENT OF STREPTOMYCIN In this section, patients admitted to all three intakes before 1st July, 1957, who were allocated at least one year of chemotherapy have been considered (seeTable I). As described on page 205 these patients were allocated at random to two series; the patients in both series were prescribed the standard combination of isoniazid 200 mg. plus PAS (sodium) for at least one year, one with no initial supplement (the PH series), while those in the other series were prescribed, in addition, streptomycin 1 g. daily for the first six weeks (the SPH series). In this phase of the study 179 patients (95 PH, 84 SPH) were admitted (Table I). The progress of patients in the two series has been studied during the first year of chemotherapy. Twenty-eight patients (14 PH, 14 SPH) were excluded from the analysis because their treatment varied substantially from that prescribed. In the first nine weeks, 11 patients (10 PH, 1 SPH) received isoniazid plus PAS for less than six weeks, and 6 (SPH) received streptomycin for less than six weeks; 5 more patients in the SPH series received all three drugs for less than six of the first nine weeks. Three patients in the PH series were given a six weeks' supplement of streptomycin in error. Two patients (both SPH) had interruptions of chemotherapy (for definition, see page 209) for six

240

TUBERCLE TABLE

XXI I. -

R ADIOG RAPHIC E XTENT OF D ISEASE AND BACTERIOLOGICAL CONDITION ON ADMISSION

Treatment group Assessment

%

81

-

2 3 4 5 6

5 15 27 27 7

No cavity Single cavity Multiple cavities

17 25 39

Number oflung zones involved

i Direct smear examina tion"

* This

SPH

No. Total patients

Extent of cavitation

PH

I

N egative Scanty Moderate Heavy

I i

I

I I

No.

%

70

-

6 19 33 33 9

7 15 15 19 14

10 21 21 27 20

21 31

9 22 39

13 3/

56

3 13 17 37

19 24 53

,

48 I

2 23 15 40

2 29 19 50

I

I

4

assessment was not available for 1 PH patient.

weeks or more in the first six months and 1 patient (PH) took only half the prescribed dosage of drugs from four months onwards. There remain for analysis 151 patients, of whom 81 were originally allocated to the PH and 70 to the SPH series.

Pre-treatment Condition of the Patients The two series have been compared in terms of clinical , radiographic and bac teriological status before the start of chemotherapy. The average weight of the patients was 54 kg. (119 lbs.) for the PH series , and 54·5 kg. (120 lbs.) for the SPH series. The dist ributions of the ESR were similar in the two series; the ESR was abo ve 50 mm, in 51 % of the PH and 47 % of the SPH series. The radiographic and bacteriological findings at the start of chemotherapy are summarized in Table XXII. There was involvement of four or more lung zones in 75 % of the PH and 69 % of the SPH series. Cavitation was present in 79 % and 87 %, respectively; in 48 %of the PH and 56 % of the SPH series there were multiple cavities. Over two-thirds of the patients were producing sputum heavily or moderately positive on smear (PH 69 %, SPH 77 %). The two series were similar in all these respects. Before considering the results for the two series of patients as a whole, it is necessary to refer to 10 patients who did not receive a full year's che motherapy for the following reasons :(1) Deaths from tubercu losis within the firs t three weeks. Five patients (2 PH, 3 SPH) died of their tuberculosis within three weeks of starting chemotherapy. (2) Non-tube rculous deaths There were 3 deaths from causes other than tuberculosis during the first year. One patient (SPH) died of heart block dur ing the fifth month (for details, see Appendix B) and 2 patients died in the tenth month, 1 (PH) of renal failure (Appendix B), and the other (SPH) of congestive heart failure (page 218). (3) Non-tuberculous disease . One patient (SPH) developed a bronchial carcinoma which became evident radiographically at six months and th ereafter interfered with the assessment of the progress of his tuberculosis.

LONG-TERM CHEMOTHERAPY

241

(4) Self-discharge One patient (PH) discharged herself from observation at ten months. These 10 patients have been included in the analyses up to the time of these various events. They are also included in a complete assessment of all the patients presented in Table XXVI. RESULTS DEATHS FROM OR WITH ACTIVE TUBERCULOSIS AFTER THE FIRST THREE WEEKS

There were no deaths from or with active tuberculosis after the first three weeks in either series. PERSISTENT BACTERIOLOGICAL POSITIVITY

Eight PH and 1 SPH patients produced persistently positive cultures and all had their chemotherapy changed on this account before the end of the year. Isoniazid-resistant organisms emerged in all 8 PH patients, in 2 at four months, in 2 at five months, in 2 at six months and in 2 at seven months. At the time of the change of chemotherapy, isoniazid resistance had been present at four separate monthly examinations in 3 patients, at three monthly examinations in 3 patients, at two in 1 patient and at one monthly examination in 1 patient. The changes of chemotherapy were made in 1 patient in the sixth month; in 1 in the eighth month, in 5 in the tenth month and in 1 in the eleventh month. All 8 patients had positive cultures on at least two of the three monthly examinations immediately prior to the change ofchemotherapy. The SPH patient changed chemotherapy at nine months; he had produced positive cultures for the first five months, a contaminated culture at six months and negative cultures at seven and eight months. During the ninth month he had shown clinical and radiographic deterioration; the sputum at nine months was positive on smear and later produced a positive culture which was sensitive to all three drugs. BACTERIOLOGICAL RELAPSE

Four PH and 1 SPH patients (Table XXI, cases 258,322,208,246 and 191) had a bacteriological relapse, 1 at six, 3 at nine and 1 at twelve months; 1 of them (PH) relapsed with organisms doubtfully resistant to isoniazid and had his chemotherapy changed before the end of the year, at eleven months. Of the other 4 patients, 1 (PH) relapsed with organisms sensitive to all three drugs, 1 (PH, but who received streptomycin for five weeks-see page 245) with organisms resistant to streptomycin and 2 (1 PH and 1 SPH) with organisms resistant to isoniazid. CLINICALLY IMPORTANT RADIOGRAPHIC DETERIORATION

One PH patient whose chemotherapy was changed at twelve weeks, showed a radiographic deterioration which, in the opinion of the clinical assessor, warranted a change of chemotherapy. The 15 patients (13 PH, 2 SPH) described above have all been classified as having had an unfavourable response to their allocated chemotherapy and have been assessed as such in an assessment of all the patients, presented in Table XXVI. In 11 of these (10 PH, 1 SPH) the unfavourable response led to a change of chemotherapy before the end of the year. These 11patients have all been included in Tables XXIII-XXV, after their change of chemotherapy, as 'unfavourable response leading to change of chemotherapy'. CHANGES OF CHEMOTHERAPY FOR OTHER REASONS

(1) A further 11 patients (5 PH, 6 SPH) had their chemotherapy changed during the year in such circumstances that either no judgement could be made as to whether their bacteriological response was or was not unfavourable or, alternatively, where the progress was clearly favourable. They have been excluded from Tables XXIII-XXV after their change of chemotherapy, but are described below and included in the assessment of the progress of all the patients (page 248 and Table XXVI). The reasons for these changes were as follows: (a) Drug toxicity (2 PH, 2 SPH). (b) Poor clinical progress (1 PH, 1 SPH). (c) Clinical deterioration (1 PH, 2 SPH). (d) Appearance of an isolated isoniazid-resistant culture (1 PH). (e) In preparation for surgery (1 SPH).

T ABLE XXIII .--CHANGES IN G ENERAL R ADIOGRAPHI C ApPEARANCES I

Period of observation tmonths)

I

I

Improvement t

Treatmen t group

,

Total patients assessed

iI

Considerable

Mode rate

No .

%

No .

%

PH SPH

74 58

0 0

0 0

11

0-3

18

15 31

77 61

3 3

4

0-6

PH SPH

30 39

39 64

0-1 2

,

I

PH

72

SPH

58

14 16

5

19 28

34 33

I

No change

Slight

Deterioration

I No .

%

No .

%

40

54 41

20 12

27 21

2 3

3

I I

24

40

16

47

11

57

7

52 26

15

I I

I

I

12 \

5

3

4

I

2

I I

I

I

Unfavourable response leading to change of chemotherapy

2

1

4

0

0 0

2

0 0

0

I I

10 1

TABLE XXIV.- CHANGES I N CAVITATION

- -

-

-

Perio d of obse rvation (m onths)

- -- - ---c-- - - -,----- - - - -----:,----- - - - - -- - - -- - - - - - -- - - - - I I

II Trea tment group

II

Patients with initial cavitation

Patients without cavitation at beginning \ (or end) ofperiod I

Tota l patients assessed

ITotal

No .

%

I 0-3 0-6 0-12

PH SPH

PH SPH PH SPH

No .

%

No.

%

53 51

24

19

42 40

2

1 0

61

10 9

17

1

2

18

1

0

0 1

8*

74

17

2

30

I

57 47

1

11

2

4

24

I

77

I

I

59 49

10 9

17

61

18 12

I

72

58

Ir

No change

I

Cavities larger or more numerous

58

I

I Unfavo urable

I

Cavities f e wer or smaller

Disappearance of cavitation

1

respo nse leading to change of chemotherapy

{

11 11

I

SS

12

1 47

13

18

I I

22 28

,

36 30

61

29

53

26

55

6 I

6

11 13

II

* 2 further pat ients with unfavourable response did not have cavitation initially

1

TABLE XXV.-REsULTS OF ExA."dINATIONS OF S IN G LE B ACTERIOLOGICAL S PECIMENS

Culture positive I I Unfavourable response I Total to I I Total ! leading change of I S mear Treatment patients Smear I g roup assessed chemotherapy positive negative No.

3

I

I

6 9

12

Culture negative

I

I

Months after start of chemotherapy

i

I I I

PH SPH

73

PH SPH PH SPH PH SPH

I 0

20

20

40

17

11

28

74 58

2

4

6

0

0

1

72

3 0

4 1

62

,

I

I

I

55 71

56

I

10 1

,I i

2 1

55 45

I

14

5 1

I

9 2

/2

1

I I

3 1

I

%

10 1

0

\ Total I Smear Smear positive negative \ No . %

~I 6 6

2

4 4 2

II i

4 0

I I

27 27

1

1

I

I

56 51 56 53

,\ I

I

57 53

I

II J

!

