Adjuvant systemic therapy for operable breast cancer

Transcription

1 Bnmh Mahcal Bullilm (1991) Vol 47, No. 2, pp The Brmth Council 1991 Adjuvant systemic therapy for operable breast cancer H J Stewart The Scottish Cancer Trials Office (MRC), The Medical School, University of Edinburgh, Edinburgh, UK Adjuvant systemic therapy is now an important and recognized part of the initial management of patients with operable breast cancer. Its value in delaying relapse and prolonging total survival is established for disease of poor prognosis. For premenopausal patients the currently advised treatment is a 6 month course of CMF polychemotherapy and for postmenopausal patients it is daily tamoxifen for 2-5 years. For patients with disease of good prognosis there is a need to evaluate, within randomized trials, the usefulness of newer biological indicators of prognosis to improve selection for and of treatment. Continued monitoring of long-term results for delayed morbidity is also necessary. BACKGROUND TO CURRENT STATE OF THE ART Introduction Breast cancer can be a surprisingly chronic disease and, even today, often is not detected by the patient until at the relatively advanced stage of 3-4 cm in diameter. Initial therapy has two parts, each making important but not necessarily separate contributions to the overall control of the disease. Firstly, there is local therapy by surgery, radiation, or a combination of the two which is aimed at achieving local control with minimal morbidity (see Yarnold, this issue). Secondly, there is systemic therapy which is aimed at delaying the development of (or even eradicating) local and distant micrometastases.

2 344 BREAST DISEASE In the majority of cases, by the time an invasive tumour is palpable, micrometastases are already present. As a rule, metastases at distant sites are life-threatening, thus, adjuvant systemic therapy is assessed by the effect it has on life expectancy after initial surgery. This effect can be evaluated reliably only by comparing the 'new' regime with standard therapy within trials in which bias is minimized by random allocation of the treatments. Because of the variable and largely unpredictable behaviour of the disease large numbers of similarly denned patients are necessary for dependable results and widely applicable conclusions. It is in this context that the current status of adjuvant systemic therapy is considered in this chapter, with particular reference to the use of tamoxifen and CMF chemotherapy in easily definable patient subgroups. Ablation of the ovaries Taylor was one of the first to suggest that a radiation induced menopause could improve the results of conventional local therapy in premenopausal patients with early disease. 1 This was in the 1930s, when retrospective comparison with historical controls was the accepted method of evaluation. Benefit was reported in several small series in which results from prophylactic therapy (as adjuvant therapy was then called) were compared to those from the more usual post-relapse use. Delay in the onset of relapse after adjuvant treatment was reported but the affect on total survival was uncertain with only some series showing a modest increase, notably that of Kennedy. 2 The first controlled trial in breast cancer began in 1948 in the Christie Hospital in Manchester with the initial aim of randomly comparing, in women within 2 years of their final menstrual period, the effect on survival of ovarian ablation at the time of radical mastectomy with ovarian ablation for the treatment of first relapse. In fact the method used to allocate treatment (odd or even month of birth) was unsatisfactory by today's standards and the planned comparison was not achieved; only 31 of the 173 relapsed patients in the control group had had their ovaries ablated by 10 years. 3 However the long-term results are of interest, analysis at 15 years showing a significant delay in the onset of relapse and reduction in the incidence of distant metastases (P< 0.05). On the other hand there is no significant difference in overall survival between the 293 patients given adjuvant treatment and the total (303) in the

3 ADJUVANT SYSTEMIC THERAPY FOR OPERABLE BREAST CANCER 345 control group.* The reason for this latter 'failure' was considered to be due to the more frequent use of other endocrine therapies in control patients on relapse, with response-times counterbalancing the increase in disease-free interval seen in the treated group. Although adjuvant ovarian ablation for premenopausal patients, either by surgery or, as in the Manchester trial, by irradiation, was employed routinely in some centres, it never became widely established. Many clinicians preferred to delay treatment until positively indicated by relapse rather than subject all premenopausal patients to an irreversible procedure with unpleasant side effects which in the majority might never be indicated (on account of a natural menopause well before relapse) or from which they might gain nothing (only one third of metastatic patients achieve an objective remission). Interest was temporarily revived in the early 60s and again in the late 70s but although 11 further randomized trials were undertaken none accrued more than 300 premenopausal patients and the results reported were inconclusive. More recently the long-term results from 8 of these trials have been merged and, although the data are still incomplete, the findings on combined analysis are encouraging, indicating a significant long-term survival gain. 5 I believe that adjuvant ovarian ablation should have a place in the management of selected premenopausal patients with early breast cancer and that a revival of this first form of adjuvant systemic therapy should occur. More reliable methods of case selection and the avoidance of potential morbidity from surgery or irradiation, by instead suppressing ovarian function with the LHRH analogue goserelin (Zoladex ), make this approach more acceptable today. Already randomized trials with goserelin are underway. Explosion of drug trials By the 1970s the belief that breast cancer spread in a step-wise manner from primary tumour to regional lymph nodes and only then to more distant sites was replaced by the current view that regional disease represents a biological type; that lymph node involvement is a marker of a spreading tendency rather than the first step in a sequence of events. The acceptance of this theory (which explains the occurrence of distant relapse despite successful local treatment) led to an increase in the numbers of clinicians believing in the potential value of adjuvant systemic therapy. This

