Factors in decision making in the treatment of breast cancer

Radiotherapy and Oncology 55 (2000) 205±216

www.elsevier.com/locate/radonline

FECS Clinical Award lecture 1989

Factors in decision making in the treatment of breast cancer Emmanuel van der Schueren Department of Radiotherapy, University Hospital Gasthuisberg, 3000 Leuven, Belgium Received 16 July 1998; accepted 11 June 1999

Keywords: Breast cancer; Radiotherapy; Adjuvant chemotherapy; Decision making

1. Medicine is an art and science Treating patients requires continuous decision-making. For most of these decisions it is necessary to take into account a large number of factors, as it is rare that a decision is determined by a single factor of overpowering in¯uence. Decisions are rendered dif®cult by the uncertainties related to qualitative assessment of bene®ts of treatment and by problems in their objective analysis. It is well recognised that several of the elements on which decisions have to be based can not be quanti®ed and require an assessment by the doctor which is entirely or partly subjective. They can be linked to the patient or to the doctor and can cover such aspects as quality of life, related to aggressiveness and possibly outcome of treatment, psychological acceptance of disease and treatment toxicity. Decision making, also involves a number of so-called `objective' medical facts or groups of factors. In some instances it is decided by the scienti®c community or by an individual that selected `facts' carry such great importance that they override all other factors leading to `treatment policies'. This facilitates greatly the individual decision as one can leave most other factors out of consideration reducing all patients to a limited number of categories. However, it is necessary to keep the bases for such oversimpli®cations in mind as otherwise it will be impossible to analyse and correct the decision making process later on. For instance, very often one now speaks about N0 and N1 patients as though they are homogeneous groups while it is well realised that also the number of involved regions or nodes plays a very important role. Such oversimpli®cations are also very often made for the therapy results which, in many instances show no `yes' or `no' answers but gradual changes, dose-response-curves and which are often determined by a number of small factors.

The process of introducing a hierarchy in the weight of a number of factors is the basis of the scienti®c development of medicine. The development of a small number of factors with overpowering in¯uence in the decision making has been based on scienti®c clinical observation. This was initially mainly based on individual experiences, through which only very strong in¯uences could be detected with nearly direct causeeffect relations, allowing the construction and testing of hypotheses on small numbers of events. Progressively, with the retrospective analysis of larger patient groups, sometimes with more or less standardized treatments, it became possible to detect some factors of lesser power. Finally, with the prospective randomized trials in which, optimally, rigid treatment discipline should be observed, it has now become possible to detect and con®rm the signi®cance of small effects. With this we have come full circle. The ®rst identi®ed prognostic factors and treatment options were so strong that they simpli®ed the `art of decision making' in breast cancer. For decades the direct consequence of any malignancy in the breast was a mastectomy, the only limitation being `medical inoperability'. It took quite a while before `oncological limitations' were built in and, for instance, in¯ammatory breast cancer was eliminated from mastectomy indications. Finally, with the advent of breast conserving therapy a large number of factors determine the decision such as volume and location of the tumor, size of the breast, age of the patient and histology, local control, survival and cosmetic outcome. Unless one arbitrarily gives overpowering weight to a single one of these factors, for instance tumor volume, any decision will have to be weighted by a series of factors with different relative impacts.

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We are now faced with a situation in which we get an enormous amount of treatment possibilities combining different treatment modalities. To operate such selection we get an ever-increasing number of elements related to prognosis or therapeutic value. With the increasing power of study and analysis, bits of information with smaller impact are identi®ed. The global combination of many factors into a treatment decision, choosing from a large number of possibilities, has again brought an increasing amount of `art' in the decision making. To some extent we often want to deny this and tell ourselves we only make decisions nowadays based on `hard facts'. This may well be true to some extent, but upon careful scrutiny it is clear that a very large element of uncertainty remains. The way the numbers are arrived at, the selection of which of the multiple available data to take into account, the relative weight to give to different facts and the necessary extrapolation which has to be made from data which need sometimes years to mature, are all strongly in¯uenced by subjective factors. There is nothing wrong with this and it is even to some extent unavoidable but it is vital to remain well aware of this fact. However, nowadays too often data are selectively used to support a preconceived idea or hypothesis which is then subsequently enthusiastically proclaimed as being supported by hard facts. The problems can be more or less be arti®cially divided in to three groups: ² total or partial absence of data; ² scienti®c misinterpretations; ² subjective bias. Absence of data can very often be due to changes in diagnostic tools or treatment conditions. For instance the screening procedures have de®ned a new patient population for which long-term follow-up will be necessary to determine optimal treatment conditions. Meanwhile, one has to adopt a certain treatment policy. For lobular carcinoma in situ for instance treatments go from mastectomy and from bilateral mastectomy to observation. All these conclusions are based on the same available data meaning there is an important element of interpretation and subjective weighting of the elements involved. Increasingly effective treatment will wipe out the relative importance of prognostic factors, while less radical treatment will bring out new ones. For instance the possible impact of an extensive in situ ductular carcinoma next to an invasive process has only emerged as a question when limited tumorectomies were done in breast conserving treatment. Scienti®c misinterpretation very often happens due to the lack of speci®c information leading to unwarranted generalisations, inversion of arguments or the application of data which are not valid anymore because other factors have changed which were determining the value of the old data.