J

Total smear negative No .

%

32

44

47

64

34

55

38

6/

62 57

84 98

62 52

84

60 53

83

61

85

96

54

98

58

82

54

96

58 53

95

I

90

82

LONG-TERM CHEMOTHERAPY

245

(2) A group of 8 patients (I PH, 7 SPH) received streptomycin after the first nine weeks for reasons apparently unrelated to their clinical progress. These patients have therefore been left in the analysis for the whole twelve-month period. The PH patient had complicating renal disease which was at one time thought to be tuberculous in origin; streptomycin was therefore added to the treatment but was withdrawn five weeks later when the diagnosis was disproved. For the SPH series streptomycin was continued beyond the stipulated period in 5 patients (to a total of ten, twenty-one, twenty-seven, forty-one and fifty weeks-average thirty weeks); in 1 patient it was continued by the ward staff in error, in 2 by the clinician because there had been advanced disease initially, while in 2 patients there was no ascertainable reason. In 2 SPH patients, streptomycin was re-introduced (at eleven weeks and six months respectively). The first of these 2 patients was given streptomycin in error for a period of sixteen weeks when he was transferred to a different hospital; in the second, it was re-introduced by the clinician, who felt that the unusual social circumstances of the patient did not allow him to take the slightest risk of a relapse. It will be shown later (page 248) that the retention of these 8 patients in the analysis has not influenced the results and they have, therefore, been included in all the tables which follow.

CHANGES IN GENERAL RADIOGRAPHIC ApPEARANCES (Table XXIII) At three months, 15 % of the 74 PH and 31 % of the 58 SPH patients showed moderate improvement. At six months, the percentages of patients showing moderate or considerable improvement were 43 % for the PH and 69 % for the SPH series and at twelve months 67 %of 72 PH patients and 84 % of 58 SPH patients had achieved these degrees of improvement. Thus, the SPH series fared better at each assessment during the twelve-month period; at six and twelve weeks, the differences between the two series are significant at the 5 %level. CHANGES IN CAVITATION (Table XXIV) At three months, cavitation was less in 53 % of the 57 PH and 51 % of the 47 SPH patients with initial cavitation, but had disappeared only in 1 PH and 2 SPH patients. By six months, cavity closure had occurred in 17 % of the PH and 18 % of the SPH patients; at twelve months, the cavity closure rates had increased to 22 % and 28 % respectively. There was thus little difference in the rate of cavity closure in the two series. BACTERIOLOGICAL FINDINGS (Table XXV) Results of Direct Smear Examinations At three months, negative smears were found in 64 % of the PH and 61 %of the SPH patients, at six months in 84 % and 90 %, at nine months in 85 % and 98 %, and at twelve months in 82 % and 95 %, respectively. Culture Results The percentage of patients with negative cultures at each month is shown in Figure 2. At three months 44 % of the 73 PH and 55 % of the 62 SPH patients had a negative sputum culture. At six months the percentages of patients with negative sputum cultures had risen to 84 % for the PH series and 98 %for the SPH series. At nine months the figures were respectively 83 % and 96 % and at twelve months, 82 ~~ and 96 %. The differences between the two series at six, nine and twelve months are significent at the 5 % level. Summarizing the results for smear and culture examinations, the two series fared similarly in achieving negativity on smear examination in the first six months while negativity on culture was achieved more frequently in the SPH series throughout the twelve-month period. The proportions in the two series with negative cultures remained almost stationary from six months onwards. It will be noted that more specimens were negative on culture than on smear at six months in the SPH series; this was due to the considerable proportion of specimens at that time yielding positive smears but negative cultures. This phenomenon will be considered further in Section VII. Drug Sensitivity Test Results Since the sensitivity test results provided by the central laboratory have been used (see page 207), findings are available only from four months onwards. By six months isoniazid resistance had developed in 8 of the PH and none of the SPH patients, by nine months in a further 5 PH and 1 SPH patients (including 1 (PH), who showed doubtful resistance), and by twelve months in 1 more PH patient. In all, 14 PH and 1 SPH patients produced at least one isoniazid-resistant culture from the fourth month onwards.

246

TUBERCLE 100

/",,"-

o

2

4

,~

.

-./

b

, .I'

,

~

,

,

,'\-- _.. ----

PH

B

10

--

12

MONTHS AFTER START OF CHEMOTHERAPY

FIG. 2

Percentage of patients in the PH and SPH series with negative cultures. Two of the patients (both PH) who were excreting isoniazid-resistant organisms at sixmonths also had resistance to another drug, 1 to PAS and 1 to streptomycin". One PH patient with isoniazid-resistant organisms at twelve months also had resistance to PAS. One PH patient with isoniazid-sensitive organisms developed streptomycin-resistance at twelve months. (This patient had renal disease and received streptomycin for five weeks-see page 245.) Of the 14 PH patients in whom isoniazid-resistant cultures emerged, 2 produced only negative cultures subsequently. 1 produced a subsequent sensitive culture and then negative cultures, and 9 continued to produce resistant cultures (1 until twelve months, and 8 until their chemotherapy was changed); the patient who produced organisms of doubtful resistance at nine months had two further negative cultures before his chemotherapy was changed, and 1 patient produced a resistant culture for the first time at twelvemonths. The only SPH patient with isoniazid-resistant cultures relapsed at nine months and produced resistant cultures from then until twelve months.

Summarizing, in 11 of the PH patients (14 %of the 81 in the series and 79 %of those producing resistant results) and in 1 of the SPH patients (1 % of the 70 patients in the series and the only one producing a resistant result), the emergence of isoniazid resistance was associated with an unfavourable response, namely, persistent bacteriological positivity or a bacteriological relapse. ASSESSMENT OF STATUS OF ALL THE PH AND SPH PATIENTS Table XXVI presents a classification of all the patients in the PHjSPH comparison in terms of favourable, doubtful, or unfavourable response to chemotherapy during the first year. This classification is based on the bacteriological results at twelve months or, if necessary, on the bacteriological, clinical and radiographic results at the time of change of chemotherapy, self-discharge or death before the end of the twelve-month period.

* This patient's organisms were sensitive to streptomycin pre-treatment and he had not received the drug during the six months.

247

LONG-TERM CHEMOTHERAPY TABLE XXVI.-CLASSIFICATION OF PAT1ENTS ACCORDING TO THEIR BACTERIOLOGICAL STATUS AT (OR

BEFORE) TWELVE MONTHS

Status at (or before) 12 months

II

I Favourable

Negative cultures: A. At 10, 11 and 12 months

PH

SPH

!

5

!

10

14 15 7 4 3 0 0

:5 2 18 11 12 5 1 2 0

58

56

1

2

1 1

0 0

61 (75%)

58 (83/,..)

1

0

1

1

0

1

1 1

2 2

1 2

1 3

7 (9%)

lO (14%)

3

1

1

0

I

First month of persisting culture negativity 1 2 3

1 I

I

II I

,;

4 5

I I

I

6 7 8 9

All patients

I

B. For the previous 3 monthly examinations before: (i) self-discharge, non-tuberculous death or development of bronchial carcinoma (ii) change of chemotherapy during the second 6 months for: (a) development of .isoniazid resistance (see text) (b) severe toxic reaction to drug Total

A. Isolated positive culture at 10, 11 or 12 months

Doubtful

B.

One positive culture within 3 months of non-tuberculous death C. Two negative cultures before change of chemotherapy in preparation for surgery D. Change of chemotherapy within the first 6 months for: (a) clinical deterioration (b) severe toxic reaction to drug (c) poor clinical progress (but with 3 consecutive negative cultures before change) E. Deaths from tuberculosis within the first 3 weeks

Total Unfavourable

A. Positive culture in at least two of the monthly examinations at 10, 11 and 12 months B. Change of chemotherapy for radiographic deterioration (within first 3 months) C. Change of chemotherapy during the second 6 months for: (a) persistently positive cultures (b) bacteriological relapse D. Deaths from or with active tuberculosis after the first 3 weeks Total

------

I I

8

1

1

0

0 13 (16%)

Total patients assessed -,_.~--_.~_.,

I

I I

II

0 2 (3%)

81 (100%) I 70 (100 %)

248

TUBERCLE

A favourable response was obtained in 75 % of the PH series and 83 % of the SPH series. Two PH patients have been regarded as having a favourable bacteriological response even though chemotherapy was changed. One of them produced an isoniazid-resistant strain at six months, and a sensitive strain at seven months; she then produced sputum which was positive on smear, but negative on culture at the next three monthly examinations. Her chemotherapy was changed in the eleventh month. The other had her chemotherapy changed in the seventh month because of recurrent purpura. She had already produced three negative cultures. The status was classified as doubtful in 7 PH and 10 SPH patients. One patient (PH) had an isolated positive culture at eleven months. Two patients (1 PH, 1 SPH), who died of non-tuberculous causes in the fifth and tenth months, respectively, were classified as of doubtful status bacteriologically because neither had had three consecutive negative sputa in the examinations prior to their death. One patient (SPH) had two negative cultures before his chemotherapy was changed in preparation for surgery. Three patients (1 PH, 2 SPH) who had their chemotherapy changed for clinical deterioration* and 3 patients (1 PH, 2 SPH) whose chemotherapy was changed because of severe drug reactions, aU in the first three months, together with 2 patients (1 PH , 1 SPH) whose chemo therapy was changed between three and six months because of lack of clinical progress, have also been regarded as showing a doubtful response because of the short period of observation. The 5 patients (2 PH, 3 SPH) who died of tuberculosis within the first three weeks have also been placed in their category because it is doubtful to what extent these very early deaths contribute to an evaluation of the benefits of an initial six weeks of streptomycin. Thirteen PH and 2 SPH patients have been classified as showing an unfavourable response. Four of them (3 PH, I SPH) had active disease at twelve months. Eleven patients had their chemotherapy changed, 1 (PH) because of radiographic deterioration, 9 (8 PH , 1 SPH) because of persistent bacteriological positivity and 1 (PH ) because of a bacteriological relapse. The difference between the two series in the proportions of patients with favourable , doubtful and unfavourable responses to chemotherapy is significant at the 2 %level. The above differences do not strictly reflect the effect of the addition of streptomycin for the first six. weeks to the standard regimen, since, as described on page 245, I PH and 7 SPH patients received additional streptomycin. The PH patient had an unfavourable and the 7 SPH patients all had a favourable response. If these 8 patients are removed from the comparison, the proportions of patients showing a favourable response become 76 % of 80 for the PH series and 81 %of 63 for the SPH series, compared with 75 % and 83 %, respectively, when the patients are retained in the comparison. The difference between the two series in the proportions with favourable , doubtful and unfavourable responses remains significant, but at the 5 % level. DRUG REACTIONS

