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Practical chemotherapy
Tubercle, Lond., (1961), 42, 371
LEADING ARTICLES PRACTICAL CHEMOTHERAPY We know much about the efficiency of anti-tuberculosis drugs. We know little about how to persuade patients to take them. During the early investigation and use of the drugs it seems to have been assumed that patients always do what is advised by their physicians; and failure of chemotherapy was, and still is, more commonly ascribed to inadequacy of the drugs than to inadequacy ofthe patients and the physicians. The more critical approach to practical chemotherapy appears to have originated in Great Britain. Simple urine tests for PAS showed that a high proportion of patients had not taken their doses as prescribed. Enquiry into the causes of failure emphasized the importance of regular self-medication; and it became generally accepted that it was insufficient for the physician merely to advise and prescribe. This realization of the frailty of human nature in such a long-continued process as the treatment of tuberculosis can be seen in the planning of some recent clinical trials. For instance, in the classic investigations in Madras-the most important studies so far done in the history of tuberculosis chemotherapy-considerable attention was given to the problems not only of checking whether the drugs were taken, but also of finding ways of helping the patients to take them (Fox, 1958). The results of treatment of these poor and ill-fed patients in overcrowded homes should now be well-known; the initial demonstration of the lack of superiority of sanatorium over good home treatment (Tuberculosis Chemotherapy Centre, Madras, 1959), the almost equal and surprisingly small risk to close contacts in the two groups (Ramakrishnan and others, 1961), the lack of superiority of the sanatorium patients in regularity of self-administration of drugs after returning home and in freedom from relapse (Devadatta and others, 1961), and the relatively good results of treating the few initial failures with another drug combination (Velu and others, 1961). The principles of successful chemotherapy have been firmly established, though, unfortunately, they are still not generally accepted or acted upon. The practice of chemotherapy is, however, still in its infancy. Excellent results have been reported in co-operative patients in the fortunate countries with highly developed and organized medical, nursing and social services, as, for instance, those obtained in Birmingham (Thomas and others, 1960) and Edinburgh (Ross and others, 1958). But such practice is at present quite impossible in the great majority of countries. The problem of applying the principles in the local environment has only just begun to be systematicallystudied. One recent report in this journal (Gordon, 1961)may perhaps mark the change from attempts to adapt the practice of chemotherapy to local circumstances to attempts to adapt the local circumstances to the principles. Gordon, working in Tanganyika, devised a home treatment scheme, the aim of which was stated simply as 'to ensure that patients could not be "lost" and were regular in taking their medicines'. Treatment at home was conceived of as an extension of hospital treatment in the home environment, with the patient still subjected to normal 'hospital' discipline. All new patients with pulmonary tuberculosis were admitted to hospital, but they were kept there for only 2 weeks in the mildest cases and 3 months in most severe. They were treated with 19. of streptomycin and 300mg. isoniazid daily, some of them receiving PAS in addition. When they were discharged to their homes they were given a week's supply of PAS and isoniazid. At weekly intervals they attended dispensaries staffed by tuberculosis home visitors, or were visited in their homes by them. This system of treatment is, of course, widely used and by itself would not justify a report. The novelty in the Tanganyika experience lies in the adoption of existing medical facilities and of the social structure and customs to control treatment with 'hospital' discipline in the home environment. Thus, the tuberculosis health visitors were based on existing rural general dispensaries and arrangements were made that no patient had to walk more than 5 miles to where he could meet the health visitor and renew his stock of medicines without charge. Each week the urine was tested for
372
TUBERCLE