For instance, the value of postoperative radiotherapy will be determined to a large extent by the incidence with which local recurrences and metastases occur. If the selection of patients changes, eliminating a group of patients with a high risk for local recurrence or including more patients without metastases, the impact and possible use of radiotherapy will evidently be modi®ed. Finally, the in¯uence of subjectivity on data analysis and evaluation is unavoidable and pervasive. This has ®rst of all to do with the fact that many so-called, objective effects need subjective assessment as they compare incomparable things. How can one weigh `acute toxicity' against `local control' or `complication rate' against `survival'. It is evident that character and psychology of doctor and patient will in¯uence a decision towards an `aggressive' or `cautious' approach. A second, more dif®cult aspect is the subjectivity making treating doctors and investigators see some results through dark or rosy glasses. This can have many causes, amongst others, a missionary zeal with which some people pursue the ful®lment of a prophecy or the con®rmation of a hypothesis. This leads to an especially dif®cult situation for breast cancer where the heterogeneity of most patient groups and the slow evolution of the tumor process in some patients requires many years of follow-up for con®rmation or denial of new developments. Most decisions on day to day patient treatment have to be made before the data on which they are based have matured. It is interesting to analyse a number of speci®c situations today which determine the weight people give to data, thus in¯uencing the decision making process. While the arguments given for a ®nal decision are usually based on numbers, the process through which one selects these numbers and the importance that is given to them can not be quanti®ed and will be in¯uenced by subjective elements. 2. The tyranny of the badly interpreted numbers The addition of the sound statistical analysis of clinical results has made it possible to eliminate a number of `¯uke' results which sometimes took a lot of effort to disprove, especially when they looked attractive. However, sad to say, they have led to errors in reasoning, due to misinterpretation by medical doctors, unfamiliar with the ways of thinking in scienti®c statistics. A total mix-up happens between `statistical signi®cance' and `clinical relevance'. `Statistical signi®cance' only relates to the probability that a result obtained in a certain sample of patients indeed applies for the whole patient population or whether it could still be due to random differences in sampling. The `golden calf' of P ˆ 0:05 only means that, statistically, the chance of two assessed treatments being equal is 5%. This being a relatively low frequency one can say that `there is a good chance' that the observed differences in treatment results are

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real. One should also be aware however that P ˆ 0:06, which is considered as `not statistically signi®cant', means there is only 6% chance that treatments are equal. The limit value of P ˆ 0:05 is an entirely arbitrary level, which is very useful in the exchange of information between individuals and groups, to de®ne a concept. It has however no magical biological signi®cance. One has to keep in mind that many more trials are undertaken than are published (on rough estimation, between 10 and 20 times) and that through sheer numbers, some of them will give results of P ˆ ,0:05, even if no real difference exists. However, with a decreasing P-value we can get more con®dent that an observed difference is real (`statistically signi®cant'). One should now assess what the `clinical relevance' is. Indeed, statistical signi®cance is determined by the difference observed and by the number of patients in the sample. Any difference, no matter how small, will become statistically signi®cant, if the sample size is large enough. A difference of 5% can be detected with 3000 patients. The largest clinical importance is thus related to signi®cant P-values with small sample sizes. It is now frequently, and erroneously suggested that, as P-value decreases, a certain fact gets more clinical importance. This is evidently untrue. Once beyond a certain sample size, observed clinical differences will, by the weight of the numbers, change only to a very minor extent while their statistical signi®cance will continue to increase. For the clinician, the only relevant factor to help make his decision is the observed difference, which he can assume is real, based on statistical signi®cance. When one obtains, for instance, a change in disease-free-survival from 77 to 83% with adjuvant tamoxifen in node negative, receptor positive patients, the clinical relevance is an increase of 6% in disease-free survival with 4 years of follow-up. It is nice to know that the small difference observed is probably real as it has been obtained in a sample of 2644 patients. However the fact that the P-value is smaller then 0.00001 does nothing to increase the effect. The result of this study will be only one among many factors contributing to a decision which will be, no doubt, still very much different among specialists involved in the ®eld. Also, the reverse phenomenon is taking place. Just as marginal phenomena can be given great statistical weight, it is evident that some important clinical features can sometimes not be con®rmed statistically because the sample size one is investigating makes it simply impossible to get statistical signi®cance. Trials with inadequate sample size will, by de®nition, rule out the clinical fact they were set out to investigate. An infrequent, clinically known event can thus be negated in its existence due to `lack of statistical signni®cance'. A typical example of such a situation is the widespread hypothesis that a local recurrence after breast conserving therapy has no clinical relevance because its impact has not yet been statistically con®rmed.

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3. Scienti®c fashion determines whether small differences can be con®rmed or not Although, in principle, in medical science, all arguments should be evaluated purely on their scienti®c merit, it is evident that this is often not the case, sometimes simply because the hard data are not available and sometimes because emotional and non-scienti®c elements interfere. The assessment of a number of factors which have a limited, but repercussion on treatment results requires fairly large patient numbers. The immediate consequence is that a large infrastructure is necessary, requiring important material backing. This means that the enterprise requires support on a large scale, as well for the material aspect, as for the scienti®c support and the integration in accepted clinical practice in an important number of medical centers. It is logical that only hypotheses, in agreement with the majority opinion can be tested on suf®ciently large numbers to be con®rmed or invalidated. All others will remain `uncon®rmed' and are thus often considered as being unexisting. For all the facts for which no `statistically signi®cant' relevance has been investigated, we have no choice but to use common sense. Considering everything that has not been investigated as nonexisting is a non-sense. Scienti®c directions are subject to changes which have something of a pendulum movement: too rigid hypotheses lead to reactions which are also out of proportion. The Halsted-theory which focused too strongly on orderly locoregional general progression has now been replaced for some by the theory that breast cancer is always, from the outset, a generalised disease. In part this was related to the indications that even for periods of over 20±30 years after treatment there still remains an excess of breast cancer mortality in a treated population. This is often interpreted as meaning that, as lethality continues to be increased, all patients will even die from breast cancer. The important question is however her primary treatment does affect the outcome of the disease; within the period which is normally clinically relevant. On a fundamental level, the extremely long-term follow-up of 30 years, and more, is very important. From the clinical point of view however, possible negative or positive changes in the course of the disease, both relating to survival and disease-free survival, within observation periods of 5, 10 and 20 years are equally relevant. The direct corollary of the hypothesis that breast cancer would be a systemic disease is that local control would only be of limited importance and that all therapy and research efforts have to be geared towards systemic therapy. This is expressed in the impressive work carried out in recent years in systemic adjuvant trials, culminating in the gigantic analysis of the `Early Breast Cancer Trialists' Collaborative Group', including 28 896 patients. The numbers involved give already some indication as to the order of magnitude of the effects pursued.

