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Letters to the Editor

RADIOTHERAPY AND CHEMOTHERAPY IN EARLYBREAST CANCER

SiR,—I read with interest the article (May 22, p.1098) byMr McDonald and his colleagues. I was pleased to see thatradiotherapy has not been excluded in the four coordinatedtrials while adjuvant chemotherapy is included. The plannersof these trials clearly do not agree with McDonald et al. whosay: "Several suggestions have been made supporting this view[of immunodepression following radiotherapy] and this studyprovides direct evidence from a properly controlled clinicaltrial".The statistical validity of the reported decreased survival at

one year for the postoperative radiotherapy group of breast-cancer patients with nodal metastasis has been challenged byDr Haybittle (May 29, p.1242). The basis for Stjernsward’sstatistical analysis’ of five breast trials and his conclusion thatroutine radiotherapy is harmful have also been challenged.1Harmful immunodepression by clinical radiotherapy is diffi-cult to prove. The know-how has not yet been mastered, andanaesthesia, surgery, and chemotherapy are also immunode-pressive. Moreover, several reports contradict the view thatimmune reactivity is suppressed after radiotherapy. 3- Hershet al.6 have speculated that the immune-tolerance state may bebroken by radiotherapy or chemotherapy, and that there mayeven be a rebound phenomenon in immune status. Radio-therapy as a primary treatment for early breast cancer is a suc-cessful mode of treatment* and it seems to be gaining groundat recent conferences.

In general, axilla-negative patients with early breast cancerare not treated by routine radiotherapy in many centres. Sur-prising differences in 3, 4, and 5 year survival-rates wererecorded by McDonald et al. (their fig. 1) in favour of radio-therapy, yet these workers attached no significance to this. Asignificant difference was found by these workers only at oneyear in the radiotherapy group of node-positive patients. Thisknown drop in survival in the early years after radiotherapyhas unfortunately never been properly investigated in respectof other prognostic factors (e.g., presence of high axillary nodehistological grade, previous hormone treatment, and immunestatus). The patients reported by McDonald et al. had simplemastectomy with one to eight pectoral or axillary tail nodal ex-amination. Importance was not given in the analysis to thehighest axillary (infraclavicular) node or to the histologicalgrade of the tumour. Inclusion of deaths from all causes (10%)hardly justifies the complex issues at hand.The other important point in this paper, and in many

others, is local recurrence. Local radiotherapy significantlyreduced local recurrence (?< 0-001). The frequency of suchrecurrences was 3-7% after radical mastectomy with axilla-positive patients when radiotherapy was added as against20-25% in non-irradiated patients.s Local recurrence is sinis-ter for prognosis. Many authorities9-12 have concluded thatlocal recurrence is but the indicator of more widespread dis-ease which is already clinical or subclinical or will become sosoon. Yet radiotherapy, a powerful deterrent against local

1. Stjernsw&auml;rd, J. Lancet, 1974, ii, 1285.2. Levitt, S. H., McHugh, B. R. ibid. 1975,3. McCredie, J. A., Inch, W. R., Sutherland, R. M. Archs Surg. 1973, 107, 162.4. Karim, A. B. M. F. Abstracts of DePCa Symposium, held in New York, in

April, 1976, no. 341.5. Karim, A. B. M. F. Oncology (in the press).6. Hersh, E. M., Gutterman, J. U., Mavligit, G. M. Cancer Treatment Rev.

1974, 1, 65.7. Prosnitz, L. R., Goldenberg, I. S. Cancer, 1975, 35, 1587.8. Fletcher, G. H. Br. J. Radiol. 1973, 46, 1.9. Dao, T. L., Nemoto, T. Surgery Gynec. Obstet. 1963, 117, 447.

10. Donegan, W. L., Perez-Mesa, C. M., Watson, F. R. ibid. 1966, 122, 529.11. Oliver, D. R., Sugarbaker, E. D. ibid. 1947, 85, 360.12. Marshall, K. A., Redfern, A., Cady, B. ibid. 1974, 139, 406.

recurrence, is thought by many to be no good for thesepatients. Breast cancer is unpredictable in its natural history:biological variables’3 and other prognostic factors should begiven more importance in creating homogeneous subgroups sothat controlled trials may be more meaningful.