(Table XXVII)

In this sub-section are considered all the 95 PH and 84 SPH pat ients originally admitted to this study (page 239 and Table I) since the departures from the allocated chemotherapy of the patients excluded on page 239 were sometimes related to the onset of drug re actions. Gastro-intestinal disturbances attributed to PAS were encountered in 16 (17 %) of the PH and It (13 %) of the SPH series. In most, the symptoms were mild but in 2 pat ients (bo th PH), they were su fficiently severe to warrant stopp ing PAS. Six (7 %) of the SPH patients developed vertigo in the first six weeks. Hypersensitivity reactions occurred in 13 (14 %) of the PH and 17 (20 %) of the SPH series. The chief manifestations were pyrexia (1 PH, 2 SPH) and skin eruptions with or without pyrexia (8 PH, 12 SPH). In 3 more PH patients, the skin rash and pyrexia were followed by jaundice, and in 1 more SPH patient by arthritis. One patient (PH) developed purpura, which recurred on three separate occasions and only cleared when PAS was stopped . Two SPH patients developed acute circul atory collapse; 1 of them had thr ee separate attacks, while the other suffered a myocardial infarct dur ing his only attack. If all types of drug reactions are considered together , there were 29 (31 %) among the PH patients and 34 (40 %) a mo ng the SPH patients. If gastro-intestinal disturbances are left out of the comparison , the figures become 13 (14 %) '" The radiograph ic series for these 3 patients were shown to the clinical assessor, who did not observe any rad iographic deterioration which warranted a change of chemotherapy.

249

LONG·TERM CHEMOTHERAPY TABLE

XXVII.-DRUG

REACTIONS

Treatment group Drug(s) responsible

PAS

Gastro-intestinal disturbance Hypersensitivity reactions

Streptomycin

I I

No.

%

No.

16 12

17 13

11 9

-

-

6 4

5

-

3

4

1

1

3_1_1_3_4

40_

Vertigo Hypersensitivity reactions i I

I -

PAS and streptomycin

Hypersensitivity reactions

-

Uncertain

Hypersensitivity reactions

.

I

:

1

29

Total with drug reactions

SPH

PH

Nature of reactions

1

%

13 11 7

95 84 ------------'-------

Total patients originally admitted

and 23 (27 %), respectively; this difference is significant at the 5 % level and may be attributed to the development in 10 SPH patients of hypersensitivity or toxic reactions due solely to streptomycin (see Table XXVII). In a few patients, the drug reaction led to a change of chemotherapy. Reactions to PAS led to a change during the first year in 8 of the PH and S of the SPH patients-in all but 2 (I PH, 1 SPH) in the first nine weeks. In addition, 4 SPH patients had their streptomycin stopped before the end of the prescribed period, 3 of them at four weeks and 1 at five weeks. BACTERIOLOGICAL RELAPSE AFTER STOPPING CHEMOTHERAPY

The two regimens of chemotherapy may be compared not only for their ability to render the disease quiescent during the first year but for their ability to prevent bacteriological relapse after chemotherapy is stopped. The frequency of bacteriological relapse will be considered separately for the group allocated one year of chemotherapy and those allocated at least two years of chemotherapy. Of the 58 PH and 56 SPH patients who had quiescent disease at twelve months (Table XXVI), there were 30 in the PH and 22 in the SPH series who were due to stop chemotherapy at that time. Eight of these (3 PH, 5 SPH) were excluded from the comparison of the relapse rates, 7 of them because chemotherapy was continued (not in 'accordance with protocol) beyond the end of the year, and I because he developed a bronchial carcinoma between the twelfth and fifteenth month. There remained 27 PH and 17 SPH patients in the comparison. Six (22 %) of the 27 PH patients and 3 (18 %) of the 17 SPH patients had a bacteriological relapse in the second and third years, a non-significant difference. The 6 PH patients relapsed at thirteen, fifteen, seventeen, seventeen, twentyseven and twenty-nine months, respectively; the 3 SPH patients relapsed at fifteen, twenty-seven and twenty-eight months, respectively. All the patients relapsed with organisms sensitive to isoniazid, PAS and streptomycin except 1 PH patient, who relapsed at twenty-seven months with organisms resistant to isoniazid. Of the S4 patients (23 PH, 31 SPH) who were originally allocated two or more years of chemotherapy and who had quiescent disease at two years, only 1 (PH) relapsed in the third year,

In summary, there was no evidence that an initial six weeks' supplement of streptomycin reduced the risk of relapse after stopping chemotherapy, whether the total duration of chemotherapy was one or two years. CONCLUSION

It may be concluded that the addition of streptomycin for an initial six weeks to the standard combination of isoniazid plus PAS resulted in a higher rate of favourable response than was

250

TUBFRCLE TABLE XXVIII.-SMEAR-POSITIVE, CULTURE-NEGATlVE RESULTS DURING THE FIRST YEAR

Total patients i with specimens! Patients with specimens Months after Total patients positive on smear! positive on smear, but negative on culture examination start of with specimens 1 or on cultlire examination chemotherapy \ examined \ (n) No. (b) % olea) % of (b) 0

193 189 190 186 181 182 181 178 183

I

3 4 5 6 7 8

I I

1 I I

I

I

I

9

I

10 11

_ _ _ 0•• , _ . -

_,' _ _ _ _ _ _ ' ' _

to

65

15 to 10

21

18 20 18

177 175 ••

0 2 10 17 19 18 17

40 31 31 22

171

12

---.

II

203 168 143 109

206

II

1 2

0 1 5 5 9 10

26 48

10 9

58 55

8 5

68 48 56 55

6 6 3

11 6

0 1 7 9

33

~

obtained by treatment with the standard combination alone, but that it was not possible to detect any effect on the relapse rate after chemotherapy was stopped. The supplementary streptomycin did, however, lead to a higher incidence of clinically important side-effects. VII. SIGNIFICANCE OF SMEAR-POSITIVE CULTURE-NEGATIVE RESULTS During the course of the study it became evident that many sputum specimens which yielded scanty bacilli on direct smear examination did not produce growth on culture. The frequency with which such smear-positive, culture-negative results occurred during the first twelve months in patients in the 1/2J3-year intake is shown in Table XXVIII and in Figure 3. There were no such

w

10

>

8 w

:t:Z:

I::~

:i::::> "'~

~a ~~

C5~ u..

5

c,

'<2d: z~

~~

It;g z 0

It

V>

0

b

8

10

12

MONTHS AFTER START Of CHEMOTHERAPY

FIG. 3 Percentage of patients with specimens positive on smear but negative on culture,

251

LONG-TERM CHEMOTHERAPY

results at the start of chemotherapy. The number gradually increased during the first few months and at six months 18 patients produced such results. This number represents 10% of all the patients in the main analysis and as much as 58 % of all results positive on smear or on culture. The proportion remained high during the rest of the year although the absolute number of patients producing such results decreased gradually. It was found that these results occurred evenly distributed among the co-operating laboratories; however, they were found particularly frequently in certain patients. Of the 185 patients who completed one year of chemotherapy, 31 produced one such result, 5 two such results and 22 had three or more such results. Among the latter, 6 patients produced three such results, 5 produced four, 2 produced five, 3 produced six, 4 produced seven, 1 produced eight and 1 patient produced eighteen such results. In 19 of these 22 cases, the first of such a series coincided with the first month of a period of culture negativity. This suggests that in these 19 patients, at least, such results were due to nonviable organisms. A comparison has been made between the pre-treatment condition of the 22 patients who produced three or more such results with that of 36 patients who produced one or two such results and that of 127 patients who produced no such results (Table XXIX). The first group were found to have more extensive disease radiographically and larger TABLE XXlX.-PRE-TREATMENT CONDITION OF PATIENTS WITH AND WITHOUT SMEAR-POSITIVE, CULTURENEGATIVE RESULTS

Patients with smear-positive culture-negative results ConditioII an admission

Total patients

Number of I I lung zones , involved I

2 3 4 5 6

I I -_._--j

No.

%

22

-

36*

-

l27t

0 14 23 32 32

2 6 8 14 6

6 17 22 39 17

9 29 36 14

7 23 31 28 11

0 3 5 7 7

I

No.

39

% -

9

4

1l

22

17

cavity (diameter)

{2 em. or less More than 2 cm., less than 4 em. 4 cm. or more

0 2 2

0 9 9

1 3 8

3 8 22

7 22 17

6 17 13

Multiple {2 cm. or less cavities More than 2 cm., less than 4 em. (diameter 4 em. or more of largest)

0 4 12

0 18 55

4 7 9

11 19 25

14 26 19

11 20 15

5 1 23 6 18 9 55 I 19

3 17 26 54

8 30 32 54

6 24 26 44

0

2 2 14

2 2 1/ 55 3/

_

Culture examination

I

%

2

..." .._. ....

Direct smear examination

I

No.

~

I

I I

None

I

No cavity

I Single Extent of cavitation

/Three or mare One or twa I

Negative Scanty Moderate Heavy Negative Less than 20 colonies 20-100 colonies Innumerable discrete colonies Confluent growth

I

I

1 5 4 12

0 1 2 , 11 8

i

I I

0 5 9 50 36

I

0 2 1 16 I 17

I

* No assessment of direct smear was available for 1 patient. t No assessment of direct smear or culture was available for 3 patients.

