- Email: [email protected]
PROSTAGLANDINS
874
Letters
to
the Editor
SCREENING FOR BREAST AND GYNÆCOLOGICAL LESIONS SIR,-I fully agree with the approach of Dr. Stark and Mr. Way (Aug. 22, p. 407) to the detection of early mammary cancer. The encouragement you offer in your accompanying editorial (p. 404) is greatly appreciated by many of us. I must, however, take exception to your editorial implication that the real value of exfoliative cytology remains uncertain. The verdict of Knox1 that it is " not proven " is even less accurate today than it was in 1966. It is to be hoped that the evidence gathered in the mass population screening for cervix cancer in Louisville, Kentuckywill give impetus to greater mass efforts to the control of this disease. Between 1956 and 1968, 752,688 cytological screenings were performed on the female population 20 years old and Over 90% of over (average population at risk, 201,227). that age-group (including the population with lowest socioeconomic status) were screened one or more times. The age-adjusted incidence-rate for invasive squamous cancer decreased 38%. The decrease for those under 50 years was 43-2%. The proportion of cases in the in-situ stage increased over sixfold. Stage-i cases increased from 31-9% to
2. 3.
4. 5. 6.
Knox, E. G. in Problems and Progress in Medical Care (edited by G. McLachlan); p. 277. London, 1966. Christopherson, W. M., Mendez, W., Ahuja, E. M., Lundin, F. E., Jr., Parker, J. E. Cancer, N.Y. 1970, 26, 29. Christopherson, W. M., Parker, J. E., Mendez, W. M., Lundin, F. E., Jr. ibid. (in the press). Lundin, F. E., Jr., Christopherson, W. M., Mendez, W. M., Parker, J. E. J. natn. Cancer Inst. 1965, 35, 1015. Christopherson, W. M., Parker, J. E. Cancer, N. Y. 1960, 13, 711. Christopherson, W. M., Parker, J. E. New Engl. J. Med. 1965, 273, 235.
7. 8.
Department of Pathology, of Louisville School of Medicine,
University
Louisville, Kentucky.
Christopherson, W. M., Parker, J. E. Cancer, N. Y. 1969, 24, 64. Christopherson, W. M., Parker, J. E. Ca—A Cancer J. for Clinicians, 1969, 19, 107.
WILLIAM M. CHRISTOPHERSON.
PROSTAGLANDINS
56.9%.
A further report shows a highly significant decrease in death-rates from cervix cancer in Louisville,3where the mass-screening experiment was conducted, whereas there was no decrease in the remainder of the State, where no such effort was attempted. These results, in our opinion, make it both " realistic and necessary " to screen the female population 20 years old and older, rather than just those 25 to 50 years of age. Your editorial raises the further question of whether we should concentrate only on the high-risk groups. The answer has to be a qualified no, based on the above data. No-one has yet put a price on the life of a woman; and in view of this, women from higher socioeconomic areas should not be denied the protection offered by cervical cytology simply because their risk of developing the disease is somewhat less. Given limited resources, however, the easily identifiable high-risk group 4-6 should certainly be the prime target. In a study of the lowest socioeconomic group7 we found that invasive squamous carcinoma of the cervix decreased from 3-79 per 1000 on initial screening to 0-10 per 1000 on the fourth screening. (Each examination was done at least one year after a previously negative examination.) In other words, repeated screenings reduce the risk of invasive cervix cancer essentially to zero. In a separate investigation of the cost of detection and diagnosis involving these 37,209 low-income women,s we concluded that mass cytological screening is economically feasible. The total cost per cancer in the initial screening was$553.00. The cost, of course, increases with rescreening, since relatively few lesions are found. The total cost on initial screening could be decreased by$200.00 per lesion 1.