Major advances in breast-cancer therapy" are already inthe air, notably adjuvant chemotherapy."*" Yet the morethoughtful workers 1. 19 warn against regarding these experi-ments as a triumph. I favour experimentation, especially forthe problem of micrometastasis, but one must exercise cautionin planning and analysing experiments. In our haste to destroymicrometastases, we must not increase the sufferings of our patients with increasing local/regional recurrences. When thequestion of local/regional metastasis was raised at a recentconference (48% in the controls, 28% in the adjuvant chemo-therapy group in Bonadonna’s series16 as against 5% in post-operative radiotherapy historical group), Dr Bonadonna an-swered : "You should try to make a better spaghetti than Imade". May I appeal to research-workers to analyse the ingre.-dients a little more before planning for the better spaghetti?Department of Radiotherapy,Academic Hospital of the Free University,Amsterdam, Netherlands A. B. M. F. KARIM

SIR,-Dr Haybittle has raised two entirely valid criticismsof the way in which Mr McDonald and his colleagues havehandled the statistics in the Cancer Research Campaign studyof the role of postoperative radiotherapy in the treatment ofearly cancer of the breast. The authors’ reply (June 12, p.1291) suggests that they have misunderstood both points.The first point concerned the authors’ use of an uncorrected

xi test to compare the one-year-survival rates in two of theirgroups. The disadvantage of this test is that it usually (as inthis instance) gives too low a value for the correct probability(namely, that given by Fisher’s exact test), and hence tends tooverestimate the statistical importance of the difference. Yates’correction usually (again as in this instance) provides a verymuch closer approximation to the correct probability and isthus to be preferred "for almost all OJ: tests for 2x2 tables"?’Mr McDonald and his colleagues cite the first edition of theStatistical Package for the Social Sciences to support their useof uncorrected 7...3 values. The second edition21 no longer pro-vides uncorrected x.2 values for 2x2 tables, however large thesmallest cell expectation.The second and more important point concerned the

authors’ comparison of the survival curves at the point of timeat which they diverged most. Whichever of the above threetests is used for this comparison, the probability obtained isthat appropriate to a comparison between the curves at an un-selected point of time. If, as in this instance, the differencebeing tested is the largest of the set of five differences betweenthe curves (at 1, 2, 3, 4 or 5 years) which might have beentested, then, as Dr Haybittle has made plain, the appropriateprobability is much larger. Putting the point in a differentway, the authors have judged the importance of the differencebetween the mortalities at 1 year as if it was typical of the difference between the survival curves, when it is really an exceirtional difference.One way round this difficulty would be to test the difference

at 1 year as an exceptional and not as a typical difference, butthis does not make full use of the available evidence on the

13. Baum, M. Br. med. J. 1976, i, 439.14. Holland, J. F. New Engl. J. Med. 1976, 294, 440.15. Fisher, B., and others, ibid. 1975, 292, 117.16. Bonadonna, G. Abstracts of DePCa Symposium, held in New York, in April

1976, no. 212.17. Bonadonna, G., and others Proc. Am. Ass. Cancer Res/Am. Soc. clin. Oncol

1975, 16, 254.18. Krant, M. J. New Engl. J. Med. 1976, 294, 549.19. Costanza, M. E. ibid. 1975, 293, 1095.20. Armitage, P. Statistical Methods in Medical Research; p. 135. Oxford, 197121. Nie, N. H., Hull, C. H., Jenkins, J. G., Steinbrenner, K., Bent, D. H. Statis

tical Package for the Social Sciences; p. 243. New York, 1975.

37

mortality differences between the series. An alternative wouldbe to use the log-rank test, as suggested by Dr Haybittle,because this provides a comprehensive test of significance ofthe difference between the survival curves over their entireduration. Far from being inappropriate, as the authors suggest(June 12, p. 1291), the log-rank test represents the most satis-factory way of assessing fairly the reality of the mortalitydifference which they claim to exist.Mr McDonald and his colleagues estimate that the probabil-

ity of occurrence of the observed mortality difference at oneyear between those lymph-node positive patients given routinepostoperative radiotherapy and those not given radiotherapyroutinely, if there is really no mortality difference between theseries, is less than 0.05. However, because their calculationsare inappropriate this estimate is likely to be too low, and per-haps much too low. The evidence the authors have presentedfor the higher mortality after routine postoperative radio-therapy in breast cancer patients with lymph-node involve-ment must therefore be regarded as much less strong than theyclaim, and it seems to be inadequate to justify the categoricstatements in the discussion and summary of their paper.There is little advantage in having "direct evidence from aproperly controlled clinical trial" unless that evidence is alsoproperly evaluated statistically.M.R.C. Statistical Research and Services Unit,University College Hospital Medical School,London WC1E 6AS IAN SUTHERLAND

OUTPATIENT FOLLOW-UP

SIR,-My paper and your editorial2 have provoked a

number of letters that should be answered.There has never to my mind been any question of the impor-

tance of outpatient follow-up for uncommon serious diseasesuch as renal failure3 or Crohn’s disease4 or certain other long-term major disease including those with multiple pathology.3 3I also realise the educational value of follow-up appointments,especially in a specialty such as neurology.s The follow-upappointments that were considered unnecessary were themindless routine appointments of no educational value, and ofno advantage to the patient. Coggon and Goldacre6 illustratevery well indeed that while there may be a case for outpatientfollow-up for serious complicated cases of common illnesses(such as appendicitis), routine follow-up of the rest is not onlyunnecessary but also ineffective as a guard against complica-tions.