6 3 44 47

68 38

252

TUBERCLE

cavities; 64% of the patients with three or more results had at least one cavity greater than 4 ern. in diameter compared with 47 %of those with one or two such results and with 28 % of those with no results, a highly significant trend (P < '01). There were no significant differences between the three groups in the bacteriological condition of the patients pre-treatment. It was thought possible that these specimens might represent isoniazid-resistant bacilli which had failed to grow on culture because of special growth requirements. Of the 16 patients who produced isoniazid-resistant organisms and continued with chemotherapy for the remainder of the year, 5 (31%) produced one or more smear-positive, culturenegative results subsequent to the development of resistance, compared with 50 (30%) of 169 patients who did not develop isoniazid resistance. There is thus no evidence that these results are related to isoniazid-resistant bacilli. Five of the patients with three or more results, 16 of those with one or two results, and 54 of the patients with no such results had their chemotherapy stopped according to protocol at the end of twelve months. None of the 5, 6 (38 %) of the 16 and 9 (I7 %) of the 54 had a bacteriological relapse during the period of the study. Combining the first two groups, 29 % of patients producing one or more results had a relapse compared with 17 % of patients with no such results; this difference is not significant. There were 17 patients with three or more results, 19 with one or two results and 70 patients with no such results who continued chemotherapy after the end of the first year. Three (18%) of the 17,5 (26%) of the 19 and 8 (11%) of the 70 patients had a bacteriological relapse during the period of the study, that is, 22 %of patients producing one or more results had a relapse compared with 11% of patients with no such results; this difference is also not statistically significant. These rather higher relapse rates in patients with smear-positive, culture-negative results, even if they do not arise by chance, are not necessarily directly related to the occurrence of such specimens. As described above, the patients who produced these specimens had more extensive disease and larger cavities than those who did not and it will be recalled (see page 230) that patients with more extensive disease and larger cavities had a higher relapse rate than the other patients. The higher rates of relapse among the patients producing smear-positive, culture-negative results may therefore simply reflect this finding.

In summary, there was no convincing evidence that smear-positive, culture-negative results indicated the presence of living organisms in the sputum. For the purposes of this report, specimens of sputum yielding positive smears with negative cultures have therefore been regarded as negative for tubercle bacilli. VIII. THE VALUE OF THE ESR IN THE MANAGEMENT OF PATIENTS WITH CHRONIC PULMONARY TUBERCULOSIS It has already been stated that the ESR at the start oftreatment was of no prognostic value in determining whether or not the disease was likely to be bacteriologically quiescent at the end of one year, and that it was only possibly related to the likelihood oflater relapse (Section IV). An attempt was made to relate the ESR at one, two and three years in patients continuing on chemotherapy to the bacteriological status at these times. Considering first the results at one year; of the 87 patients with an ESR of 10 mm. or less, 3% had active disease compared with 5 % of the 37 with ESR Il-20mm., 10% of the 45 with ESR 21-50mm., and 22 %of the 9 patients with an ESR of 51 mm. or over. There was thus an association between the presence of a raised ESR and the presence of bacteriologically active disease. However, 5 (45%) of 11patients with active disease at one year had an ESR of 20 mm, or less (of whom 3 had an ESR of 10 mm. or less). At two years, 2 of the 8 patients with active disease had an ESR of 20 mm. or less (both had ESR's of 10 mm. or less) and at three years, 1 of the 2 patients with active disease had an ESR in this range (13 mm.). Thus, although a higher proportion of patients with raised ESR's had active disease, it was impossible to judge the disease activity reliably from the ESR for individual patients. An analysis was also performed to relate the ESR at one year in patients with g~iescent disease to subsequent bacteriological relapse. It was found that 16% of the 38 patients with an ESR of 10 mm. or less relapsed compared with 7 % ofthe 14with an ESR of 11-20 mm., 41 % of the 17 with an ESR of 21-50 mm., and 0 % of the 3 patients with an ESR of over 50 mm. Again the level of the ESR at one year was of little help in deciding on the likelihood of later relapse in individual patients. Scrutiny of the three-monthly readings of the ESR (not presented here) in the 14 patients from the one-year group who relapsed did not suggest that serial examinations were of any greater use in the prognosis of bacteriological relapse.

It may be concluded that the customary routine of performing serial ESR examinations is of little value.

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IX. DISCUSSION The present report is primarily concerned with the results of long-term chemotherapy in the treatment of chronic pulmonary tuberculosis in patients infected with organisms sensitive to isoniazid, PAS and streptomycin, and with the frequency of relapse after different durations of chemotherapy. THE EFFECTS OF AN INITIAL STREPTOMYCIN SUPPLEMENT

Although standard regimens of chemotherapy were prescribed, there were departures from them in a substantial minority (20%) of the patients. Incorporated in the study, however, were two groups of patients for whom treatment was allocated at random, one group being prescribed isoniazid plus PAS (the PH regimen) and the other isoniazid plus PAS with an initial six weeks' supplement of streptomycin (the SPH regimen). Because the two regimens differed only in the early weeks, there was no option, when comparing their effects, but to exclude some patients from each group who departed from their prescribed regimen in the first few weeks. The effects of one year's treatment have been compared in the remaining 81 PH and 70 SPH patients. In the evaluation of the results, the progress of all these patients has been assessed and none has been excluded from consideration for such reasons as a change of chemotherapy after the early weeks, or death during the course of the study. Similar complete assessments have also been made in other recent studies (Tuberculosis Chemotherapy Centre, Madras, 1959, 1960; East African/British Medical Research Council Thiacetazone/Diphenylthiourea Investigation, 1960b). The results of the comparison (see Table XXVI) reveal a significantly higher rate of unfavourable response at twelve months with the pH regimen (16 %) than with the SPH regimen (3 %). However, the incidence of drug reactions was higher in the SPH series than in the PH series, the difference being attributed to the initial streptomycin supplement which was administered daily. It should be noted that about two-thirds of the patients were over 45 years of age, an age-group which is particularly susceptible to streptomycin toxicity. Nevertheless, the extra toxicity due to streptomycin did not greatly inte rfere with the administration of the drug for the full six weeks . Of the patients originally admitted to the study, only 10% of the SPH patients had their chemotherapy changed within the early weeks because of toxicity, compared with 7 % of the PH patients. There was little difference between the two groups in the proportions of patients who relapsed bacteriologically in the second or third years, having remained on the allocated regimen throughout the first year and having stopped chemotherapy with quiescent disease at the end of one year; the rates were 22 % for the 27 PH and 18 /~ for the 17 SPH patients. However, the findings are based on small numbers. Two previous controlled comparisons of the effects of isoniazid plus PAS with those of isoniazid plus PAS plus streptomycin have been reported. In both, the drugs were all administered for a period of eight months, the streptomycin being given thrice weekly in the first (Mount & Ferebee, 1954) and daily in the second (Livings, 1959). The results of both these studies indicated little difference in the clinical efficacy of the two regimens at eight months, although in both the toxicity rate was higher with the three-drug regimen. On the other hand, the present study, comparing the effects of treatment for twelve months, has shown a superiority of this three-drug over the two-drug regimen, even though the streptomycin was administered daily for a period of only six weeks. The reason for this difference may lie in the different t ypes of case admitted to the present and to the two earlier studies. In the present study only patients with extensive disease were selected for admission, whereas the two investigations quoted were conducted on patients with, in general, less advanced disease. Indeed, Mount & Ferebee (1954) have themselves suggested that their selection of cases of recent origin may have excluded from investigation those patients for whom three drugs might be more effective. There were additional differences in the conduct of the studies. For example, nearly a quarter of the patients in one of the earlier studies (Mount & Ferebee, 1954) and a large unspecified proportion in the other (Livings, 1959) left hospital and were not

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assessed at eight months; whereas in the present study, as already mentioned, an assessment of all the patients in the comparison was made at twelve months. In addition, the criterion of bacteriological quiescence, namely, the finding of negative cultures at three consecutive monthly examinations, was more stringent in the present study. The use of all three drugs has been advised in the past (Fox and others 1957; Crofton, 1960; Thomas and others, 1960) mainly as a precaution lest the patient had been infected initially with drug-resistant organisms. The comparison of the PH and SPH regimens in the present study has shown, in patients with extensive disease and sensitive organisms, that supplementation of the PH regimen with streptomycin for an initial period increased the therapeutic efficacy. It is possible that this greater efficacy may merely reflect a superiority of a daily regimen of isoniazid plus streptomycin over isoniazid plus PAS. However, these regimens were found by the Medical Research Council (1955) to be bacteriologically similar at six months (although there was more radiographic clearing with isoniazid plus streptomycin at three months), and by Hutton and others (1956) to be bacteriologically and radiographically similar at six months; most of the patients in these studies had acute disease. Livings (1959) also found no bacteriological or radiographic advantage of isoniazid plus streptomycin over isoniazid plus PAS over an eight-month period, in patients with a wide range of disease. Nevertheless, in the absence of a direct comparison of the SPH regimen with isoniazid plus streptomycin in the present study, it would be unwise to conclude that the SPH regimen is necessarily superior to isoniazid plus streptomycin in patients with extensive cavitated disease. Although the relative merits of these various regimens have not been fully established, it is justifiable, from the present findings, to supplement the isoniazid plus PAS regimen with streptomycin, at least in the initial period of chemotherapy, for its greater efficacy in patients with extensive cavitated disease as well as for its protective effect against the possibility of infection with drugresistant organisms. THE RESULTS OF LONG-TERM CHEMOTHERAPY