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One of the initial, interesting, side effects of this reduced importance given to local control has been the possibility to investigate the modalities for breast conserving therapy, to which surgeons were initially staunchly opposed, as they were afraid to lose patients due to inadequate local control. As is very often the case, the slide down from a very rigid viewpoint has proved very dif®cult to stem and one is now frequently confronted with a situation in which totally inadequate measures are taken to ensure local control. It is interesting to analyse the available data which have contributed to this concentration upon systemic therapy and the relative neglect of local control. 4. Fashionable hypothesis orienting scienti®c research: breast cancer, a generalised disease? A few numbers are of interest: the overall 10-year survival of patients after mastectomy, before the era of systemic therapy, was 50%. For node negative patients, which constitute about 50% of the patients, 10-year survival is about 75%. Node positive patients still have a 10-year survival of 25±45% depending on patient selection. For all practical purposes one should thus accept that a sizeable part of the patients, varying between 25 and 75% in function of stage, have disease that is localised, or clinically behaves as such for a period of at least 10 years. With regard to the time periods involved, one should take this fact as one of the primary elements in decision making in the management of breast cancer. Nobody can dispute the high incidence of distant metastases occurring, even very late, which will determine the ultimate outcome in this group of patients. Everyone should actively participate in the search for more active systemic treatment modalities and the best way to administer them. It is however evident that the means at our disposal have clear limitations and their impact on the total group of patients will not become any larger than what we know now. In the patient group which has localised disease, oncology logic demands that the primary aim of therapy is complete eradication of the tumor through effective local treatment. Several questions can be asked. When do metastases occur? Is the risk of metastases similar for a second local growth as for a ®rst? 5. Relation between tumor size and incidence of metastases The myth about breast cancer as a generalised disease, has two aspects. On the one hand it is suggested that all tumors are metastasised at clinical diagnosis, but some take a long time to express this, and on the other hand it is suggested that tumors are more or less `programmed' as `metastasising or not metastasising', meaning that metastases, if occurring, would always develop before clinical

diagnosis and, when a tumor is still localised at diagnosis, metastases would not occur anymore when further growth is allowed, as is the case in a local relapse. Very interesting data on this point were provided by the group of the Institut Gustave Roussy. Small tumors, with a diameter of 2 cm have an incidence of distant metastases of about 25% This frequency goes up to 50% for tumors of 4 cm and to 90% for a tumor diameter of 8 cm. It is important to remember that, at a volume of 2 cm, there is already a certain frequency of metastases while, even for very big tumors, about 10% of the patients remain metastases-free over long periods. These data show that any delay in treatment, leading to larger tumor volumes could be linked to progressively higher incidences of metastases. Roughly, one can say 10% of metastases per cm in diameter. This means that none of the studies available would be able to detect this as several thousands of patients would be necessary to con®rm in controlled conditions a difference of 10%. When giving a treatment modality which is not effective on part of the patients they will progress in volume. This could happen in neo-adjuvant chemotherapy in breast cancer. In order to give the adjuvant chemotherapy a few weeks earlier in the responding patients, and to spare 3 months of treatment to the non-responders, one would have to allow continued growth of the primary for half of the patient population (the non-responders). It is highly unlikely that any result will be obtained in such context. The progressive, random increase in the chance of a tumor to metastasize, during the period of clinical tumor growth signi®es, that the majority of distant localisations occur in that period, making local tumor control a mandatory objective, as early and as effectively as possible. This is the factual basis of all systematic screening programs and of all efforts to detect tumors as early as possible in individual patients. This relation between clinical tumor volume and distant spread is also con®rmed by all data on occurrence of axillary lymph node metastases in relation to tumor size going from about 25% for tumors less than 1 cm to 60% in tumors more than 5 cm. Treatment results are thus certainly affected by the volume of the primary tumor at diagnosis, when effective local treatment is given. This in¯uence is mainly mediated by the metastasising process, occurring during the clinical growth phase. It could thus reasonably be expected that effectiveness of therapy to eliminate all local growth should be one of the determining factors in the ultimate course of the disease. It is strange that such endless discussions have taken place on local control, at a time and in a situation when the problem was only marginally signi®cant as most of the patients involved had metastases while it has been nearly completely eliminated from the concerns, now that the patient group at risk is much more vulnerable as the majority has localised disease.

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Again, this is due to a combination of wrongly applied statistical arguments, of unacceptable inversions of arguments and of extrapolation of general conclusions from one patient group to another. 6. Unwarranted reversions of conclusions: differences and similarities in local recurrences after mastectomy and BCT It is clear that there are important differences between local recurrences occurring after mastectomy or after breast conserving treatments. Relapses after mastectomy are accompanied, or immediately followed in more than half of the cases, by distant metastases. They appear fairly rapidly, and ultimate survival is very low. Local recurrences after BCT appear at a much slower, but continuous rate. Many recurrences can be rescued by second-line mastectomy and it is often suggested that survival of the `rescued' patients would be the same as for the whole patient group. We are now in a situation where on the one hand it is said that local relapses after mastectomy do not matter very much because they occur anyway only in patients who have generalised disease, and on the other hand that local recurrences after breast conserving therapy are not important, as breast relapses are totally devoid of any effect upon the course of the disease. One can not have the same argument working two different ways. Still this message is easily accepted by the medical community at large as it provides justi®cation for failures after inadequate initial management. Already one sees a rising incidence of cases which are locally inadequately managed. It is therefore useful to critically assess the available data and see which data are integrated in the global process of decision making. The basic question is: in which patients could treatment outcome be improved by better local control? This was the question as it was asked in the decades in which postoperative radiotherapy was extensively investigated. The question which should now be asked is whether inadequate local control does not detract from therapy results. Strangely enough it appears that neither of the questions has been adequately answered in a scienti®c, solid way. We have a reasonable estimation of the order of magnitude of the potential in¯uences in both directions but still no de®nite answer. What is more interesting in the context of this discussion, is the fact that not only were several studies seriously ¯awed technically, but also most of them were done on patient sample sizes which would not even have been able to demonstrate statistically the existence of the differences which were investigated. Indeed, the studies on post-mastectomy adjuvant radiotherapy had two aims. One was to assess the effect of irradiation on locoregional control. Although many of the