detected if only women who are married or pregnant before the age of 20 years were involved. The observed decrease in incidence must be based on the fact that carcinoma-in-situ is a stage in the development of invasive cancer. It is difficult to see why anyone questions the validity of this concept in 1970. Stewartstated the fact briefly and logically: " Every infiltrative cervix cancer must come from in-situ cancer, there being no other thing it can come from, this irrespective of various doubts cast on the relationship." There is admittedly a tendency to overinterpret intraepithelial atypias. This perhaps explains the sanguine attitude a few still cling to concerning the signifiIf one identifies cervical cance of carcinoma-in-situ. and from carcinoma-in-situ, as apart dysplasia separate progression-rates for carcinoma-in-situ are highly significant. Whereas only 4 out of 269 patients with untreated cervical dysplasia progressed to invasive cancer in from one to thirteen years, 10 out of 29 patients with untreated carcinoma-in-situ showed progression to invasion in from one to five years. The risk of progression for the latter group would seem to be too great to temporise with.
SIR,-The opinion expressed by Dr. Wiqvist and Dr. Bygdeman (Oct. 3, p. 716) that the earliest stages of pregnancy are more susceptible to the abortifacient action of prostaglandin than the later weeks might be questioned. Their studies were made with p.G.F2IX’ In the induction of mid-trimester abortion I have found p.G.E2 to be the more effective prostaglandin. It may well be that the results merely reflect variations in uterine sensitivity to a particular prostaglandin with the period of gestation. Having demonstrated some years ago 10 that intermittent intrauterine instillation of very small amounts of p.G.F2
"
"
"
around the corner ". To this extent, certain aspects of the publicity lately afforded the prostaglandins via the mass 9. 10.
Stewart, F. W. Proceedings of the Third National Cancer Conference; Philadelphia, 1957, p. 62. Embrey, M. P., cited by Pickles, V. R. Mem. Soc. Endocr. 1966, 14, 90.
875 media be
seem likely deprecated.
to
mislead the
general public
and
are to
That the presence or absence of side-effects may distort destroy the integrity of double-blind studies is well recognised.8 Methodological ingenuity may be required to overcome such defects, but seldom seeing and hardly speaking to the patient is an ostrich-like resolution of the dilemma, particularly since the incidence of side-effects is known to depend closely on how carefully they are elicited.& This highlights another fault in the authors’ design; they could only conceal their purpose by not disturbing the patients’ routine, and in doing so, were unable to make the critical observations required of an adequate experiment. Further evidence to support the suggestion that this basic design is faulty was unwittingly provided in a recent study by Melia," using similar " double-blind " methodology. In that study patients maintained on lithium did not improve but those switched to placebo deteriorated." Discoveries in biological psychiatry seldom originate from double-blind studies,12 but, provided such experiments are properly designed, they remain an indispensable tool for distinguishing between worthwhile discoveries and worthless panaceas. For many reasons lithium fits the panacea paradigm 13 as well as being an undesirably toxic substance with a narrow therapeutic index. I hope Dr. Schou has made a worthwhile discovery, but I fear it has not yet been scientifically proven. Department of Psychiatry and Pharmacology, Cincinnati General Hospital, BARRY BLACKWELL. Ohio 45229
or
Nuffield Department of Obstetrics and Gynæcology, University of Oxford.
MOSTYN P. EMBREY.