The results of long-term chemotherapy have been assessed in those patients with drug-sensitive organisms admitted to the largest intake of the present study. These patients had been allocated at random to chemotherapy for one, two or three years, so that the numbers available for assessment of long-term chemotherapy diminish in the second and third years; 187 were assessed at one year, 86 at two years and 35 at three years. Of the patients originally admitted, 30 % received the two-drug regimen (isoniazid plus PAS) for the prescribed period and most of the remaining patients (52 %of the total) received the three-drug regimen (isoniazid plus PAS plus streptomycin) for an initial period, followed by isoniazid plus PAS (the initial period of streptomycin administration was six weeks or less in 35 % and from seven to twelve weeks in 17 % of the total patients). The remaining 18 % received chemotherapy for the prescribed period with various combinations of streptomycin, PAS, isoniazid and sometimes other drugs. At one year, 91 % of the patients had achieved bacteriological quiescence, at two years 86 % and at three years also 86 %. Thus, a high rate of quiescence was achieved at the end of one year with chemotherapy alone and this rate was maintained (but not improved upon) by continuation of chemotherapy for a second or a third year, with the same drugs in the great majority of patients. The proportions of patients either with bacteriologically active disease or who had died of their tuberculosis were 7 %at one year, 12 % at two years and 14 %at three years (see Table VI). In comparing the present findings with those of other studies, it must be remembered that, for the present study, cases with extensive cavitated disease were specially selected, whereas most other studies included cases of less severe extent, which might be expected to make their results more favourable. Smart & Gough (1958) treated 75 patients with streptomycin, PAS and isoniazid for at least a year. One patient died with active tuberculosis and 2 patients still had a positive sputum at the time of stopping chemotherapy (after one to three years), giving a failure rate of 4 %. The United States Public Health Service (1959) in a large-scale comparison of five regimens, found that the

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lowest failure rate was achieved by the use of daily streptomycin plus pyrazinamide for sixteen weeks, followed by isoniazid plus PAS; among an unstated number of patients with far advanced disease, 7 % were still producing positive cultures at thirty-two weeks. Russell and others (1959) treated a group of patients with daily streptomycin plus high-dosage isoniazid (16 mg.Jkg. or more) for at least ninety days followed by the high dose of isoniazid alone for a total of at least eighteen months; some of these patients also received PAS, some an initial three-weeks' course ofpyrazinamide plus cortisone and some had surgical treatment. All but 1 of the 142 who had received treatment for one year had achieved sputum conversion by the end of that time. Among the patients described by Batten and others (1960) who were treated for at least nine months with various regimens consisting of two or three of the standard drugs, there were 79 who had a positive sputum initially and who were treated with drugs alone; it is not stated how many had achieved sputum conversion at one year, but only 1 had persistently positive sputum at the end of treatment, which varied from nine to more than twenty-four months. Satisfactorily low though the failure rates just quoted may appear, it has been urged by Crofton (1958) that they are still unnecessarily high. In a series of publications (1958,1959, 1960), Crofton has claimed no failures of chemotherapy to bring about sputum conversion by one year in patients with organisms sensitive to at least two of the three standard drugs; the latest of these publications deals with 348 such patients treated over the period 1952-8 (Crofton, 1960). These results were obtained by using a number of different regimens. The initial treatment (while the patient was in hospital) was daily streptomycin plus daily isoniazid in about a quarter of the patients, and all three standard drugs in half the patients; the remaining patients received streptomycin plus PAS or isoniazid plus PAS. After discharge, patients continued chemotherapy with isoniazid plus PAS. With the use of daily streptomycin plus isoniazid, or thrice-weekly streptomycin plus isoniazid plus PAS, no failures were found at one year in 178patients whether given an initial hormone supplement or not, from the Tuberculosis Society of Scotland's investigation of prednisolone (Horne, 1960); 21 of them, however, underwent surgery before the end of the year. Thomas and others (1960) have also claimed no failures to bring about sputum conversion by one year in 530 newly diagnosed patients with organisms sensitive to at least two of the three standard drugs. All three drugs were used daily until the results of sensitivity tests were known; details of later treatment were not given. However, 5 patients died of tuberculosis within the first month of chemotherapy and were excluded from consideration. Johnston and others (1961) used streptomycin daily (either 1 g. or 0·75 g.) with isoniazid 200 mg. daily (and PAS for the first six weeks). By six months culture negativity was attained in all the 65 patients on these two regimens who had positive cultures before treatment. The incidence of vertigo was significantly lower with the use of the 0·75 g. dose of streptomycin. Reviewing all these series, it appears that a factor common to the most successful regimens is the use of streptomycin at the outset of chemotherapy, either daily if used with only one other drug (e.g. pyrazinamide-United States Public Health Service, 1959; isoniazid-Russell and others 1959), or daily Or thrice weekly when used with isoniazid plus PAS (Crofton 1960; Thomas and others, 1960; Johnston and others, 1961; and the present study). The better results obtained by Crofton, compared with the present study, may be due partly to his longer average period of administration of streptomycin, as well as to the difference in type of case. RELAPSE AFTER STOPPING CHEMOTHERAPY

Relapse in this study has been defined purely in bacteriological terms, as the appearance of at least two positive cultures in any period of four months in a patient who had previously produced negative cultures for at least three consecutive months. The appearance of an isolated positive culture has not been regarded as a bacteriological relapse (except in one instance, see page 215), nor has a finding of one or more positive smears in the absence of positive cultures. Radiographic changes, in the absence of positive cultures, have not been regarded as evidence of relapse, although a few of these were considered by an independent clinician (who reviewed them all) to warrant a

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change or re-introduction of chemotherapy and were classified as 'clinically important radiographic deteriorations' (see below). The definition of relapse adopted here is slightly more stringent than that recommended by the American Trudeau Society (1959), but is in conformity with their main recommendation that radiographic changes alone should not be regarded as relapses. The frequency of relapse after chemotherapy of different durations has been studied in two separate intakes of patients. In the smaller intake, chemotherapy was allotted at random for periods of six months, one year or two years. Eight (62 %) of the 13 patients who had 'quiescent' disease at six months (that is, had negative cultures at five and six months) and then stopped chemotherapy had a bacteriological relapse and 1 more patient showed clinically important radiographic deterioration (without bacteriological relapse) during the next two-and-a-half years of observation. None of the 11 patients who continued on chemotherapy beyond six months relapsed while on chemotherapy and only I (among the 6 patients who received chemotherapy for one year) relapsed after stopping drugs, during the same period of observation. All but 1 of the patients who relapsed had organisms sensitive to the three standard drugs; the exception relapsed with isoniazid-resistant organisms but 10 later cultures were sensitive. It may be concluded from these results that chemotherapy for a period of only six months, even when it renders the sputum negative for at least two months, is inadequate to prevent later relapse. This finding is in keeping with the results obtained by Carroll and others (1955). For the larger intake, chemotherapy was allotted at random for periods of one, two Or three years. The relapse rates for these patients have been looked at in three different ways. First, the relapse rate in the second and third years among those who stopped their chemotherapy at one year has been compared with that in those who continued chemotherapy for a second or a third year. Of the 74 patients who had bacteriologically quiescent disease at one year and then stopped chemotherapy, 10 had a bacteriological relapse in the second year and 4 more in the third year; in other words, 19% of the 74 patients relapsed in the second and third years combined. In contrast, only 3 (4 %) of the 82 patients with quiescent disease at one year who then continued chemotherapy for a second or a third year had a bacteriological relapse; 2 of them relapsed during the second year, while still on chemotherapy, and 1 patient, among the 42 who had stopped chemotherapy at two years, relapsed in the third year. It will be recalled (page 226) that more patients relapsed in the first year in the two- and three-year groups than in the one-year group. It is possible that this difference might have resulted in a reduced relapse rate in the former and an exaggerated relapse rate in the latter during the second and third years. For reasons given in the text this seems unlikely and it may therefore be accepted that there is a benefit to the patients who continued on chemotherapy. Secondly, comparison may be made of the relapse rates in the first year after stopping chemotherapy, that is, the second year for those who had received one year of chemotherapy and the third year for those who had received two years' chemotherapy. Ten (14 %) of the 74 patients with quiescent disease at the end of one year of chemotherapy had a bacteriological relapse in the first year after stopping chemotherapy compared with only 1 (2 %) of the 42 patients with quiescent disease at two years. Thus it appears that the second year of chemotherapy led to a true reduction in the relapse rate; it did not simply postpone the relapses. Thirdly, the incidence of relapse may be analysed according to the duration of bacteriological quiescence (that is, to the number of months of culture negativity) up to the time ofstopping chemotherapy. It was found that there was a considerable incidence of relapse (21 %) in 73 patients for whom chemotherapy was stopped when cultures had been negative for seven to twelve months compared with 5 % in 42 patients with periods of bacteriological quiescence of more than eighteen months when chemotherapy was stopped. There were too few patients who stopped chemotherapy after having had negative cultures for thirteen to eighteen months to allow any conclusion to be drawn about the adequacy of these periods of bacteriological quiescence in the prevention of relapse. It may be concluded that stopping chemotherapy when cultures had been negative for

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twelve months or less led to a high relapse rate; stopping chemotherapy after cultures had been negative for more than eighteen months greatly reduced the risk of relapse although it still did not prevent it completely. Turning from bacteriological relapses to clinically important radiographic deteriorations, there were 2 such deteriorations among the 74 patients who stopped chemotherapy at one year compared with 1 among the 82 patients who continued chemotherapy for a second or a third year; all 3 deteriorations occurred in the second year. It is difficult to compare the relapse rates in the present investigation with those from most other studies (Raleigh, 1957; Ross and others, 1958; Low, 1959; Batten and others, 1960), because so many different factors obtain. Thus, results have been given for patients with different types of initial disease, treated with different regimens of chemotherapy for different durations. The definitions of quiescence and the duration of chemotherapy at which quiescence has been assessed have varied from study to study. So have the durations of observation of patients after the attainment of quiescence, and the criteria of relapse. In particular, many authors have considered radiographic changes alone to be as important as bacteriological relapse. It is also difficult in many series to separate relapses occurring while the patients were still on chemotherapy from those occurring after chemotherapy had been stopped. Surgical treatment was employed in many series, both during chemotherapy and subsequently. One study, however (Devadatta and others, 1961), approximates sufficiently closely in its design to the present investigation for comparisons to be made; in particular, the criteria of relapse were similar. It differs from the present study in that the patients were on average younger and had more acute disease. Among the patients who attained quiescence at one year on treatment with isoniazid plus PAS, 10% of the 61 who stopped chemotherapy at one year relapsed in the second and third years, compared with 5 % of the 65 who continued on isoniazid alone for a second or a third year, a non-significant difference. The relapse rate among those who stopped chemotherapy at one year was higher in the present series than in that of Devadatta and others (1961) and this may be related to the type of case studied. On the other hand, the reduction in relapse rate resulting from a second or third year of chemotherapy seems to have been greater in the present series, perhaps because combined chemotherapy was used instead of isoniazid alone. 'OPEN-NEGATIVE SYNDROME'