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studies had great problems with totally inadequate irradiation techniques and with patient selection, the effect on locoregional control is so clear that it was signi®cant in nearly all the studies. The most important fact, which was already learned from these early trials in adjuvant setting, was that such type of treatment should only be given to patient groups where the problem one wants to solve is frequent enough. Although several factors are prognosticators for local recurrence, the most powerful was the axillary involvement. In those studies many node-negative patients were included, where local relapse rates are very low (,10 or even 5%). For this patient group, inevitably, every treatment will carry nearly exclusively toxicity and side effects, while few or no patients will have a bene®t. On top of this individual negative effect for the patients, the large number of patients in whom treatment can have no bene®cial effect will drown out potential bene®ts generated for other patient groups. The second aim was more ambitious. It was hoped to improve survival by increasing local control after mastectomy. This could obviously only be the case for those patients having locoreegional tumor deposits, while having no distant metastases yet. All patients without local tumor or with metastases can not have bene®t in cure rate. Both for the N0 and the N1 patients, this frequency can be estimated to be only between 5 and 10%. Indeed, this is the frequency of local relapses in N0 patients, which still has to be reduced by about 20% for patients with initial metastases. For the N1 patients where local relapse is around 20%, the nodal involvement also predicts for more than 50% of metastases, leaving about 10% of patients, potentially curable by more extensive local treatment in this patient group. None of the trials has patient samples which are large enough to hope to demonstrate this possible effect. Still, in several of the trials (NSABP, Stockholm, Oslo) a small survival difference was found which was for obvious reasons not `statistically signi®cant'. Several interesting conclusions can be drawn from the results of these trials and other, large scale retrospective studies. It is even more fascinating to observe how the results are used and, by unwarranted generalisation, wrongly applied. While it was known that the most important effect would be on local control, this well established fact is now thrown out by many oncologists, because they feel the second aim of the studies has not been achieved, even though in the circumstances, this was impossible. 7. Extrapolating results from bad treatment to a whole treatment modality The second aspect is the indiscriminate use and pooling of all data on `postoperative radiotherapy'. Everyone agrees on the necessity for adequate doses in chemotherapy. Still, there seem to be few qualms in using data of which it is generally accepted that they do not correspond to adequate

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radiotherapy, concerning neither dose nor treated volume. Even with all the evolutions in equipment, insight in to dose distribution and better biological knowledge, especially relating to late side effects, the old results are still taken as representative of what `postoperative radiotherapy' achieves in tumor control and sequellae. Still, nobody reading and accepting these conclusions as such would accept today to let a radiotherapist, proposing many of the techniques used in these trial, near his patients. Realising the potential negative effects of such therapy, this becomes critical. Everybody accepts now that unwarranted side effects of any therapy can occur, but especially so with defective techniques. Analyses of the late results of post-mastectomy trials are mainly dominated by the earliest studies, especially the one from Manchester, the initial technique of which was bound to lead to problems. The normal assessment today should require the question `is it possible nowadays to avoid the situation which led to these problems in the past, while preserving the potential bene®t?' One is thus left with the strange situation in which a proven fact is largely ignored, or not effectively accounted for, that a potential small bene®cial fact is considered as being non-existent, while it has mainly not been proven and that side effects of treatment modalities of 20±40 years ago are being labelled as representative for current techniques. 8. Unwarranted extrapolations of conclusions The conclusion that better local control is not important, because it has not been proven to improve cure rate in these early studies, is being generalised into an idea that local control is not important. Conclusions, whether right or wrong are often extrapolated from one patient population to another. As various other prognostic factors will become important, the whole situation may be altered. In the post-mastectomy situation one is faced with a situation that the vast majority of local relapses are the expression of a biologically aggressive behaviour of the tumor which has already permeated tissues outside the mastectomy specimen. Most of these processes are already generalised and improved cure chances have to be, by de®nition, rare. A totally different situation exists after breast conserving therapy. Here also, part of the recurrences are the expression of the invasive and metastasising characteristics of the tumor. This would be the same group of patients which would also recur after mastectomy. A second potential group of local recurrences could be found after adequate therapy because the tumor is radioresistant. We do not know if this group exists and, if it does, how big it is. These recurrences would be inherently linked to the breast conserving policy and are unavoidable. The last group are the patients recurring because of clear

de®ciencies in treatment technique (geographical misses, inadequate resections or radiation doses). It is this last group of `avoidable' recurrences which we should be worried about. Indeed, the conclusions of the early trials in which `more local control in bad prognosis patients' did not clearly improve survival have led to the idea that `less local control in good prognosis patients' will not be deleterious. Not only unjusti®ed inversions of arguments are done, also unwarranted generalisations of results, obtained in speci®c circumstances, are made to justify totally different techniques. Indeed, it is now widely accepted that `breast conserving treatment' yields the same survival as mastectomy. However, the published results are obtained in experienced centers or groups, sticking rigidly to speci®c selection criteria and treatment modalities. The most frequently quoted results of Veronesi are speci®cally for small tumors treated with very wide surgery and aggressive radiotherapy. It is still one of the series with the lowest frequency of local relapse. One can not justify the comparison of these results with other much less selected or less aggressive which have already been shown to carry much higher relapse rate. It was seen that most metastases originate during the phase of clinical growth of a breast tumor. If this is so, what would make us think that a ®rst growth leads to metastases, but a relapse would not? Looking at the numbers, it is evident that the statistical demonstration will be dif®cult. Indeed, if a relapse would generate about the same incidence of metastases as the ®rst growth when detected early (20%), even local relapse rates of 20±40% would generate only 4±8% of additional metastases in the whole group. Still, apart from statistical arguments a local relapse can never be considered as a positive fact for the patient. It is interesting to see how proponents of breast conserving therapy have gone to great lengths to prove that a local recurrence does not negatively affect survival. There are few instances in which the evidence is as weak. There are also few occasions where such circumstantial evidence has been accepted with greater enthusiasm as its consequences are very convenient indeed and will require major efforts to be disproved, if this will even be possible. At relapse there is always a certain percentage of patients which is discounted for further evaluation because of simultaneous metastases. A second group is eliminated because it is not eligible for rescue mastectomy. Usually it is very dif®cult to determine how many there are of these patients. Among the rescue mastectomies, some contain no tumor. Finally, the remaining patients are assessed and their survival is considered to be `in the range' of the non-relapsing patients. In view of the selective procedures and the calculated differences to be expected it is evident that with the few dozens of patients available in most series no solid conclusion will ever be reached. The only certain point for the moment is that a relapse