LITHIUM
SIR,-The paper on lithium prophylaxis, by Dr. Schou and his colleagues (Aug. 15, p. 326), perpetrates a remarkable volte-face. These workers’ original objections to a double-blind study, which are reiterated in this recent paper, rested on two premises: the probity of denying patients a remedy which was regarded as effective, and the technical impossibility of concealing the side-effects of lithium medication. Yet the same workers who found it impossible to deny an unproven remedy to untried patients have now been able to remove it from a group of patients whose dependency on the medication (psychological or physiological) was the criterion for their selection. The patients’ ability to detect this subterfuge by missing the same side-effects previously held to negate a double-blind study is now brushed aside. Such plastic logic undermines what at first sight appears to be a reasonable attempt to meet previous criticism of the authors’ earlier uncontrolled observations.1 The scientific objection
to this recent paper can be the fact that patients dependent on medication react adversely to its withdrawal provides no certain indication of any therapeutic benefit to be derived from presenting the drug afresh to untried patients. For instance, the response of barbiturate addicts to withdrawal is not a valid test of barbiturates as drugs for insomnia (even though insomnia is also a major symptom of abstinence). This is not simply a theoretical objection. Alterations in sleep patterns occur with lithium,2 and rebound can be expected following its sudden withdrawal. Suppression of rapid-eye-movement sleep and withdrawal rebound may partly account for dependency on many psychotropic drogs.3.4 A subliminal abstinence syndrome could certainly provide a cue to relapse in patients selected for their loyal attendance at a lithium clinic for up to 7 years. Such patients would be closely attuned to detect change and to react adversely to it. The loss of familiar side-effects due to lithium, such as polyuria or tremor, is a still more likely source of alarm, particularly since the patients were informed that a mistake had been made in medication and had been given a fresh supply of tablets. We are even told that four patients discovered the subterfuge for themselves and obtained more reliable supplies elsewhere. The reassurances given that patients did not report changes in side-effects must be further tempered by noting that they attended the clinic infrequently on a 2-4 month schedule and were only asked " how are you ?" This hardly forms the basis for close observation, and even this opportunity did not occur often since all relapses took place between outpatient visits and within 5 months. The authors themselves note that this lack of change in side-effects was " surprising " ; one can share their perplexity after reading another paper on methodological problems in lithium research co-authored by Dr. Schou,6 which comments that " during long observation periods even slight side-effects may render the blindness illusory."
succinctly stated:
* * * We showed this letter
Dr.
Schou, whose reply
SIR,-Dr. Blackwell finds it strange that we have now carried out a double-blind study on lithium prophylaxis when previously we considered the ethical justification of such studies dubious and the maintenance of their blindness questionable. However, as is explained in detail in our paper, we decided to do the study because a design became available that was acceptable on both points. This attitude seems to us medically and scientifically correct, and we cannot understand the scorn with which it is treated by Dr. Blackwell. Previous studies of lithium treatment for recurrent endogenous affective disorders have shown that the frequency of relapses falls when lithium is administered and rises again when it is discontinued. Our report in The Lancet now demonstrates that the same rise in the frequency of relapses is seen when patients are transferred from lithium to placebo. We consider a prophylactic action of lithium the most likely explanation of these observations. Dr. Blackwell puts forward different explanations: 1. The trial
was not
really blind
suspected--even though they
to the placebo patients; they did not tell us-that they had
been switched to an inactive preparation. 2. This suspicion arose because the patients noted-again without mentioning it-that familiar side-effects disappeared, or because they experienced symptoms (never before described and not reported by the patients) that were caused by hypothetical sequelae of lithium withdrawal. 6. 7. 8.
1. Blackwell, B., Shepherd, M. Lancet, 1968, i, 968. 2. Kupfer, D. J., Wyatt, R. J., Greenspan, K., Snyder, F. Archs gen. Psychiat. 1970, 23, 35. 3. Oswald, I., Priest, R. G. Br. med. J. 1965, ii, 1093. 4. Kales, A., Preston, T. A., Tan, T-L., Allen, C. Archs gen. Psychiat. 1970, 23, 211. 5. Grof, P., Schou, M., Angst, J., Baastrup, P. C. Br. J. Psychiat. 1970, 116, 599.
to
follows.-ED. L.
9.
10. 11. 12. 13.
Oliver, J. E. Clin. Trials J. May, 1968. Englehardt, D. M., Margolis, A., Rudofer, L., Paley, H. M. Archs gen. Psychiat. 1969, 20, 315. Rickels, K., Lipman, R. S., Fisher, S., Park, L. C., Uhlenhuth, E. H. Psychopharmacologia, 1970, 16, 329. Avery, C., Ibelle, B. P., Allison, B., Mandell, X. Am. J. Psychiat. 1967, 123, 875. Melia, P. E. Br. J. Psychiat. 1970, 116, 621. Blackwell, B. ibid. (in the press). Ayd, F., Blackwell, B. (editors). Discoveries in Biological Psychiatry. Philadelphia, 1970. Blackwell, B. Med. Counterpoint, 1969, 1, 52.