4 346 BREAST DISEASE coincided with the successful testing of new anti-mitotic drugs, used singly and in combination, and of the non-steroidal antioestrogen, tamoxifen, in the treatment of established metastases. These factors and some reports of early successes led to many randomized trials of different adjuvant therapies in 'early' disease. OVERVIEW ANALYSIS OF RANDOMISED TRIALS By 1983 the literature on the merits of numerous different adjuvant therapies was confusing, in part because of conflicting results from similar but small trials. Consequently, Richard Peto and his colleagues in Oxford sought the co-operation of breast cancer trialists throughout the world for a combined (meta) analysis of trial results. Following the publication of an interim report in 1984, 6 individual patient data from almost all of the known adjuvant therapy trials of either tamoxifen or chemotherapy have been recorded and checked and the results of trials with identical aims combined for re-analysed. The outcome from this combined analysis of results has been reported in detail 7 and in book form. 5 As well as the merged results at 5 years, outlined in Table 1 for the two most commonly tested treatments, the book contains separate descriptions of over 100 individual trials, involving over women, on which the meta analysis is based. For the sake of uniformity, age rather than menstrual status has been used to subdivide the patients in each trial. These results indicate that, at 5 years, a 9% absolute reduction in mortality (35% down to 26%) from adjuvant CMF in the young and a 7% absolute reduction from adjuvant tamoxifen in patients aged 50 years or more can be expected. These same figures can be expressed differently as proportional or relative reductions in mor- Table 1 The percentage survival to be expected at 5 years, following the use of either adjuvant tamoxifen or adjuvant CMF, and the absolute increase in the % surviving, given a 65% survival in control patients, the majority of whom had no adjuvant therapy Under 50 yrs 50 or over All ages Control group (65) (65) (65) Adjuvant tamoxifen % Surviving Gain 67 72* 71* Adjuvant CMF % Surviving Gain 74* * 5 'statistically highly significant survival compared to 65% m control!

5 ADJUVANT SYSTEMIC THERAPY FOR OPERABLE BREAST CANCER 347 tality of 25.7% (9/35) and 20% (7/35) respectively. They tell us nothing about the proportion of patients who do not gain anything from these adjuvant therapies. Readers should be aware that a further publication from the Early Breast Cancer Trialists' Collaborative Group, with results updated to 10 years, is expected in the near future. For the tamoxifen trials the regime most commonly studied has been 20 mg daily for 2 years and for polychemotherapy, conventional CMF for 6-12 months. For both these treatments, the relative proportions benefiting are the same for those with node negative disease as for node positive. It can also be concluded from the combined analysis that single-agent chemotherapy (peri-operative or long-term) is of minimal benefit only, that polychemotherapy is significantly more effective than single-agent, that a 6 month course of CMF is as effective as 12 months and that the addition of prednisolone does not improve the results. Despite these strongly significant overview findings, clinicians faced with individual patients still have decisions to make regarding adjuvant therapy. While some of the answers have been suggested by the meta analysis others are or will become available from large trials with selected intake and from subsequent merging of updated results. DECISION-MAKING FOR THE INDIVIDUAL PATIENT The questions to be addressed when considering individual patients are whether to treat, what to give, when to give it and how selective to be. The key variables relevant to the answers are menstrual status, nodal status and oestrogen receptor status (ER) which, taken together, allow patients to be divided into 8 subgroups. These are listed in Table 2 in the order in which they will be considered and with the adjuvant therapy which, from existing data, is currently thought to be appropriate. Biological variables influencing decision-making Until there are other biological indicators of risk of relapse which are widely available, reproducably reliable and more descriminating than nodal status, axillary lymph node involvement will remain an important identifier of poor prognosis and thus a selection factor for adjuvant therapy. Many 'new' markers are already being studied (e.g. the thymidine labelling index of growth, DNA ploidy