I recognise that from the point of view of care after dis-charge from hospital (and from other points of view) there arebad G.P.S just as there are bad barristers and butchers, dentistsand dockers, or members of any other profession or occupa-tion. Olsen’s plan of identifying bad G.P.S in the patient’s notesby a code word seems to me a sensible plan compared to thosewho advocate routine outpatient follow-up because all or mostor 50% of G.P.s are not to be trusted.4 The question of the qua-lity of care provided by general practitioners often underliesstatements in defence of the unnecessary follow-ups. Let ussuppose that we could all agree on the criteria for measuringthe quality of care provided by each G.P. (and criteria basedon G.p./hospital contact would be only a part since this formsonly a minority of our work). It would then, in theory, be pos-sible to classify G.P.S into good, mediocre, and bad. This has notbeen done, and it surprises me how often consultants makesweeping statements about general practice (a branch of medi-cine of which they seldom have any postgraduate experience)based soley on subjective impressions. I would plead with con-

1 Loudon, I. S. L. Lancet, 1976, i, 736.2. ibid. p. 1168.3 Kerr, D. ibid. p. 1287.4. Paulley, J. W. ibid p. 1347.5. Matthews, W. B. ibid. p. 1287.6. Coggon, D., Goldacre, M. J. ibid. p. 1346.7. Olsen, N. D. L. ibid. p. 854.

sultants to apply the same objectivity to statements about

general practice that they would expect to be applied to thera-peutic trials within their own specialty.

Paulley4 asserts that "while many of one’s general practi-tioner colleagues are excellent ... quite frankly there are asmany who are not". How does he know? What criteria did he

apply to end up by finding 50% excellent and 50% not? Else-where in his letter he asserts that G.P.s rush to the "consul-tant’s doorstep when they or their families take ill". Somemay, but how many? Does he know? I suspect not. In our five-man partnership each of us chooses a partner with whom heand his family are registered. The partner who looks after myfamily, and does so superbly, uses the same criteria for referralto hospital as he does for all his patients; and so do the restof us.

Paulley says that my figure of 10.6 new outpatients perweek for each general physician is "undoubtedly wrong". Ichecked again and found that inadvertently I had stated that10.6 applied to whole-time equivalents: in fact it is the correctfigure for the total number of consultants. The figure forwhole-time equivalents is 12. 1. I apologise for the error. ButPaulley’s suggestion that I should "check with consultant col-leagues" to arrive at the "true" figure is so unscientific as tobe ridiculous. The source of the data on which the figures arebased is shown in the references at the end of my paper. Paul-

ley’s final suggestion that either I or you (or both of us) deli-berately distort the truth for political reasons is too absurd tobe insulting.

Everything I have written stems from my belief that thefuture of medicine in Britain is grim unless it is firmly basedon general practice of high quality.The unnecessary routine follow-up does four things: (a) it

leads, to overcrowding in outpatients; (b) it fails to be an effec-tive guard against serious complications; (c) it removes all in-centives for G.P.S to undertake the care of their patient on dis-charge from hospital; and (d) most of all, it devalues generalpractice in everyone’s eyes and undermines the mutual respectand confidence on which the care of our patient depends.

Health Centre,Garston Lane,Wantage,Oxon OX12 7AS I. S. L. LOUDON

SEROTYPING OF E. COLI

SIR,-We have expressed concern’ at the suggestion thatserotyping of Escherichia coli is no longer necessary in thestudy of infantile enteritis and that the ability to detect entero-toxin may be all that is required. We welcome the letter by DrSack in which he supports the value of serotyping in the studyof epidemic diarrhoeal disease. It has been shown in numerousstudies that outbreaks of infantile enteritis in many countriesare frequently caused by E. coli belonging to a restricted rangeof serotypes. 3Dr Sack doubts the value of serotyping E. coli from sporadic

cases of diarrhoea in infants and children, but this argumentdoes not take into account the common epidemiological pat-tern of hospital outbreaks of infantile enteritis. Outbreaks fre-quently occur in units housing young babies, and epidemicspread of infection follows the admission of a sporadic case.During a survey in a Dublin hospital4 E. coli 0142.H6 wasfound in 13 of 70 apparently sporadic cases of diarrhoea onadmission to hospital. A cross-infection outbreak subsequentlyoccurred, and 49 of 68 babies who developed diarrhoea afteradmission were shown to have acquired E. coli 0142.H6 whilstin hospital. Recognition of an enteropathogenic serotype insporadic cases of diarrhoea on admission to hospital allows the

1. Rowe, B., Gross, R. J., Scotland, S. M. Lancet, 1975, ii, 925.2. Sack, R. B. ibid. 1976, i, 1132.3. Taylor, J. J. appl. Bact. 1961, 24, 316.4. Hone, R., Fitzpatrick, S., Keane, C., Gross, R. J., Rowe, B. J. med. Micro-

biol. 1973, 6, 505