Letters
to
the Editor
SCREENING FOR BREAST AND GYNÆCOLOGICAL LESIONS SIR,-I fully agree with the approach of Dr. Stark and Mr. Way (Aug. 22, p. 407) to the detection of early mammary cancer. The encouragement you offer in your accompanying editorial (p. 404) is greatly appreciated by many of us. I must, however, take exception to your editorial implication that the real value of exfoliative cytology remains uncertain. The verdict of Knox1 that it is " not proven " is even less accurate today than it was in 1966. It is to be hoped that the evidence gathered in the mass population screening for cervix cancer in Louisville, Kentuckywill give impetus to greater mass efforts to the control of this disease. Between 1956 and 1968, 752,688 cytological screenings were performed on the female population 20 years old and Over 90% of over (average population at risk, 201,227). that age-group (including the population with lowest socioeconomic status) were screened one or more times. The age-adjusted incidence-rate for invasive squamous cancer decreased 38%. The decrease for those under 50 years was 43-2%. The proportion of cases in the in-situ stage increased over sixfold. Stage-i cases increased from 31-9% to
2. 3.
4. 5. 6.
Knox, E. G. in Problems and Progress in Medical Care (edited by G. McLachlan); p. 277. London, 1966. Christopherson, W. M., Mendez, W., Ahuja, E. M., Lundin, F. E., Jr., Parker, J. E. Cancer, N.Y. 1970, 26, 29. Christopherson, W. M., Parker, J. E., Mendez, W. M., Lundin, F. E., Jr. ibid. (in the press). Lundin, F. E., Jr., Christopherson, W. M., Mendez, W. M., Parker, J. E. J. natn. Cancer Inst. 1965, 35, 1015. Christopherson, W. M., Parker, J. E. Cancer, N. Y. 1960, 13, 711. Christopherson, W. M., Parker, J. E. New Engl. J. Med. 1965, 273, 235.
7. 8.
Department of Pathology, of Louisville School of Medicine,
University
Louisville, Kentucky.
Christopherson, W. M., Parker, J. E. Cancer, N. Y. 1969, 24, 64. Christopherson, W. M., Parker, J. E. Ca—A Cancer J. for Clinicians, 1969, 19, 107.
WILLIAM M. CHRISTOPHERSON.
PROSTAGLANDINS
56.9%.
A further report shows a highly significant decrease in death-rates from cervix cancer in Louisville,3where the mass-screening experiment was conducted, whereas there was no decrease in the remainder of the State, where no such effort was attempted. These results, in our opinion, make it both " realistic and necessary " to screen the female population 20 years old and older, rather than just those 25 to 50 years of age. Your editorial raises the further question of whether we should concentrate only on the high-risk groups. The answer has to be a qualified no, based on the above data. No-one has yet put a price on the life of a woman; and in view of this, women from higher socioeconomic areas should not be denied the protection offered by cervical cytology simply because their risk of developing the disease is somewhat less. Given limited resources, however, the easily identifiable high-risk group 4-6 should certainly be the prime target. In a study of the lowest socioeconomic group7 we found that invasive squamous carcinoma of the cervix decreased from 3-79 per 1000 on initial screening to 0-10 per 1000 on the fourth screening. (Each examination was done at least one year after a previously negative examination.) In other words, repeated screenings reduce the risk of invasive cervix cancer essentially to zero. In a separate investigation of the cost of detection and diagnosis involving these 37,209 low-income women,s we concluded that mass cytological screening is economically feasible. The total cost per cancer in the initial screening was$553.00. The cost, of course, increases with rescreening, since relatively few lesions are found. The total cost on initial screening could be decreased by$200.00 per lesion 1.