6 348 BREAST DISEASE Table 2 Key variables used to divide patients into 8 subgroups, listed in order in which they are considered and with the adjuvant therapy which (from existing data) is currently thought to be appropriate No. Menstrual status Node status ER status Therapy 1 prcmenopausal positive rich CMF 2 poor CMF 3 negative rich tamoxifen 4 poor CMF? 5 postmenopausal negative rich tamoxifen 6 poor tamoxifen? 7 positive rich tamoxifen 8 poor tamoxifen? and oncogene expression) but their place in the selection of patients for specific therapy remains uncertain (see Ellis, this issue). The presence of significant amounts of ER protein in the primary tumour (a level of 10 fmol/mg protein is the commonly used cut off point) is accepted as a short-term indicator of good prognosis and of endocrine responsiveness. Thus ER subgrouping relates more to the type of systemic therapy to advise than to whether or not any should be given, and in this respect is similar to the use of menstrual status (or age). I have intentionally omitted tumour histopathology special histological type, tumour grade, vascular invasion and necrosis as a 4th key variable. These histological features are recognized to be indicators of prognosis, and as such have been used retrospectively to demonstrate different levels of tumour responsiveness. 8 Their powers of discrimination relate most effectively to a relatively small group of tumours (those with excellent prognosis) and they are not in general use (see Sloane, this issue). None the less, they could be helpful with treatment decisions in node negative disease. Pointers to the likely influence of the 3 listed variables (Table 2) on outcome from adjuvant chemotherapy or tamoxifen are available from analysis of individual trials as well as from the merged trial results. Most, but not all, are based on indirect comparisons of subgroups, the results from which are less reliable statistically than those from direct (randomized) comparisons and so must be interpreted cautiously. Other factors of importance which should also be taken into account when making decisions about adjuvant systemic therapy for the individual are the patient's general health, her preconceived

7 ADJUVANT SYSTEMIC THERAPY FOR OPERABLE BREAST CANCER 349 beliefs about therapy and whether she considers duration or quality of life to be the more important factor in relation to her remaining years (see Fallowfield, this issue). PATIENT SUBGROUPS The poor prognosis premenopausal patient Adjuvant polychemotherapy, usually a 6 month course of CMF, can now be recommended unreservedly for premenopausal patients with disease deemed to be of poor prognosis, e.g. node positive or ER negative. 5 These patients are usually in good general health, are more tolerant of the unavoidable toxicity of chemotherapy than their older counterpart and value the chance of an improved life expectancy, even if this involves short-term distress from side effects. Timing of chemotherapy course Chemotherapy should be commenced as soon as feasible after initial surgery. As dose intensity is of greater importance to effectiveness than duration of therapy, 9 interrupted courses should be avoided. Thus, in theory, the chemotherapy course should be completed before post-operative radiotherapy is commenced but some employ an interrupted schedule, 'sandwiching' the radiation between the second and third injections. Giving both together may result in CMF dose reductions because of rarely occurring marrow suppression (see Yarnold, this issue). Alternative therapies Tamoxifen on its own can also be beneficial in premenopausal patients, 10 but overall the benefit would appear (on indirect not direct comparison) to be less than that from polychemotherapy alone. 5 Also from the meta analysis, no gain seems to follow the addition of tamoxifen to chemotherapy when given independently of ER status to premenopausal patients although in postmenopausal patients survival is increased by so doing. Perhaps the lack of demonstrable effect in the young is because fewer of them have ER rich tumours, 11 and that if endocrine therapy by ovarian ablation (e.g. with goserelin) was added only to the ER-rich subgroup, a significant extra benefit might be large enough to be detected.

8 350 BREAST DISEASE Another possible explanation for the lack of demonstrable benefit from added tamoxifen in the young is that chemotherapy acts in part by chemical castration. Thus the beneficial effect could be endocrine in origin and so benefit from other additional endocrine measures such as tamoxifen is pre-empted. Although this remains a realistic explanation, the lack of contradictory evidence should not take away from the undoubted advantage of adjuvant chemotherapy in these young women. However, it should be remembered that some young women may prefer ovarian ablation in order to avoid temporary hair loss and sickness and that, when ER levels are high, ovarian ablation alone could prove to be a reasonable alternative to adjuvant polychemotherapy with possibly a longer lasting beneficial effect on total survival. We in Scotland, with valuable support from Guy's Hospital, London, have just completed entry to a trial involving only premenopausal patients with involved nodes, in which oophorectomy and CMF chemotherapy are being directly compared. 12 Randomization was carried out without reference to ER status but knowledge of this is available in 80%. This trial is the only such direct comparison known and, although the total intake is disappointingly low at 332, analysis should throw some light on the answer to the above question. Node negative disease To treat or not to treat The main question to be answered, for premenopausal and postmenopausal patients alike in this category, is whether or not to advise adjuvant systemic therapy. The answer is not a clear-cut one although chemotherapy outside trials is still believed by many to be contraindicated. Although the majority of these patients do well, 25-30% are likely to die from relapse within 10 years, so attempting to improve overall prognosis is still a worthwhile goal. When to treat As already stated, for maximal benefit, adjuvant systemic therapy should be commenced as soon as possible after initial surgery. Also accepted but proven only by inference is the advantage to total survival of adjuvant over post-relapse therapy. This can be assumed from the results of the Scottish adjuvant tamoxifen