Since the advent of chemotherapy, the persistence of cavitation in the absence of positive sputum (the 'open-negative syndrome') has frequently been noted. In the present investigation, patients with this syndrome form an important sub-group of those with quiescent disease at one year. Of the patients admitted to the relapse study 108 (70 %) still had cavitation, as judged from single posteroanterior radiographs (before treatment and at one year) by a panel of three assessors. Of these 108 patients, 15 (14 %) relapsed during the second or third year. Of the 47 patients without cavitation at one year, 2 (4 %) relapsed. The difference between these two relapse rates is not statistically significant; there is, therefore, suggestive but not conclusive evidence that relapse rates are higher in patients with residual cavitation. The effects of stopping or continuing chemotherapy have been studied in the sub-group of patients with the 'open-negative syndrome'. The relapse rate in the second and third years was 24 % for the 50 who stopped chemotherapy at one year compared with 5 %for the 58 who continued on chemotherapy for a second or a third year; the difference is significant at the 5 %level. Thus the conclusion already reached that continuance of combined chemotherapy for a second or third year will reduce the incidence of relapse applies also to patients with the 'open-negative syndrome' at one year. When the relapses among patients with the 'open-negative syndrome' were considered in relation to the duration of bacteriological quiescence before chemotherapy was stopped, it was found that 12 (24%) of the 51 patients who continued chemotherapy for seven to twelve months after attaining quiescence relapsed compared with 2 (5 %) of the 37 patients who continued chemotherapy for more

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than twelve months after attaining quiescence; these 2 patients had had quiescent disease for twenty and twenty-four months at the time chemotherapy was stopped. The difficulties of comparing relapse rates in different series apply equally to patients with the 'open-negative syndrome', as has been emphasised by the American Trudeau Society (1959). The chief difficulties lie in the different periods of bacteriological negativity required for inclusion in the category by different authors and in the different ways of defining relapse (Bell and others, 1957; Corpe & Blalock, 1958; Ross, 1959). One study, however (Velu and others, 1961) used criteria similar to those of the present study. The relapse rate in the second year among patients with the 'open-negative syndrome' at one year was 10 % for the 42 who stopped chemotherapy and 7 % for the 55 who continued chemotherapy for a second year with isoniazid alone. In other words, the use of isoniazid alone in the second year made little difference to the incidence of relapse. In the present study, in contrast, the use of combined chemotherapy in the second year reduced the relapse rate substantially. It has been claimed (Webb, Wofford, & Stauss, 1960) that surgical treatment is necessary for the treatment of the 'open-negative syndrome'. The findings in the present study suggest that good results can be obtained in this group of patients by the use of effective combined chemotherapy, but that even if the 'open-negative' state has been achieved by one year such chemotherapy must be administered for at least a further year. The relapse rate after such a period of chemotherapy is sufficiently low to raise the question whether the use of surgery, with its attendant operative mortality and post-operative complications (Mitchell & Auerbach, 1959; Webb, Wofford, & Stauss, 1960), is an acceptable alternative to long-term chemotherapy. DRUG SENSITIVITY IN PATIENTS WITH BACTERIOLOGICAL RELAPSE

It is of interest to consider the drug sensitivity of the organisms at the time of relapse. Among 24 patients who relapsed after stopping chemotherapy, 20 (83 %) had organisms sensitive to isoniazid, PAS and streptomycin, whereas only 3 (27 %) of the 11 patients who relapsed while still on chemotherapy had organisms sensitive to all three drugs, a difference significant at the 1 %level. With further chemotherapy, for the most part with at least two of the three standard drugs, 82%of those who relapsed after stopping chemotherapy achieved quiescent disease at three years, compared with 30% of those who relapsed while still on chemotherapy, a difference significant at the 5 % level. These findings on resistance and subsequent response indicate that patients who relapse during chemotherapy may have a worse prognosis, because they will usually have organisms resistant to the standard drugs, than those who relapse after chemotherapy has been stopped. For the former further chemotherapy with the standard drugs is likely to fail to render their disease quiescent; the choice for these patients lies between medical treatment with an effective combination of 'reserve' drugs and surgical treatment. In contrast, for those who relapse after stopping chemotherapy, further treatment with effective combinations of isoniazid, PAS and streptomycin is likely to control the disease. OTHER BACTERIOLOGICAL FJNDlNGS

During the course of the study there emerged a number of other bacteriological findings of interest. Isolated Positive Cultures The present investigation has confirmed the findings of other studies (Raleigh, 1957; Velu and others, 1960; Devadatta and others, 1961; Vein and others, 1961) that isolated positive cultures in patients undergoing frequent bacteriological examinations are of little clinical importance and should not be regarded as evidence of bacteriological relapse. Their occurrence during and after chemotherapy, even at quite a late stage, provides evidence that the lesions in the lung may not be sterilized even by prolonged periods of chemotherapy, in support of studies on resected material. Emergence of Isoniazid Resistance It was found in this study that the development of isoniazid resistance, at least from four months onwards, was usually an adverse prognostic sign. However, the production of only a single isoniazid-resistant culture did not lead

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to an unfavourable response to chemotherapy. Isoniazid resistance emerged much more frequently with the PH regimen than with the SPH regimen. Pers istence of Isoniazid-sensitive Organisms Other noteworthy features of the present study were the persistence of ison iazid-sensitive organisms in a few of the patients continuing on chemotherapy which contained isoniazid , and the presence of isoniazid-sensitive organi sms in the sputum of patients at the time of relapse while on such chemotherapy . Patients with persistently sensitive organisms, or relapsing with sensitive organisms, after the first six months were not found in other recent studies (Tuberculosis Chemotherapy Centre, Madras, 1959, 1960; East African/British Medical Research Council Investigations, 1960a, 1960b). Theoretically, there may have been three possible reasons for the continued production of isoniazid-sensitive strains in this study;(i) The patients may have taken their drugs irregularly. The supervision of drug-taking in the present study was less rigorous than in the other studies just cited, and urine tests were performed infrequently. The information from urine tests is therefore insufficient to determine whether irregularity in drug-taking was more common in patients with persistently sensitive organisms than in the others, but the possibility cannot be excluded. (ii) The sensitivity tests may have failed to detect especially low degrees of resistance. This is unlikely, first because isoniazid-sensitive cultures were usually found on several occasions in these patients and secondly because the criterion of resistance used in this study was strict , namely growth on 0 ·2fig./ml.'Isoniazid, (iii) The dosage of isoniazid used (200 mg. daily) may have been too low, especially for patients who metabolize isoniazid rapidly (Russell & Middlebrook, 1956). However, in another study, in which a substantial proportion of the patients were rapid inactivators of isoniazid and in which approximately the same dosage of isoniazid plus PAS was employed, persistently positive sputum with sensitive organisms did not occur during the second six months of chemotherapy (Tuberculos is Chemotherapy Centre, Madras, 1960; Selkon and others, 1961). Smear-positive, Culture-negative Results In the present study, there was a high incidence of sputum specimens which were positive on direct smear but negative on culture. No such results occurred before the start of treatment, but they made an increasing contribution to the total of patients positive on smear or on culture during the first year, particularly from four months onwards . In a small group of patients such results were found frequently and these patients had significantly more extensive disease and larger cavities initially than the remainder. Since t heir occurrence commonly coincided with the first month of the period of culture negati vity (in confirmation of the findings of Marks & Thomas, 1958) and since the patients producing such results did not relapse unduly frequently, they have been classed as bacteriologically negative results. It may be surmised that in the few patients who produced such results repeatedly, there had been an especially large bacterial population initially and that a nidus of dead or damaged bacilli remained in the lungs ; these bacilli were being sampled month after month. The same phenomenon was observed at the Tuberculosis Chemotherapy Centre (1959), although the incidence was lower than in the present study. The possibility of a carry-over of PAS from the sputum of the patient to the culture medium (Yegian, Budd & Bala, 1955; Duerr & Black, 1956) was excluded in that study (Subbaiah and others, 1960), but cannot be excluded in the present study because of the wide variety of cultural techniques used in the co-operating laboratories.

ESR The present investigation has shown that, for individual patients, the ESR is not a reliable guide to the activity of the disease as judged bacteriologically, and that neither the ESR at one year nor serial three-monthly readings subsequently were of help in presaging bacteriological relapse. It must therefore be regarded as an unsatisfactory measure of progress, a finding in keeping with that in patients in East Africa (Courdurier & Brygoo, 1947; McGregor & Deegan, 1954 ; Hutton and others, 1956) and in South India (Devadatta and others, 1961). It may be concluded that the routine of performing serial ESR examinations on patients with tuberculosis is of limited value. VALUE OF THE

ADDENDUM RELAPSES IN THE FOURTH YEAR The numbers of patients at risk of relapse in the fourth year (that is, those with bacteriologically quiescent disease at thre e years) were 47 of the one-year group, 37 of the two-year group and 27 of the three-year group. (These figures can be derived from Table XII .) All these patients had stopped chemotherapy at the appropriate time. Withdrawals From Analysis During the Fourth Year Six patients (4 one-year, 2 three-year) could not be observed for the whole of the fourth year ; all

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6 died from causes other than tuberculosis. One patient (one-year) died of bronchopneumonia in the forty-first month. Three patients died of congestive cardiac failure, secondary to cor pulmonale in 2 (lone-year, 1 three-year), in the forty-fourth and forty-seventh months, respectively, and to pulmonary infarction in 1 (one-year), in the forty-fifth month. Two patients (lone-year, 1 threeyear) died of bronchial carcinoma in the forty-first and forty-fourth months, respectively. All these 6 patients had negative sputum cultures until their death. They have been included in the analysis up to the time of their death. RESULTS

Bacteriological Relapse During the fourth year there were 2 (4 %) relapses in the one-year group, none in the two-year group and none in the three-year group. The 2 patients in the one-year group relapsed at thirtyseven and thirty-nine months, respectively. Both had had sputum negative on smear and culture since stopping chemotherapy; both relapsed with organisms sensitive to all three drugs. These 2 patients had extensive disease and cavitation initially and both had residual cavitation at one year; they had had bacteriological quiescence for eight and ten months, respectively, before stopping chemotherapy. Clinically Important Radiographic Deterioration Three patients (all one-year) showed a clinically important radiographic deterioration without bacteriological relapse. One developed a new lesion at thirty-nine months, 1 showed a spread at forty-two months, and 1 developed an empyema, also at forty-two months. CONCLUSIONS

A comparison may now be made of the cumulative relapse rates during the second, third and fourth years, for patients who had quiescent disease at one year. Of the 74 patients who stopped chemotherapy at one year, 16 (22 %) had a bacteriological relapse in the subsequent three years compared with 3 (4 %) of the 82 patients who continued chemotherapy for a second or a third year. The corresponding figures for clinically important radiographic deteriorations, in the absence of bacteriological relapse, were 5 (7 %) and 1 (1 %), respectively. Thus, the results for the fourth year strengthen the conclusion already reached that, in cases of extensive cavitated disease, one year of chemotherapy is inadequate to prevent relapse.