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after breast conserving therapy is a biologically different phenomenon then what happens after mastectomy. Whether one can state that the one is `hopeless' and the other `harmless' seems a case of oncologic optimism for which there are, for the moment, no solid facts in support. Two studies have given, or will possibly give, indications of the importance of good, initial local control, especially for smaller tumors, the majority of which is not yet metastasised at ®rst treatment. Both have used clearly insuf®cient local treatment. In the Guy's Hospital study a very low dose of irradiation was given while in the NSABP, no adjuvant radiotherapy was applied. In both studies very high incidences of locoregional failure were recorded. In the Guy's Hospital study, which has a very long follow-up, there is a small difference in survival for the T2 patients. A reduction of 20% in survival was found after the inadequate local treatment. This difference is statistically signi®cant. With only 140 patients involved one has to exert caution in the interpretation but too often these results which are unique due to their long follow-up, are ignored when discussing impact of local control. John Hayward has remained one of the strong advocates for adequate local control. The NSAB trial will potentially yield interesting data in the future. Presently there is a 30% difference in local relapse rate between irradiated and non-irradiated patients. The node negative patients will be the most interesting population, as they will have the lowest incidence of metastases from the primary tumor. In this group the difference in local recurrence between irradiated and unirradiated patients is about 25% and there are 738 patients in the two groups together. This number of patients gives a 90% chance to detect a difference of about 10%. Such a difference would be due to seeding of secondary metastases from the relapse and will thus, by de®nition, become apparent only several years after the clinical development of the local recurrences. Of the relapsing patients an average of about 25% would already have had metastases from the primary growth. This is assuming that there is no big difference between local relapse rates in metastasised and nonmetastasised patients. About 20% of the total patient group would then be left, which would have developed a local recurrence, without having had already distant metastases at initial diagnosis. If these local relapses lead to reseeding in 25 or 50% of the patients, incidence of metastases for the total group would then go up with 5 or 10%. To be able to con®rm or deny this small difference, a patient number of 1500 to 3000 would be necessary. It is regrettable that already now, it is stated that no in¯uence exists from local relapse, as, in the conditions it was searched for, it could not possibly be detected. It is true that in breast cancer, tumor activity in one site is often accompanied by localisations in other sites. It would be destructive pessimism (or optimism?) to suggest that any local tumor activity would only happen in patients who already developed metastases beforehand.

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The postmastectomy situation in which CR are reduced from 25 to 10% in a patient group with 70% of metastases is applied to the BCT patients where local relapses can go up from 5 (Milan group) to 40% (NSABP) while 75% of these patients had initially localised disease. 9. Optimization in breast conserving therapy In view of the preceding data, it would seem that local control is an important factor in the treatment of breast cancer and especially in breast conserving therapy, where a very high percentage of the patients still has initially localized disease. Does this mean that local control has to be pursued at any price? Evidently not. From the available data, it becomes more and more apparent that local control is dependent on the width of excision and on the radiation dose given. Breast conserving therapy is a form of treatment, developed as an alternative to mastectomy, which has been based on the improved quality of life in circumstances where a breast amputation can be avoided. This means that the cosmetic outcome of the treatment becomes one of the relevant factors upon which treatment result is assessed. The incidence of local control is dependent on the extent of surgery and the radiation dose. Again, too often this discussion is simpli®ed into black or white questions. For instance, the in¯uence of irradiation dose has been extensively studied in the Leuven department. Treatment outcome is determined, both by local control and by cosmetic sequellae. A local failure will on the one hand carry a risk for metastases and, on the other hand, has as a consequence a rescue mastectomy which evidently does not re¯ect positively on the cosmetic outcome. Very high radiation doses, with good local control, also result in a high incidence of cosmetically inadequate results. Looking at the dose response for local control, one sees that, with very low radiation doses, a local failure rate of about 40% is apparent. With increasing radiation doses, this rapidly rises to a local control of 90%. For signi®cantly higher radiation doses, local recurrence increases slowly to a local control rate which approaches a 100%. On the other hand however, the cosmetic outcome is also critically dependent on irradiation dose. At very low doses, nearly all patients show a cosmetically excellent result. The dose response curve here is also very steep and, for doses above 70 Gray, only a minority of patients still have a cosmetically satisfactory outcome. If one wishes to assess the optimal treatment outcome, one has to assess both factors and the balance occurring between them. This can be plotted in a curve, de®ning the frequency of patients in whom the tumor is locally controlled and for whom cosmetic treatment outcome is satisfactory. This shows that for lower doses, there is an increase in the frequency of this combination, as local control increases while cosmetic outcome is little or not affected. However, beyond

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a certain dose, local control increases only very slowly while the incidence of cosmetically satisfactory results still continue to decrease sharply. It is thus possible to de®ne an optimum dose range where the best combination of local control and cosmetic sequellae are reached. The dose at which this is reached, is dependent upon the level of sequellae one is willing to accept, or conversely, the incidence of local recurrence one is willing to have in any group of treated patients. This balance can be predetermined, but only if one has been able to quantitatively assess effects, as well as local recurrence rates. This is a very good example to demonstrate that different answers can be given the same question in function of the accepted premises . In this case, two different levels of sequellae can be proposed, namely, a nipple retraction level of 2 or 4 cm. The different incidence of local recurrences will not have a demonstrable, statistically signi®cant effect on the ultimate survival. Still, for the treating doctors involved, there may be a very significant difference in accepted risk levels. 10. Treatment of the axilla This is again one of the paradoxes in present day thinking about breast cancer. While it used to be considered an essential part of locoregional treatment its place in curative treatment is nowadays often questioned and it is only considered necessary `as a staging tool to de®ne the patient group in whom systemic treatment is necessary'. The direct consequence is that of axillary treatment is being gradually reduced. What is the potential bene®t of treatment of the axilla? This could only be the case if there is a subset of patients having axillary involvement and no distant metastases. There is a small but signi®cant group of patients with extensive (.4) nodal involvement in the axilla which remain disease free for over 10 years. In the large series from M.D. Anderson a 33% 10-year survival is demonstrated for these patients after aggressive locoregional treatment. This proves there is no complete overlap of the patient groups with nodal or distant metastases. If the axilla has to be treated, how should it be done? A number of studies have demonstrated that a proper axillary dissection and technically adequate radiation therapy have effects on local control which differ so little that they cannot be distinguished with the patient numbers investigated until now. The main advantage of the surgery is to yield the histologic information on nodal involvement which can be used as a selection criterion for adjuvant chemotherapy. If both modalities (radiotherapy and surgery) are used to their full extent, their capacity for local control and curative potential would be equal. It would then be dependent upon the subsequent treatment decision of the physician whether the nodal histology would be useful. This would only be the case if adjuvant chemotherapy is given selectively to only N1 patients. If chemotherapy is also given to N0 or to none