detected if only women who are married or pregnant before the age of 20 years were involved. The observed decrease in incidence must be based on the fact that carcinoma-in-situ is a stage in the development of invasive cancer. It is difficult to see why anyone questions the validity of this concept in 1970. Stewartstated the fact briefly and logically: " Every infiltrative cervix cancer must come from in-situ cancer, there being no other thing it can come from, this irrespective of various doubts cast on the relationship." There is admittedly a tendency to overinterpret intraepithelial atypias. This perhaps explains the sanguine attitude a few still cling to concerning the signifiIf one identifies cervical cance of carcinoma-in-situ. and from carcinoma-in-situ, as apart dysplasia separate progression-rates for carcinoma-in-situ are highly significant. Whereas only 4 out of 269 patients with untreated cervical dysplasia progressed to invasive cancer in from one to thirteen years, 10 out of 29 patients with untreated carcinoma-in-situ showed progression to invasion in from one to five years. The risk of progression for the latter group would seem to be too great to temporise with.
SIR,-The opinion expressed by Dr. Wiqvist and Dr. Bygdeman (Oct. 3, p. 716) that the earliest stages of pregnancy are more susceptible to the abortifacient action of prostaglandin than the later weeks might be questioned. Their studies were made with p.G.F2IX’ In the induction of mid-trimester abortion I have found p.G.E2 to be the more effective prostaglandin. It may well be that the results merely reflect variations in uterine sensitivity to a particular prostaglandin with the period of gestation. Having demonstrated some years ago 10 that intermittent intrauterine instillation of very small amounts of p.G.F2
"
"
"
around the corner ". To this extent, certain aspects of the publicity lately afforded the prostaglandins via the mass 9. 10.
Stewart, F. W. Proceedings of the Third National Cancer Conference; Philadelphia, 1957, p. 62. Embrey, M. P., cited by Pickles, V. R. Mem. Soc. Endocr. 1966, 14, 90.
875 media be
seem likely deprecated.
to
mislead the
general public
and
are to
That the presence or absence of side-effects may distort destroy the integrity of double-blind studies is well recognised.8 Methodological ingenuity may be required to overcome such defects, but seldom seeing and hardly speaking to the patient is an ostrich-like resolution of the dilemma, particularly since the incidence of side-effects is known to depend closely on how carefully they are elicited.& This highlights another fault in the authors’ design; they could only conceal their purpose by not disturbing the patients’ routine, and in doing so, were unable to make the critical observations required of an adequate experiment. Further evidence to support the suggestion that this basic design is faulty was unwittingly provided in a recent study by Melia," using similar " double-blind " methodology. In that study patients maintained on lithium did not improve but those switched to placebo deteriorated." Discoveries in biological psychiatry seldom originate from double-blind studies,12 but, provided such experiments are properly designed, they remain an indispensable tool for distinguishing between worthwhile discoveries and worthless panaceas. For many reasons lithium fits the panacea paradigm 13 as well as being an undesirably toxic substance with a narrow therapeutic index. I hope Dr. Schou has made a worthwhile discovery, but I fear it has not yet been scientifically proven. Department of Psychiatry and Pharmacology, Cincinnati General Hospital, BARRY BLACKWELL. Ohio 45229
or
Nuffield Department of Obstetrics and Gynæcology, University of Oxford.
MOSTYN P. EMBREY.