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APPENDIX A BACTERIOLOGICAL PROCEDURES GRADING OF SPUTUM POSITIVITY BY DIRECT SMEAR EXAMINATION

The principle was to make a smear from a homogenised sputum specimen and to compare the numbers of acidfast bacilli in this smear with the numbers in standard smears. Direct smear examinations of laryngeal swabs or gastric lavage specimens were not made for this purpose. A portion of the sputum specimen was added to a screw-capped bottle together with an equal volume of sterile saline or water. The bottle was shaken mechanically for at least one minute, or by hand for ten minutes (with the addition of a few glass beads), until the contents appeared homogeneous. A smear was then prepared by spreading a standard loopful (3 mm. external diameter) of the homogenate on an area 1 x 2 ems. on a slide. The bacteriological content of this smear was compared with two standard smears distributed by the Central Laboratory, heat-fixed but not stained. These smears were stained and examined by the routine method employed in the laboratory. Counts on the standard smears at a total magnification of x 576 indicated that smear I contained 3 '58 bacilli per field, and smear 2 contained 0·28 bacilli per field. The degree of positivity of the sputum specimen was graded as follows: Heavy -more acid-fast bacilli than in standard smear 1. Moderate-more acid-fast bacilli than in standard smear 2 but less than in standard smear 1. Scanty -less acid-fast bacilli than in standard smear 2. CULTURE OF SPECIMENS

Sputum specimens were cultured by whatever method was usually employed in the co-operating laboratory. Cultures were incubated for eight weeks at 37° C. and read once a week. The results were reported as soon as the culture became positive, or, if negative, at the end of eight weeks. The degree of positivity of cultures was recorded as follows: CG -confluent growth. IC -innumerable discrete colonies. 20/100-20-100 colonies. A number, e.g. 7, where there were less than 20 colonies. SENSITIVITY TESTS

The techniques for sensitivity tests were similar to those described for isoniazid by the Medical Research Council (1953), for PAS by Mitchison & Monk (1955) and for streptomycin by Stewart (1955). The tests were set up from the diagnostic cultures within two weeks of their becoming positive, or, if this was not possible, from a subculture within a few days of it becoming positive. The inoculum suspension was made by adding approximately 2 mg. (moist weight) of bacilli obtained as a representative sample from all parts of the growth to i-oz. screwcapped bottles containing 0·5 ml, sterile distilled water and glass beads and then shaking the bottle mechanically for one minute. Standard loopfuls (3 mm. external diameter) of this suspension containing approximately 0·01 mg. bacilli, were inoculated on to Lowenstein-Jensen medium slopes containing concentrations of the drugs set out below as well as on to a drug-free slope as a control. The standard sensitive strain H37Rv was also set up with each series of tests. The drug concentrations employed for strain H37Rv covered a serial range of two-fold dilutions above and below the minimal inhibitory concentration expected for this strain as well as a drug-free slope as a control. Drug concentrations in I,J.ff./ml.

Isoniazid: Test strain H37Rv Sodium PAS dihydrate: Test strain H37Rv Streptomycin: Test strain H37Rv

0'2,1,5,50 0'025, 0'05,0'1,0,2, 1 1,2,4,8, /6 0'25, 0'5, 1,2 8, 16, 32, 64, 1024

2, 4, 8, 16

The results Of the test were read after four weeks' incubation. The term 'growth' has been used to mean the presence of twenty or more colonies on any slope. If the control (drug-free slope) yielded one hundred or fewer colonies, the result was ignored and the test was repeated. Strain H37Rv was usually inhibited by 0'1 p..g./ml. isoniazid, by 1 I,J.g,fmI. sodium PAS dihydrate and by 8 I,J.g./ml. streptomycin. The results of PAS and streptomycin sensitivity tests were expressed as resistance ratios, namely, the minimal drug concentration inhibiting growth of the test strain divided by

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the minimal drug concentration inhibiting strain H37Rv. If growth was obtained on the slope containing 0·2 p.g./ml. isoniazid, but not on that containing I J.Lg./ml., or if the resistance ratio to PAS or streptomycin was 4, the test was repeated. DEFINITIONS OF BACTERIAL DRUG RESISTANCE

Isoniazid Resistance was defined as growth on 1 flg./ml. or a higher concentration, or growth on 0·2 flg./ml., provided that a repeat test on the same strain yielded growth on 0·2 flg.jml. or a higher concentration. If there was growth on 0·2 J.Lg.jml. and a repeat test could not be performed, the strain was termed 'doubtfully resistant'. PAS A strain was called resistant if the result of a test was either a resistance ratio of 8 or more, or a resistance ratio of 4, followed by a ratio of 4 or more in a repeat test. Streptomycin A strain was considered resistant if a resistance ratio of 8 or more was obtained, or a resistance ratio of 4, followed by a ratio of 4 or more in a repeat test.

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APPENDIX B PATIENTS WHO COULD NOT BE RETAINED IN THE ANALYSIS UNTIL THE END OF THEIR ALLOCATED PERIOD OF CHEMOTHERAPY As stated on page 210, 31 pat ients could not be retained in the analysis for the whole of the alloca ted period of chemotherapy for the following reasons:Non-tuberculous Deaths Eight patients are regarded as having died from causes other than tuberculosis while still on chemotherapy, 3 in the first six months, 1 between six and twelve months, I between twelve and eighteen months and 3 between eighteen months and two years. A woman of 27 (one-year) who had gross emphysema of both lower lobes died of congestive heart failure secondary to her lung disease at five weeks. No bacteriological examinat ions were made after the start of chemotherapy, nor was a po st-mortem examination performed. A man of 57 (two-year) died of a spontaneous pneumothorax secondary to widespread emphysematous bullae in the third month . His sputum was negative on smear and culture at one and two months; no tubercle bacilli were found in the lungs on smear or culture at post-mortem examination . Apart from some collections of epithelioid cells in the left upper lobe, there was no histological evidence of active tuberculosis. A man of 61 (one-year, SPH) died in the fifth month from Stokes-Adams attacks due to heart block . His sputum was positive on smear and culture for the first three months and was positive only on smear at four months . Tubercle bacilli were cultured from his lungs at post-mortem examination . There was histological evidence of active tuberculosis. A man of 54 (two-year, PH) died of renal failure in the tenth month. At postmortem examination, one kidney was found to be absent and the other to be infiltrated with amyloid. H is sputum had been positive on culture up to four months and negative on smear and culture at five and six months. The last available sputum examin ation, at seven months, yielded a negat ive smear but a positive culture. At post-mortem examination, very scanty tubercle bacilli were seen in three of the nine sites. None of these specimens was positive on culture. Histologically , the lesions in the lungs were mostly inactive or healed. During the second year , there were 4 more deaths in pat ients continuing with chemotherapy. A man of 61 (three-year) died ofa cerebral haemorrhage in the fourteenth month. His sputum had been negat ive on smear and culture from one month onward s. At post-mortem examinat ion, fibrosis of the lungs was found ; no detailed histological or bacteriological examinations weremade. A man of 46 (three-year) died in the nineteenth month. His sputum had been negative on smear and culture from three months onwards. The cause of death was found at post-mortem examination to be an alveolar-cell carci noma of the lung with a metastasis in the frontal lobe of the brain; no tubercle bacilli were found on smear or culture. A man of 37 (two-year) collapsed and died suddenly in the twentieth month having had a myocardial infarct. His sputum had been negative on smear and culture from two months onwards; no post-mortem was performed. A man of 52 (three-year) died in the twenty-fourth month from influenzal bronchopneumonia. His sputum was negative on smear and culture from three months onwards. No tubercle bacilli were cultured on post-mortem examination. Histologically, the appearances were those of healing tuberculosis. In summary, there was evidence of activity of the tuberculous process at the time of death in only 3 of these 8 patients, namely, in those who died in the second, fifth and tenth months, respectively. However, in these 3 patients, tuberculosis was not the principal cause of death and the patients are not included in the analysis after their death. Non-tuberculous Disease Two patients developed non-tuberculous diseases and could not be retained in the analysis for the full period . One (one-year) developed obstructive jaundice secondary to carcinoma of the pancreas . His chemotherapy was stopped at six months; he had had negative cultures from one month onwards . One patient (three-year) developed a bronchial carcinoma, later confirmed a t autopsy, which first became clearly visible on the radiograph at six months and thereafter interfered with the assessment of the progress of his tuberculosis; thi s patie nt had negative cultures from four months onwards. Premature Stopping of Chemoth erapy In add ition to the pat ient with obstr uctive jaundice described above, there were 5 more pa t ients whose chemother apy was stopped before the end of the allocated period . Three patients (all three-year) stopp ed chemotherapy of their own accord at fifteen months because of symptoms which they attributed to the medication. Two of these pat ients had bacteriolog ically quiescent disease, their sputum having been negative on culture from two and four months, respectively. The third patient had negative cultures from two to five months but relapsed bacteriologically at six months ; his disease was still active when he stopped chemotherapy. One pat ient (two-year) had bacteriologically active disease for the first nine months, at which time the regimen was changed to streptomycin plus cycloserine because of the development of ison iazid-resistant bacilli. His sputum became