of the patients, for instance in a postmenopausal group, no advantage would be obtained with surgery over radiotherapy. If the surgery is very limited, nodal involvement remains in the axilla. As patients having nodal involvement in the higher level often have distant metastases, the loss of locoregional control would only have a real impact on a small group of patients. However, also for the assessment of adjuvant chemotherapy on distant metastases, it would seem a poor starting point to leave local tumor which the chemotherapy will not be able to control. What is the possible impact of a so-called `diagnostic nodal sampling?' Looking at a population of T1N0, one can expect about 25% of patients with a false negative clinical examination, who will still have histologic involvement. In this patient group, a 10% survival advantage could at best be expected after adjuvant chemotherapy. For the whole patient group, the axillary dissections in 100% of the patients and the CMF in 25% would lead, at most, to a survival advantage of 2.5%. Never would there be a trial able to con®rm the usefulness of such a procedure. Indeed for all we know, this small advantage in survival could even be completely lost and even counteracted if, through too much stress on systemic therapy only, local treatment would be insuf®cient. If the same illogical reasoning would be followed as is often done, we should cancel axillary dissection and subsequently adjuvant chemotherapy for the whole group as the potential difference would not be statistically demonstrable. However, in such instances it is better to make a clinical judgement based on available margins of effects and incidences of side effects. As this will involve many unknown facts or overlaps it is evident that the outcome of this decision making process could be very different in function of the value attached to the available evidence by the doctor as well as the patient. 11. Systemic adjuvant treatment Never has there been a single clinical question in oncology in which similar gigantic efforts have been invested than the assessment of the impact of systemic therapy in the management of operable breast cancer. The premises, theory, practical approach and initial results are well known and need not be reiterated. What is surprising, are the emotional aspects of the discussion which have carried way beyond any possible impact that this therapy modality will ever have in its present form. The small, but, real effect is negated by some for not being ®rm enough. Yet, on the other hand it is arti®cially rendered much more important by creating new types of endpoints. Hopes and wishes are projected instead of scienti®c caution or complete negation of results is proposed until longer follow-up is available. The hypothesis that a certain type of therapy should work is put as a dogma which creates dif®cult circumstances for

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the analysis and the assessment of the results. Assessments of toxicities are done in the most different ways possible, based on the same data. Statistical signi®cance is substituted for clinical relevance and interesting interim trial results are pushed vigorously and endorsed for routine application. Assessments of toxicities are done in the most different ways possible, based on the same data. Statistical signi®cance is substituted for clinical relevance and interesting interim trial results are pushed vigorously and endorsed for routine application. Still it would appear that it should be possible to stick to the facts as they are available now, and provide these to everybody needing to make decisions. As breast cancer is a slowly growing disease in a sizeable part of the patients, it always takes years before ®nal outcome is available. Meanwhile everybody will have to extrapolate as well as possible what can be expected. There is no need to cram speci®c guidelines down people's throats. The ®nal data are not yet available, and even when they will be, it is highly likely that the discussion will still not be over yet as the ®nal effect will probably not be so powerful in most patient groups as to override all other elements in the decision making. Gradually, a body of information is emerging and, rather than mainly speculate on whether some effects are likely to remain or to disappear, it would be more constructive to assess continuously what the clinical relevance is of the data available, at the present time. This means one cannot simply destroy or in¯ate a fact because of what one hopes it will become. Indeed, the discussion is too often reduced to a black or white distinction with `yes' or `no' answers. It is true that for every individual patient or for patient groups such a decision on whether or not to give systemic treatment, will have to be made, the ®nal conclusion of which will require some oversimpli®cations. Does adjuvant chemo- or hormonotherapy work? Of course it does, and there is no reason why it would not. We know that the classically used chemotherapy schedules can reduce metastatic lesions with a factor of 10 in more than half of the patients, and that clinical masses can be rendered subclinical in about a quarter of the patients. We also know its limitations, namely that patients with overt metastases can never be cured, even if the only known localisations are controlled by surgery or radiotherapy. The therapeutic ratio for possible cure will thus be limited to a narrow group of those patients with only 10 3±10 5 malignant cells. This possibility to signi®cantly reduce the number of subclinical breast tumor cells has been con®rmed. In the Peto analysis a global increase of 3.5% in survival is found. The natural course of a sizeable number of the breast cancers and the fact that adjuvant chemotherapy has its best chance for achieving cure in patients with minimal tumor burden are directly related to the fact that in¯uence of systemic adjuvant treatment on survival will automatically be expressed very late. It is impossible to delay all therapeutic decisions for patients, waiting for the ®nal outcome of the studies. Meanwhile the best parameter on which to

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base projected effects is the present effect on DFS. Without such an effect there will probably be no effect on survival. All cured tumors will show tumor growth delay. Not all delayed tumors will be cured. It is, therefore, a surprise that the con®rmation of CMF to induce tumour growth delay is considered as a certain predictor for its ability to cure. Indeed, this possibility to induce delay was known beforehand and was the basis for the attempt to achieve cure. The discussion should thus not be on `does it work, or does it not' but rather based on what effect can reasonably be expected and what price is one willing to pay for the potential advantage that can be obtained? The price that the individual patient pays is unchangeable. The global burden a patient group bears could however be reduced by focusing treatment on groups in which more patients could be eligible for a favourable outcome. This means patients with some metastatic localisations but without too big a tumor load and to whom effective treatment can be given. Such a distinction can already be seen for pre- or postmenopausal patients. In the Peto analysis a global survival increase for chemotherapy is seen of 3.5%. For premenopausal patients this becomes 6.9% and for postmenopausal patients 0.5%. The fact that the potential effect of systemic therapy is solidly con®rmed, but small, leads everyone to the conclusion that the next most important step is the identi®cation of subgroups of patients to be treated. The way in which one is proceeding in this matter is sometimes surprising. Indeed, very many prognostic factors have been investigated, all of which seem to have some power but nearly all being too weak independently or awaiting con®rmation. The strongest by far is still nodal involvement. It is interesting, taking into account the amount of effort by many of the people involved in the theory of the generalised nature of breast cancer, to demonstrate that nodal involvement is only an epiphenomenon of a disease which would always spread through the hematogenous route, that they still use this parameter basically as the main predictor for distant metastases. Still using only the numbers of Milan for the sake of simplicity, one can state that in the population treated, about 70% develop metastases without therapy, within a time period of 12 years, 30% remaining disease free. Of the whole group, supposedly 12% were cured, meaning that about 20% of potentially metastasising patients remained disease free due to the treatment. In the patients with a smaller tumor load (,3 nodes) the number of patients not at risk and thus uselessly treated, seemed larger, namely 40%, but the percentage of those at risk in whom potential tumor growth was delayed was larger, namely about 30%. This immediately points to the dif®cult dilemma, namely that if one looks for patient populations in whom tumor load is small enough for cure, one has a rapidly increasing proportion of patients not needing any treatment. When one only considers the increase in DFS one groups