9 ADJUVANT SYSTEMIC THERAPY FOR OPERABLE BREAST CANCER 351 trial, 13 in which total survival has been significantly prolonged (P = at 8 years, unpublished update) despite the unique requirement for post-relapse tamoxifen in the control arm patients. Only in this trial can analysis of total survival be said to compare adjuvant therapy with post-relapse use. In it, post-relapse survival is significantly longer in control arm patients than in adjuvantly treated patients. Although data-derived, and as such not truly reliable, this finding, when taken in conjunction with the increase in total survival, suggests that the gain in disease-free survival from adjuvant tamoxifen remains dominant overall despite the gain in post-relapse survival produced by post-relapse use. This conclusion is at variance with that, described earlier in this chapter, from the Manchester adjuvant ovarian ablation trial. That the same is true for chemotherapy is likely, 9 but can only be assumed. ER-positive disease It is now established that endocrine therapy is likely to be more effective in ER positive than ER negative disease. Tamoxifen with its low toxicity is an obvious choice and of proven value. Over premenopausal and postmenopausal patients in this subgroup have been entered into an American trial (NSABP B-14) comparing tamoxifen to placebo. 14 At 4 years there has been a highly significant prolongation of the total disease-free and distant disease-free periods in both age groups despite the overall low incidence of relapse. Furthermore, side-effects from the placebo have been more frequently recorded than from tamoxifen confirming the insignificance of tamoxifen toxicity. Thus this trial adds support to the conclusions from the meta analysis that adjuvant tamoxifen should be considered for old and young alike and that, despite the different rates of dissemination, response in node negative disease is similar to that in node positive disease, there being symmetrical reductions in the relative risks of relapse. Reliance on significant prolongation of disease-free rather than total survival is acceptable and is necessary since, in good prognosis disease, long-term follow-up is required before mortality data, adequate for reliable statistical analysis, become available. Duration of adjuvant tamoxifen The optimal duration of tamoxifen is not firmly established but the meta analysis does suggest that 2 years is better than 1 year.

10 352 BREAST DISEASE Although treatment for 5 years is now being advocated by many, whether or not the extra 3 years will convey additional benefit will only be established by results from current trials directly comparing different durations. Indeed there is experimental evidence to support continuous tamoxifen, (i.e. until relapse). 15 But, although this is also being tested, there is no proof of improved effectiveness. Potential risks and additional benefits from tamoxifen No serious risks from long-term tamoxifen at a dose of 20 mg/day have been identified, although the report from Sweden of an increase in endometrial carcinomas in patients randomized to 40 mg/day indicates the need for continued vigilance. 16 In the Scottish trial, 13 subsequent endometrial carcinomas are equally distributed at a median follow-up of 6 years while, in both menstrual categories, node negative patients receiving adjuvant therapy have had a significant prolongation of disease-free survival (P= and P= respectively). 17 Two additional beneficial effects presumed due to tamoxifen have been identified in this trial. Firstly, a reduction to date in the development of new primary tumours in the contralateral breast (7 and 22 in treatment and control arms respectively in patients presenting originally with node-negative disease); 17 and, secondly, a significant reduction in fatal myocardial infarction in postmenopausal women (x 2 = 6.88, 0.001<P<0.01). 18 These additional potential benefits from adjuvant tamoxifen should perhaps not be forgotten when faced with the argument that disease of good prognosis does not need adjuvant therapy and that tamoxifen should be kept for the treatment of relapse. The problem of ER negativity ER negativity in association with node negative disease places the prognosis in some doubt. Premenopausal patients in this category have been included with those with node positive disease for whom polychemotherapy is currently advised. In postmenopausal women without histologically confirmed nodal involvement the knowledge of ER negativity may lead some to advise polychemotherapy rather than tamoxifen for them also. This is more likely to be the case in America than in Britain where the possibility of gain from adjuvant tamoxifen in ER poor disease (reported first in the NATO trial and then in the Scottish trial)