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negative on culture at ten months and remained so, but the patient developed vertigo from the streptomycin and chemotherapy was discontinued by the physician at fifteen months. In 1 patient (three-year), chemotherapy was stopped in error by the clinician at two years. The patient had had negative cultures from three months onwards. Inadequate Chemotherapy One patient (one-year) was withdrawn from the study at four months because after this time he only took half the prescribed dosage of isoniazid plus PAS. Excessive Interruptions of Chemotherapy Nine patients (4 one-year, 2 two-year, 3 three-year) were withdrawn from the study after varying lengths of time because they had interrupted chemotherapy for longer than the permitted periods (for definition see page 209). In 7 of these patients, the interruption was a direct result of drug toxicity. One patient who had previously undergone a gastrectomy and still had a residual stomal ulcer was unable to tolerate PAS after ten weeks. For the next forty-two weeks he received intermittent streptomycin with daily isoniazid. The other 6 patients suffered interruptions of chemotherapy for more than six weeks in the first year (for seven, eight, ten, eleven, twenty-five and thirty-two weeks respectively). One of these 6 patients (who had an interruption of eleven weeks) also received intermittent streptomycin with daily isoniazid for ten weeks in the first nine months. The 6 patients had hypersensitivity reactions to PAS (5 cases) or streptomycin (1 case)-see Table VII. The interruptions all occurred early in the course of chemotherapy, 2 at two weeks, 2 at four weeks, and 2 at five weeks. Two patients (1 two-year, 1 three-year) had interruptions of chemotherapy in the second year. In 1 patient (twoyear) chemotherapy had been discontinued in error by the clinician at twelve months and was not resumed until four months later; this patient had negative cultures from two months onwards. The other patient stopped chemotherapy of his own accord for a period of five months in the second year. He had had negative cultures from four months onwards. Self-discharge Three patients discharged themselves from supervision before the end of the allocated period of chemotherapy. One patient (one-year) stopped attending the clinic after ten months. She had had negative cultures at four, five and six months but had been irregular both in taking her chemotherapy and in attending for examination thereafter. No bacteriological results are available for the four months before she discharged herself. One patient (two-year) stopped attending the clinic at nine months. He first produced a negative culture at four months, and failed to give any sputum specimens until nine months, when the culture was again negative. One patient (two-year) did not attend the clinic after eighteen months. His sputum had been negative on smear and culture from six months. Surgery

Surgical measures were employed in 3 patients (2 one-year, 1 three-year). One (one-year), a man of 48, had negative cultures from six months; a left upper lobectomy was performed during the ninth month. Another (one-year), a woman of 25, had negative cultures from five months. Radiographic deterioration, confirmed by the radiographic assessor but not associated with bacteriological relapse, occurred at nine months; a left pneumonectomy was performed during the eleventh month. The third patient (three-year), a man of 66, had persistently positive sputum throughout the first six months and isoniazid-resistant bacilli emerged. The regimen was changed in the sixth month, from isoniazid plus PAS to streptomycin plus tetracycline; a left thoracoplasty was undertaken during the ninth month. Thus, during the period of chemotherapy, 31 patients no longer contributed to the analysis for the various reasons stated above. Eleven were withdrawn before six months, 8 between six and twelve months, 7 between twelve and eighteen months, 4 between eighteen months and two years and 1 more between twenty-four and thirty months. All these patients have been included in the analysis until the various events occurred which led to their withdrawal.

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ACKNOWLEDGEMENTS

The centres and doctors co-operating in the study reported here are as follows: Clinicians Drs. V. Cotton Cornwall, W. D. Gray and the late Dr. O. F. Thomas. Aintree Drs. T. M. Wilson and L. Doyle. Baguley Drs. G. J. Summers and J. H. Rolland Ramsay. Bangour Barrow-in-Furness Drs. J. R. Edge and J. C. P. Weber. Drs. N. Wynn-Williams, R. D. Young and J. H. Baylis. Bedford Drs. J. Morrison Smith, G. R. W. N. Luntz, R. J. Austin and M. H. Birmingham: Romsley Hill Hospital Zirko Drs. D. Forbes, H. E. Thomas, M. Hemming and D. C. Waddy. West Heath Hospital Drs. V. H. Springett, H. J. T. Ross, L. F. Dale, T. B. D'Costa and Yardley Green Hospital E. Shieff. Dr. J. Mitchell. Bolton Bradford Dr. D. K. Stevenson. Drs. A. T. M. Roberts and D. T. Davies. Bristol Drs. J. L. Armour, F. R. Glover and F. Husain. Bury Cambridge Drs. M. J. Greenberg and R. A. Bruce. Drs. O. Clarke and N. F. Crofts. Canterbury Drs. S. H. Graham, H. A. Evans and M. E. H. Jones. Cardiff Carshalton Drs. H. J. Partington and J. Berry. Drs. J. K. Scott, J. Viner and T. Marmion. Dews bury Drs. A. W. B. MacDonald, R. J. Posner and M. Sheldon. Dudley Drs. C. Clayson, B. R. Hillis and J. A. Cameron. Dumfries Drs. R. N. Johnston, D. H. Smith, W. Lockhart and R. T. Ritchie. Dundee Ealing Drs. H. Climie and G. Beven. East Fortune Dr. R. Donaldson. Edinburgh Dr. H. M. MacLeod. Edmonton Drs. V. Davies and R. S. Francis. Epping Dr. V. U. Lutwyche. Drs. S. D. Bowlands and E. L. Feinman. Gateshead Glasgow: Central Tuberculosis Department Dr. J. E. Geddes, G. B. Marshall Clarke, G. Johnston, and S. W. Wimsett. Drs. A. W. Lees, W. F. Tyrrell, J. Smith and G. W. Allan. Ruchill Hospital Gloucester Drs. F. J. D. Knights, R. H. Ellis and J. B. W. Hayward. Halifax Dr. B. Mann. Dr. A. W. Anderson. Hastings Drs. D. van Zwanenberg and M. Barry. Ipswich Islington Drs. J. Wallace Craig and H. O. Williams. Kidderrninster Dr. R. C. Cronin. Drs. P. G. Arblaster, R. Davies and L. E. Burkeman. Leamington Spa Drs. G. F. Edwards. H. A. Grunwald and D. A. Herd. Leeds Drs. J. B. Shaw, M. A. Erooga and D. Langford. Luton Drs. W. Robinson and F. W. A. Turnbull. Manchester Newcastle-upon-Tyne Dr. G. Hurrell. Newport Dr. M. 1. Jackson. Drs. E. L. Brown, A. H. C. Couch and P. H. Sutton. Norwich Paddington and Kensington Drs. J. A. Keeping, P. A. Zorab and Z. M. Hall. Plymouth Drs. J. J. Y. Dawson, J. C. Mellor and G. Sheers. Drs. J. Glyn Cox and T. Walker. Pontypridd Drs. J. H. Dadds and N. Landau. Portsmouth Southend Drs. E. G. Sita Lumsden, J. D. Stevens and M. A. Pasha. Stepney Dr. R. M. Orpwood. Stockport Drs. E. R. Smith and L. D. Walker. Sunderland Drs. A. B. White and D. M. Calvert. Dr. H. F. Harwood. Sutton Drs. T. W. Davies and G. Ll. Lewis. Swansea Tottenham Drs. T. A. C. MCQuiston, J. H. Pratt-Johnson and R. H. S. Hirst. Uxbridge Drs. J. T. Nicol Roe, H. R. C. Riches and S. L. O. Jackson. Drs. D. J. Leahy and J. N. Macartney. Walsall Drs. D. J. Lawless, R. Shoulman and G. Hanson. West Ham

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Dr. C. H. C. Toussaint. Dr. F . J. H. Walters. Drs . E. N. Moyes and S. Z. Kalinowski.

Bacteriolog ists and Pathologists Mr. D . Allan Dr. C. H . JeJlard Dr. J. M. Alston Dr. J. C. Kerrin Dr. R. D . Andrews Dr . W. F . Lane Dr. E. H. Bailey Dr. K. V. Lodge Dr. D. F . Barrowcliff Dr. G. B. Ludlam Dr. A. Beck Dr. A. McFarlane Dr. D. Bottrill Dr. P. G. Mann Dr. L. G. Bruce Dr. G . Manning Dr. H . R . Cayton Dr. J. Marks Dr. D. M. H. Cogman Dr. N. A. H . Marston Dr. P. B. Crane Dr. P. H. Martin Dr. J. L. Dale Dr. A. 1. Messer Dr. E. E. Davies Dr. E. Nassau Dr. J. M. S. Dixon Dr. R . N orton Dr. L. M . Dowsett Prof. W. J. O'Donovan Dr. J. M . Dunbar Dr. W. M. A. Picton Dr. Joan M. B. Edwards Dr. R . D. Popham Dr. R. M. Fry Dr. 1. A. Purdie Dr. G. B. Forbes Dr . K. Rafinski Dr. R. A. Garson Dr. J . A. Rycroft Dr. W. J. Godden Dr . B. R. Sandiford Dr. T. E. W. Goodier Dr . N . Schuster Dr. E. G . Gordon Dr. D. A. Skan Dr. W. 1. Gordon Dr. H. G . Smith Dr. J. H. Hale Dr. 1. M. Tuck Dr. J. F . Heggie Dr. A. T. Wallace Dr. R. J. Henderson Dr . F. Whitwell Dr. M. A. Wilson D r. D. Hewspear Dr. H. D . Holt Dr. A. R. H. Worssam Dr. Lynne Reid performed histological and bacteriologic al examina tions on specimens of lung tissue obtained at surgery or from post-mortem material. The above cannot be a comprehensive list of all the doctor s who have contributed to the results reported here, nor has it been possible to name the many laboratory technicians who have done detailed and valuable work. The Tuberculosis Chemotherapy Trials Committee expresses its thanks to all members of hospital staffs who have assisted in the investigation, particularly for the ir willing response to the urgent requests for information for inclusion in this report. Finally, the Committee thanks the secretarial staff of the Tuberculosis Research Unit for their unst inting efforts and the contributions they have made to the smooth running of the trial.

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