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together the patients in whom treatment was super¯uous and those for whom therapy was ineffective. While this is correct and expresses exactly the limitations of the therapy, there is in therapy decision a psychological difference in which there should be much greater reluctance to treat, and impose toxicity, to patients which are already cured and in whom ®nal outcome can only be negatively in¯uenced, both in relation to quality of life, and even for ®nal survival. For patients with too heavy a tumor load one comes closer to the palliative situation in which all patients with overt metastases are. They are as a rule treated even knowing the limitations of the therapy which will be able, at best, to induce tumor delay. This is due to the fact that we still have the feeling that we have no way of predicting tumor response to therapy and thus feel justi®ed to try treatment, for which there is a reasonable chance for effectiveness. On the other hand we feel more or less responsible for determining the number of `disease-free patients' we will be treating as we have at least a reasonable estimate for this. This is the context in which one has to project the recent controversy in relation to the adjuvant treatment of N0 patients. Motivated by the suggestion that patients with few nodes involved would have a more favourable relative effect from adjuvant therapy, it was tempting to further extrapolate this to patients without nodal involvement. It is clear that a patient group without axillary node involvement has only about half of the incidence of metastases compared to the N1 patients. This would mean that at least twice as many of the patients with metastases in this group would have to be in the `curable bulk group' than amongst the N1 patients to obtain the same absolute effect in the whole group. Looking at the numbers, there seems to be very little evidence of this for the moment. The ®rst analyses of the NSABP studies published recently show a 9% DFS advantage for CMF and a 6% for tamoxifen, while no survival advantages are apparent yet. While it is interesting to see that these differences can be demonstrated thanks to the disciplined work of a large group of investigators and while these results should be incorporated by everybody in the elements on which treatment decisions should be made, the way in which these results have been presented, exploited, manipulated and fought for is not the most elevated example of the scienti®cally objective analysis of which these results were certainly worthy. The mention of the exact absolute extent of the effect is avoided in all discussions. In the accompanying editorial in the New England Journal one of the leading US oncologists succeeds in discussing the studies without once mentioning numbers. The effect is described as `an impressive reduction in the risk of recurrence' and `the clear effectiveness of chemotherapy', but there is no hard data. Apart from this, the statistical signi®cance of data, related to patient numbers, is used to suggest great clinical signi®cance. The exact numerical data are interesting and should be taken in account by every clinician. By 4-years of followup, 71% patients remaining disease-free until that time,

without treatment, had received therapy, 20% of patients with metastases had unsuccessfully been treated and 9% of the patients had been kept disease-free, thanks to chemotherapy. There is no way of going around these numbers which are the only ones truly accounting for the effect of adjuvant therapy. All the other numbers which are being used such as relative risks and relative odds ratios may be useful as tools to analyse the fundamental mechanisms but they are also very often used to build a psychological burden on the casual reader for whom they can be misleading, or maybe as an encouragement to the dedicated clinical investigator to con®rm the value of his undertaking. If adjuvant chemotherapy works in N1 patients, there is no reason it should not work in N0 patients. However, the effect on DFS could be expected to be, and has been con®rmed to be, still smaller than for N1 patients as fewer patients are at risk. For the effect on survival to be even equal to that in N1 patients one has to hope for a signi®cantly larger group of metastasised N0 patients to be in the `ideal, curable tumor bulk' group. With the data available up to now it is impossible to predict whether this will be the case. This discussion of N1 versus N0 patients is another example of the oversimpli®cation that very often takes place and can lead to unbalanced decision making. Lumping all N1 patients together, the incidence of patients developing metastases is signi®cantly higher than in those having no known nodal involvement. The next step is very often to consider the N1 group as a homogeneous population. For a patient with a small tumor and single microscopic nest of cells in one axillary node, this becomes the main factor for clinical decision making, as she is equalled to patients with multiple nodes. Still, looking at the data it is obvious that the prognostic difference between N0 and one positive node, is much smaller than the increase in metastases occurring between one and four involved nodes. An increase in the extent of nodal involvement causes a progressively higher incidence of metastases. Decisions on which populations are to be given adjuvant therapy could thus be dependent on this gradual difference and will have to be analysed in these subsettings when enough data is available. The exacerbation of the discussion around N0/N1 is thus an arti®cial isolation of a part of the problem, which might be the most easy way to identify it, but which focuses on differences which are smaller than those existing in other patient groups where no questions are raised. It is very important to have these distinctions in mind in order to keep enough ¯exibility in decision making and not to be tempted into sticking to absolute guidelines dependent on gross generalisation. The second aspect, necessary to take into account in assessing the effect of adjuvant therapy, is the toxicity involved. This is especially critical for the patient group which is already cured as they will have no bene®t from therapy and a high proportion of long-term survivors. It is pointless to go into an in-depth analysis of the different aspect of this problem. It is informative to look at the