PAS and if it was negative the patient was sternly warned. But if a second negative test was recorded he was taken to the local chief for summary admonition; and if persistently negative he was returned to hospital. The results of the control scheme were remarkably good. Of 100 patients first admitted to hospital in ]957, only 2 were lost sight of during the next 3 years. Three died. All but one of the remaining 95 had sputum negative on smear examination. Such results can hardly be bettered in countries with elaborate control measures and abundant staff. Yet the territory concerned had poor communications, many of its people were undernourished, and the staff dealing with the population of 800,000 consisted of one medical officer, one nurs ing sister, two medical assistants and a few nursing orderlies. The conditions in Tanganyika may be especially favourable for such a scheme of control. The Government, for instance, provides all treatment of t uberculosis free of charge, which is a large economic burden on a country with little heavy industry. The commun ications, though poor , may be far better than in many other under-developed countries, and the population less migratory . From other parts of tropical and sub-tropical Africa there have been reports of less than half the patients continuing to attend hospitals and dispensaries ; and Bell, Brown and Hom (1961) recently recorded 60 % loss over ]2 months in a series of ] 59 patients treated in Ghana. It seems to be accepted that such high losses are unavoidable. But, in Tanganyika the losses were similarly high before the control scheme was introduced. It appears likely that th e failure of patients to continue taking their drugs may, to a slight extent, arise from intolerance of or distaste for PAS. This is a factor in all countries ; though its importance varies between different countries and even between different physicians in the same country. Its effect may have been exaggerated. PAS is, however, also an expensive drug ; and a cheap, effective substitute for it would be welcome, The recent report of the East African/Brit ish Medical Research Council trials of thiacetazone with isoniazid suggests that such a substitute may have been discovered or rediscovered, for the thiosemicarbazones were introduced as long ago as 1946 and almost entirely abandoned in most countries after reports of excessive toxicity. If these results are confirmed by further study, one cause of irregular self-medication may have been removed. But it is doubtful whether patients will continue regularly to take drugs even though they have no unpleasant effects at all, unless they are helped and disciplined to do so. Even a small, pleasantly flavoured tablet to be taken once a day can be forgotten. Much more enquir y is needed into the reasons for missing doses or stopping treatment and into ways in which existing patterns of behaviour can be used to achieve regularity of such an abnormal activity as self-medication. Planned, controlled clinical trials in tuberculosis began in hospitals. In the last few years techniques have been extended to out-patient studies, largely because of the difficulties of keeping in hospital long enough for the full assessment of drug regimens. It might be considered a secondbest imposed by necessity, except when out-patient and in-patient treatment are being compared, as in the Madras study. But, as out-patient treatment will continue to be the more extensively used-and in some countries is the only possible treatment-deliberate comparative investigation of different regimens of out-patient chemotherapy are required. The design of an experiment is determined by the question it is desired to answer. Thus, if the question concerns the efficiency of a new drug, the experiment will be designed so that all variables are reduced to a minimum in the groups compared, the only remaining one being the drugs under examination. In this case it is desirable to have the patients in hosp ital, so that the actual administration of the drug in the prescribed dose can be assured. On the other hand, the question may concern practical aspects of chemotherapy, such as, for instance, whether one combination of drugs and dosage gives better results than another when administered in the conditions that exist in a particular country. It is required to know whether one prescribed regimen is in practice better than another, not whether one drug combination actually taken by the patients is better. There is a great need and scope for more research on practical chemotherapy. The tools for effective treatment of tuberculosis are available : we must learn how to use them.
373
LEADING ARTICLES REFERENCES
BELL, W. J., BROWN, P. P., and HORN, D. W. (1961). Tubercle, Lond., 42, 159. DEVADATTA, S., ANDREWS, R. H., ANGEL, J. H., BHATIA, A. L., Fox, W., JANARDHANAM, B., RADHAKRISHNA, S., RAMAKRISHNAN, C. V., SUBBAIAH, T. V., and VELU, S. (1961). Bull. WId. Hlth. Org, 24, 149. EAsT AFRICAN/BRITISH MEDICAL RESEARCH COUNCIL, THIACETAZONE/DIPHENYTHIOUREA INVESTIGATION. (1960).
Tubercle, Lond., 41, 399. Fox, W., (1958). Tubercle, Lond., 39, 269. GORDON, C. G. I., (1961). Tubercle, Lond., 42, 148. RAMAKRISHNAN, C. V., ANDREWS, R. H., DEVADATTA, S., Fox, W., RADHAKRISHNA, S., SOMASUNDARAM, P. R., and VEW, S., (1961). Bull. WId. Hlth. Org., 24,129. Ross, J. D., HORNE, N. W., GRANT, 1. W. B., and CROFTON, J. W., (1958). Brit. med. J., i, 237. THOMAS, H. E., FORBES, D. E. P., LUNTZ, G. R. W. N., Ross, H. J. T., MORRISON SMITH, J., and SPRINGETT, V,
H., (1960). Lancet, ii, 1185. TUBERCULOSIS CHEMOTHERAPY CENTRE, MADRAS. (1959).