LITHIUM
SIR,-The paper on lithium prophylaxis, by Dr. Schou and his colleagues (Aug. 15, p. 326), perpetrates a remarkable volte-face. These workers’ original objections to a double-blind study, which are reiterated in this recent paper, rested on two premises: the probity of denying patients a remedy which was regarded as effective, and the technical impossibility of concealing the side-effects of lithium medication. Yet the same workers who found it impossible to deny an unproven remedy to untried patients have now been able to remove it from a group of patients whose dependency on the medication (psychological or physiological) was the criterion for their selection. The patients’ ability to detect this subterfuge by missing the same side-effects previously held to negate a double-blind study is now brushed aside. Such plastic logic undermines what at first sight appears to be a reasonable attempt to meet previous criticism of the authors’ earlier uncontrolled observations.1 The scientific objection
to this recent paper can be the fact that patients dependent on medication react adversely to its withdrawal provides no certain indication of any therapeutic benefit to be derived from presenting the drug afresh to untried patients. For instance, the response of barbiturate addicts to withdrawal is not a valid test of barbiturates as drugs for insomnia (even though insomnia is also a major symptom of abstinence). This is not simply a theoretical objection. Alterations in sleep patterns occur with lithium,2 and rebound can be expected following its sudden withdrawal. Suppression of rapid-eye-movement sleep and withdrawal rebound may partly account for dependency on many psychotropic drogs.3.4 A subliminal abstinence syndrome could certainly provide a cue to relapse in patients selected for their loyal attendance at a lithium clinic for up to 7 years. Such patients would be closely attuned to detect change and to react adversely to it. The loss of familiar side-effects due to lithium, such as polyuria or tremor, is a still more likely source of alarm, particularly since the patients were informed that a mistake had been made in medication and had been given a fresh supply of tablets. We are even told that four patients discovered the subterfuge for themselves and obtained more reliable supplies elsewhere. The reassurances given that patients did not report changes in side-effects must be further tempered by noting that they attended the clinic infrequently on a 2-4 month schedule and were only asked " how are you ?" This hardly forms the basis for close observation, and even this opportunity did not occur often since all relapses took place between outpatient visits and within 5 months. The authors themselves note that this lack of change in side-effects was " surprising " ; one can share their perplexity after reading another paper on methodological problems in lithium research co-authored by Dr. Schou,6 which comments that " during long observation periods even slight side-effects may render the blindness illusory."
succinctly stated:
* * * We showed this letter
Dr.
Schou, whose reply
SIR,-Dr. Blackwell finds it strange that we have now carried out a double-blind study on lithium prophylaxis when previously we considered the ethical justification of such studies dubious and the maintenance of their blindness questionable. However, as is explained in detail in our paper, we decided to do the study because a design became available that was acceptable on both points. This attitude seems to us medically and scientifically correct, and we cannot understand the scorn with which it is treated by Dr. Blackwell. Previous studies of lithium treatment for recurrent endogenous affective disorders have shown that the frequency of relapses falls when lithium is administered and rises again when it is discontinued. Our report in The Lancet now demonstrates that the same rise in the frequency of relapses is seen when patients are transferred from lithium to placebo. We consider a prophylactic action of lithium the most likely explanation of these observations. Dr. Blackwell puts forward different explanations: 1. The trial
was not
really blind
suspected--even though they
to the placebo patients; they did not tell us-that they had
been switched to an inactive preparation. 2. This suspicion arose because the patients noted-again without mentioning it-that familiar side-effects disappeared, or because they experienced symptoms (never before described and not reported by the patients) that were caused by hypothetical sequelae of lithium withdrawal. 6. 7. 8.
1. Blackwell, B., Shepherd, M. Lancet, 1968, i, 968. 2. Kupfer, D. J., Wyatt, R. J., Greenspan, K., Snyder, F. Archs gen. Psychiat. 1970, 23, 35. 3. Oswald, I., Priest, R. G. Br. med. J. 1965, ii, 1093. 4. Kales, A., Preston, T. A., Tan, T-L., Allen, C. Archs gen. Psychiat. 1970, 23, 211. 5. Grof, P., Schou, M., Angst, J., Baastrup, P. C. Br. J. Psychiat. 1970, 116, 599.
to
follows.-ED. L.
9.
10. 11. 12. 13.
Oliver, J. E. Clin. Trials J. May, 1968. Englehardt, D. M., Margolis, A., Rudofer, L., Paley, H. M. Archs gen. Psychiat. 1969, 20, 315. Rickels, K., Lipman, R. S., Fisher, S., Park, L. C., Uhlenhuth, E. H. Psychopharmacologia, 1970, 16, 329. Avery, C., Ibelle, B. P., Allison, B., Mandell, X. Am. J. Psychiat. 1967, 123, 875. Melia, P. E. Br. J. Psychiat. 1970, 116, 621. Blackwell, B. ibid. (in the press). Ayd, F., Blackwell, B. (editors). Discoveries in Biological Psychiatry. Philadelphia, 1970. Blackwell, B. Med. Counterpoint, 1969, 1, 52.