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assessment which is made of the side effects of adjuvant chemotherapy in the recently published adjuvant trials on node negative patients. One of the editorials remarks that `the toxic effects ranged from very mild to severe, including treatment-related deaths. Furthermore, the possibility of very late toxicity with such adjuvant treatments has never been evaluated.' In the second editorial however, the analysis is `short-term side effects were not excessive and the risk of long term adverse effect seems minimal.' Obviously, a lot of the value of the treatment is labelled in adjectives which do not need quanti®cation. Besides `increasingly effective treatment' toxicity is `not excessive' and long term risk `minimal'. The lethal complications are completely eliminated from the analysis because the investigators state that, after a change in the treatment protocol, such events were not observed anymore. While the risk of long term effects is minimized, it is still said that `one trial omitted the alkylating agents, that because of their latent carcinogenic effects, cause so much concern' and also `short-term, more intensive treatment may well be more effective than long term treatment' and presumably lower risk, of long term side effects. It is obvious that in the analysis of these studies, too many projections are done and that these are only partly based on hard data and are partly hanging on to hopes and expectations. Also, the projections and proposals for future studies and routine treatment of patients are under heavy pressure in which psychological arguments are not shunned. There is general agreement that there is a de®nite effect of the adjuvant chemotherapy in a relatively small subgroup of the patients. The best way to relatively improve the results would be to be able to treat patients more selectively. Sadly, there are for the moment no clear indications as to how this could happen. The most consistently pointed at prognosticators are nodal invasion and, surprisingly, tumor volume. All other prognostic factors will, independently, be too weak and will have to be used in combination sets, the value of which is still unclear. There is deliberate confusion which is now created, stating that none of the published guidelines, should be generally applied, but that treatment should be given, based on individual decisions related to prognostic factors which are not available. Still, the suggestion is made that the great puzzle of the adjuvant therapy will soon be solved if even larger numbers of patients are entered into trials. From the 2% presently entered in clinical studies, one should go up to 10%, a ®vefold increase. For the con®rmation of the extent of the effect, this would not seem to be useful as this seems very well settled by now. The application of prognostic factors will only be possible in a very limited way prospectively, with the data presently available. It has to be hoped that prognosticators, to be discovered in the future will be evaluable retrospectively. Apart from long term follow-up of known treatment schedules, probably alternative treatment schedules with differ-

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ent intensities and lengths of treatment will be assessed. Again, it is surprising to see that already the conclusions are predicted with great strength and statements are made such as `a minimal increasing toxicity should be more than offset by the convenience of a short duration of treatment, especially if results are enhanced'. Apart from the directions of the clinical studies, important questions are raised on decisions in routine treatment. It has been stated that `what is good medicine and ethical behaviour in a clinical trial should be a good option for patients with breast cancer... The 30% chance of a recurrence is terrifying to most women and the risk of death due to the toxic effects is miniscule by comparison.' An inversion in reasoning is made through which, `what is considered good medicine in a clinical trial' is being suggested as a routine therapy. All the existing limitations on extent of the effect and unknown factors of long term effect could just as well be considered as good reasons to keep doing such a treatment only in controlled settings, in order to be sure that the necessary information, which is still lacking for the moment, will become available as soon as possible. The argument that the risk of recurrence is terrifying to the patient and the risk of death due to toxic effect miniscule, is a false reasoning. The only justi®able argument is whether the advantage that can be obtained is larger than the price to be paid, both results being quantitatively assessed. 12. Conclusion We are for the moment in a dif®cult, and sometimes strange situation. The easy framework, existing a few decades ago, in which any malignant breast pathology automatically led to a mastectomy, has disappeared. This was the logical consequence of the fact that a hypothesis, carried to its extreme, did not solve the existing clinical problem. Indeed, the progress achieved with the Halsted operation was not prolonged with the supraradical operations and the combinations with postoperative radiotherapy. The hypothesis of the systemic nature of breast cancer in all patients has created a scienti®c climate in which not only the main thrust of research was put on systemic treatment but which resulted also subsequently, in a lack of interest in local control, which probably goes further than what was initially intended by the scientists proposing the theory. One of the indirect consequences of the reduced rigidity of the local control hypothesis was the possibility to investigate breast conserving therapy. This has introduced a new factor in the decision making process, which is `quality of life'. This has very often proved very dif®cult to cope with for many physicians as it is a factor which is qualitatively different from the arguments which are usually included in the decision making process, and thus dif®cult to compare. On top of that, the development of clinical trials has created the dif®culty of how to integrate `small effects' into

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a decision-making process and how to avoid being in¯uenced psychologically by trial results which are inconclusive. Indeed, clinical trials are, by de®nition, set up to analyze small differences. Any clinical trial in which a large difference would be expected, would be mythical. The small differences are extremely dif®cult to prove, as they require an extreme rigidity in the discipline of the participants and require very large patient numbers. Most of the trials evaluated do not even reach the number of patients which would be necessary to prove or disprove the theoretically expected difference. The erroneous conclusion which is now often made is that, when a difference is not demonstrated, it is clinically non-existent. Conversely, very large statistical signi®cances are no additional help in clinical decision making. Changes in treatment policies affect the value of all prognostic factors and of other treatment modalities. If, rather than pleading limits in knowledge, one tries to press available data in a predetermined framework, one is evidently determining the outcome of the process in the direction one wishes it to go. Besides the unjusti®ed application of statistical signi®cance and the subjective in¯uence of convictions on the acquisition of data, the main problem is the bias in analysis. Unjusti®ed generalisations create great confusion. Good results in one type of BCT are used to justify all kinds of techniques, complications of inadequate therapy are highlighted or wiped out depending on convictions and, general de®nitions such as `local recurrence' are used to extrapolate data between totally different situations. In decision making in breast cancer therapy, it is as important to stick to logic as it is to stick to the facts and also clearly to realise the limits of the impact of `facts'.

It is true that very many logical hypotheses are as yet not proven, and there is a very good chance that they never will be. One should however not throw them out as non-existent unless they have been proven to be so. One should avoid being blinded by statistical signi®cance thinking that the result with the lowest P-value is the overriding argument and primary decision mover. Pursuing one aim, one has to be careful not to loose, at the same time, just as much on another ®eld. Indeed, doing subsequent studies, each time reducing the treatment result by about 5%, it would be impossible to ever prove that treatment is getting worse within each trial. In between studies patient populations would change enough through, for instance, new study procedures to blur the differences. One would thus, against all logic, progressively worsen treatment policy each time, hiding behind the fact that nobody can statistically prove that this is the case. Applying this to the present situation in breast cancer one can say that interesting progress has been made with the systemic adjuvant therapy. It is the natural inclination of a human being to feel that the newest things are the most important. In breast cancer it is important to be constantly reminded of acquired values. If we lose patients on one hand, the progress we make on the other side will be lost and the problem will only be shifted. Good adjuvant treatment deserves optimal local control. In decision making one should always be aware of the premises on which the decisions are based, the advantage that can be expected and the price that has to be paid. One should, however, not preselect the cards with which one is playing in order to make the game easier.