Bull. WId. Hlth. Org., 21, 51 (abstracted in Tubercle, Lond.,
1959, 40, 468). YELU, S., ANDREWS, R. H., ANGEL, J. H., DEVADATTA, S., Fox, W., JACOB, G. KRISHNAN, C. V. (1961). Tubercle, Lond., 42, 136.
J.,
NARAYANAN NAIR, C., and RAMA-
CLINICAL TRIALS The activities of the Clinical Trials Sub-Committee of the Research Committee of the British Tuberculosis Association are briefly mentioned on page 384 of this number. The purpose of this Sub-Committee may not be widely known among the members of the Association and others. It was formed to try to provide a service for pharmaceutical firms in the organization and conduct of clinical trials of their products. Drugs are still being marketed without adequate clinical assessment; and this is by no means always the fault of the manufacturers, who have to rely on the clinicians themselves to do the investigations. The work of the sub-committee is to some extent advisory and therefore unpublished. Not all the requests received from pharmaceutical firms lead to clinical trials; the pharmacological and clinical evidence presented may be insufficient to justify further study. The sub-committee has adopted high standards of assessment. This is essential. There is already far too much inefficient clinical study of drugs, presented as scientific investigation and misleading to both the manufacturers and the clinicians. Information about the drugs presented to or under test by the Clinical Trials Sub-Committee can be obtained by writing to the Chairman, Dr. R. W. Riddell, Brompton Hospital, London. There is no doubt that the sub-committee can provide a valuable service if it is used. This value could be increased if members of the Association, when asked to use new drugs in the treatment of chest conditions, would enquire from the representative of the firm whether clinical assessment of the drug has been referred to the Research Committeee of the British Tuberculosis Association.
LEADING ARTICLES PRACTICAL CHEMOTHERAPY We know much about the efficiency of anti-tuberculosis drugs. We know little about how to persuade patients to take them. During the early investigation and use of the drugs it seems to have been assumed that patients always do what is advised by their physicians; and failure of chemotherapy was, and still is, more commonly ascribed to inadequacy of the drugs than to inadequacy ofthe patients and the physicians. The more critical approach to practical chemotherapy appears to have originated in Great Britain. Simple urine tests for PAS showed that a high proportion of patients had not taken their doses as prescribed. Enquiry into the causes of failure emphasized the importance of regular self-medication; and it became generally accepted that it was insufficient for the physician merely to advise and prescribe. This realization of the frailty of human nature in such a long-continued process as the treatment of tuberculosis can be seen in the planning of some recent clinical trials. For instance, in the classic investigations in Madras-the most important studies so far done in the history of tuberculosis chemotherapy-considerable attention was given to the problems not only of checking whether the drugs were taken, but also of finding ways of helping the patients to take them (Fox, 1958). The results of treatment of these poor and ill-fed patients in overcrowded homes should now be well-known; the initial demonstration of the lack of superiority of sanatorium over good home treatment (Tuberculosis Chemotherapy Centre, Madras, 1959), the almost equal and surprisingly small risk to close contacts in the two groups (Ramakrishnan and others, 1961), the lack of superiority of the sanatorium patients in regularity of self-administration of drugs after returning home and in freedom from relapse (Devadatta and others, 1961), and the relatively good results of treating the few initial failures with another drug combination (Velu and others, 1961). The principles of successful chemotherapy have been firmly established, though, unfortunately, they are still not generally accepted or acted upon. The practice of chemotherapy is, however, still in its infancy. Excellent results have been reported in co-operative patients in the fortunate countries with highly developed and organized medical, nursing and social services, as, for instance, those obtained in Birmingham (Thomas and others, 1960) and Edinburgh (Ross and others, 1958). But such practice is at present quite impossible in the great majority of countries. The problem of applying the principles in the local environment has only just begun to be systematicallystudied. One recent report in this journal (Gordon, 1961)may perhaps mark the change from attempts to adapt the practice of chemotherapy to local circumstances to attempts to adapt the local circumstances to the principles. Gordon, working in Tanganyika, devised a home treatment scheme, the aim of which was stated simply as 'to ensure that patients could not be "lost" and were regular in taking their medicines'. Treatment at home was conceived of as an extension of hospital treatment in the home environment, with the patient still subjected to normal 'hospital' discipline. All new patients with pulmonary tuberculosis were admitted to hospital, but they were kept there for only 2 weeks in the mildest cases and 3 months in most severe. They were treated with 19. of streptomycin and 300mg. isoniazid daily, some of them receiving PAS in addition. When they were discharged to their homes they were given a week's supply of PAS and isoniazid. At weekly intervals they attended dispensaries staffed by tuberculosis home visitors, or were visited in their homes by them. This system of treatment is, of course, widely used and by itself would not justify a report. The novelty in the Tanganyika experience lies in the adoption of existing medical facilities and of the social structure and customs to control treatment with 'hospital' discipline in the home environment. Thus, the tuberculosis health visitors were based on existing rural general dispensaries and arrangements were made that no patient had to walk more than 5 miles to where he could meet the health visitor and renew his stock of medicines without charge. Each week the urine was tested for
372
TUBERCLE
PAS and if it was negative the patient was sternly warned. But if a second negative test was recorded he was taken to the local chief for summary admonition; and if persistently negative he was returned to hospital. The results of the control scheme were remarkably good. Of 100 patients first admitted to hospital in ]957, only 2 were lost sight of during the next 3 years. Three died. All but one of the remaining 95 had sputum negative on smear examination. Such results can hardly be bettered in countries with elaborate control measures and abundant staff. Yet the territory concerned had poor communications, many of its people were undernourished, and the staff dealing with the population of 800,000 consisted of one medical officer, one nurs ing sister, two medical assistants and a few nursing orderlies. The conditions in Tanganyika may be especially favourable for such a scheme of control. The Government, for instance, provides all treatment of t uberculosis free of charge, which is a large economic burden on a country with little heavy industry. The commun ications, though poor , may be far better than in many other under-developed countries, and the population less migratory . From other parts of tropical and sub-tropical Africa there have been reports of less than half the patients continuing to attend hospitals and dispensaries ; and Bell, Brown and Hom (1961) recently recorded 60 % loss over ]2 months in a series of ] 59 patients treated in Ghana. It seems to be accepted that such high losses are unavoidable. But, in Tanganyika the losses were similarly high before the control scheme was introduced. It appears likely that th e failure of patients to continue taking their drugs may, to a slight extent, arise from intolerance of or distaste for PAS. This is a factor in all countries ; though its importance varies between different countries and even between different physicians in the same country. Its effect may have been exaggerated. PAS is, however, also an expensive drug ; and a cheap, effective substitute for it would be welcome, The recent report of the East African/Brit ish Medical Research Council trials of thiacetazone with isoniazid suggests that such a substitute may have been discovered or rediscovered, for the thiosemicarbazones were introduced as long ago as 1946 and almost entirely abandoned in most countries after reports of excessive toxicity. If these results are confirmed by further study, one cause of irregular self-medication may have been removed. But it is doubtful whether patients will continue regularly to take drugs even though they have no unpleasant effects at all, unless they are helped and disciplined to do so. Even a small, pleasantly flavoured tablet to be taken once a day can be forgotten. Much more enquir y is needed into the reasons for missing doses or stopping treatment and into ways in which existing patterns of behaviour can be used to achieve regularity of such an abnormal activity as self-medication. Planned, controlled clinical trials in tuberculosis began in hospitals. In the last few years techniques have been extended to out-patient studies, largely because of the difficulties of keeping in hospital long enough for the full assessment of drug regimens. It might be considered a secondbest imposed by necessity, except when out-patient and in-patient treatment are being compared, as in the Madras study. But, as out-patient treatment will continue to be the more extensively used-and in some countries is the only possible treatment-deliberate comparative investigation of different regimens of out-patient chemotherapy are required. The design of an experiment is determined by the question it is desired to answer. Thus, if the question concerns the efficiency of a new drug, the experiment will be designed so that all variables are reduced to a minimum in the groups compared, the only remaining one being the drugs under examination. In this case it is desirable to have the patients in hosp ital, so that the actual administration of the drug in the prescribed dose can be assured. On the other hand, the question may concern practical aspects of chemotherapy, such as, for instance, whether one combination of drugs and dosage gives better results than another when administered in the conditions that exist in a particular country. It is required to know whether one prescribed regimen is in practice better than another, not whether one drug combination actually taken by the patients is better. There is a great need and scope for more research on practical chemotherapy. The tools for effective treatment of tuberculosis are available : we must learn how to use them.
373
LEADING ARTICLES REFERENCES
BELL, W. J., BROWN, P. P., and HORN, D. W. (1961). Tubercle, Lond., 42, 159. DEVADATTA, S., ANDREWS, R. H., ANGEL, J. H., BHATIA, A. L., Fox, W., JANARDHANAM, B., RADHAKRISHNA, S., RAMAKRISHNAN, C. V., SUBBAIAH, T. V., and VELU, S. (1961). Bull. WId. Hlth. Org, 24, 149. EAsT AFRICAN/BRITISH MEDICAL RESEARCH COUNCIL, THIACETAZONE/DIPHENYTHIOUREA INVESTIGATION. (1960).
Tubercle, Lond., 41, 399. Fox, W., (1958). Tubercle, Lond., 39, 269. GORDON, C. G. I., (1961). Tubercle, Lond., 42, 148. RAMAKRISHNAN, C. V., ANDREWS, R. H., DEVADATTA, S., Fox, W., RADHAKRISHNA, S., SOMASUNDARAM, P. R., and VEW, S., (1961). Bull. WId. Hlth. Org., 24,129. Ross, J. D., HORNE, N. W., GRANT, 1. W. B., and CROFTON, J. W., (1958). Brit. med. J., i, 237. THOMAS, H. E., FORBES, D. E. P., LUNTZ, G. R. W. N., Ross, H. J. T., MORRISON SMITH, J., and SPRINGETT, V,
H., (1960). Lancet, ii, 1185. TUBERCULOSIS CHEMOTHERAPY CENTRE, MADRAS. (1959).
Bull. WId. Hlth. Org., 21, 51 (abstracted in Tubercle, Lond.,
1959, 40, 468). YELU, S., ANDREWS, R. H., ANGEL, J. H., DEVADATTA, S., Fox, W., JACOB, G. KRISHNAN, C. V. (1961). Tubercle, Lond., 42, 136.
J.,
NARAYANAN NAIR, C., and RAMA-
CLINICAL TRIALS The activities of the Clinical Trials Sub-Committee of the Research Committee of the British Tuberculosis Association are briefly mentioned on page 384 of this number. The purpose of this Sub-Committee may not be widely known among the members of the Association and others. It was formed to try to provide a service for pharmaceutical firms in the organization and conduct of clinical trials of their products. Drugs are still being marketed without adequate clinical assessment; and this is by no means always the fault of the manufacturers, who have to rely on the clinicians themselves to do the investigations. The work of the sub-committee is to some extent advisory and therefore unpublished. Not all the requests received from pharmaceutical firms lead to clinical trials; the pharmacological and clinical evidence presented may be insufficient to justify further study. The sub-committee has adopted high standards of assessment. This is essential. There is already far too much inefficient clinical study of drugs, presented as scientific investigation and misleading to both the manufacturers and the clinicians. Information about the drugs presented to or under test by the Clinical Trials Sub-Committee can be obtained by writing to the Chairman, Dr. R. W. Riddell, Brompton Hospital, London. There is no doubt that the sub-committee can provide a valuable service if it is used. This value could be increased if members of the Association, when asked to use new drugs in the treatment of chest conditions, would enquire from the representative of the firm whether clinical assessment of the drug has been referred to the Research Committeee of the British Tuberculosis Association.