11 ADJUVANT SYSTEMIC THERAPY FOR OPERABLE BREAST CANCER 353 seems more often to be preferred to the inevitable reduction in quality of life produced by chemotherapy toxicity. While further results from these and other trials now confirm that a more reliable benefit from tamoxifen occurs in patients with ER rich tumours than ER poor, no ER subgroup has been identified for which there is no gain. 5 Also the gains from tamoxifen in different ER categories do not differ statistically one from the other. In my opinion, this justifies the use of adjuvant tamoxifen in patients for whom no receptor evaluation is available (although it does not justify either the non-availability of or lack of reference to the ER assay in many centres in the UK). If available, oestrogen receptor status should be considered when deciding which treatment to advise and the fit 'younger' postmenopausal patient should be offered adjuvant chemotherapy if she has receptor negative disease without node involvement, as well as her premenopausal counterpart. The early results of the NSABP trial B-13 have already confirmed that this subgroup of patients can significantly benefit in terms of disease-free survival (/ ) =0.01) following adjuvant methotrexate and 5-fluorouracil. 19 An even stronger case can be made for this approach for the subgroup of ER negative 'fit' postmenopausal patients who have involved nodes (vide infra). The problem of the small lesion With the advent of mammographic screening, diagnosis of impalpable breast cancer is becoming more common. Lesions without nodal spread and less than 1 cm, or non-invasive lesions with or without microinvasion, are being detected and treated by complete local excision and breast irradiation. They have an excellent prognosis and cure is more likely than for the majority of lesions detected by palpation. The argument for no adjuvant systemic therapy is thus a strong one but evidence in support of such a policy is assumptive. It is for these lesions in particular that evaluation of the newer more sophisticated tests for biological variables, such as thymidine labelling index, DNA ploidy, oncogene expression etc., is most needed. In the meantime, while awaiting the results of randomized trials, of which there are now many, adjuvant tamoxifen for 2-5 years for receptor positive lesions could be advised in the hope of not only delaying recurrence but also of reducing the development of new primary lesions in the

12 354 BREAST DISEASE residual or contralateral breast. In my opinion chemotherapy is not indicated here. The poor prognosis postmenopausal patient ER-positive disease Least controversial should be the use of adjuvant tamoxifen in postmenopausal patients with proven lymph node spread and receptor rich tumours. Such treatment is well tolerated and of proven advantage even when given without ER selection The dose most commonly in use is 20 mg daily for 5 years with the possibility of longer left open while justification for this from the trials directly comparing different durations is awaited. For those who wish to consider a combined chemo-endocrine approach, there is some supportive evidence. Firstly, in the NSABP trial B-09, significant benefit from adding tamoxifen to melphelan and 5-fluorouracil has been demonstrated but only in ER positive postmenopausal patients. 20 Secondly, in the meta analysis, the addition of tamoxifen to chemotherapy has been evaluated without reference to ER status and, at 5 years, compared to chemotherapy alone, the combination would seem to be more effective. On the other hand, combined analysis of the results of those few trials in which polychemotherapy has or has not been added to adjuvant tamoxifen therapy has shown no significant additional benefit. ER-negative disease As already indicated, the use of adjuvant tamoxifen for postmenopausal patients with nodal spread from tumours known to be ER negative remains controversial, particularly in America where polychemotherapy is in wider general use. Those patients in this subgroup who are in good general health should be offered chemotherapy with the knowledge that the chance of benefit is greater than from tamoxifen, but if they refuse, tamoxifen should be considered since this would still seem to be better than no adjuvant therapy. 5 ' 10 ' 13 CONCLUSIONS The systemic therapies currently in use as adjuncts to local treatment for operable breast cancer are far from optimal and it seems

13 ADJUVANT SYSTEMIC THERAPY FOR OPERABLE BREAST CANCER 355 unlikely that different combinations or sequencing of existing drugs will produce more than small additional improvements on what has already been achieved with CMF and tamoxifen. Other potentially effective adjuvant systemic therapies have been evaluated in a few isolated trials (e.g. aminoglutethimide, bromocriptine and immune modulators such as BCG and levamisol) but have been without convincing benefit. The value of further assessing some as additives to established adjuvant regimes is uncertain but may prove worthwhile in selected patients. The main hope for the future must surely lie in the development of new anti-tumour drugs. In the meantime we must develop and test ways of identifying high-risk subgroups most suited to different regimes and await the long-term assessment of the usefulness of the newer potential indicators of prognosis. In this way the numbers exposed to toxicity with a low chance of significant gain could be reduced without depriving those most likely to benefit. An additional gain from better selection of patients and more frequent use of adjuvant therapy would be an increased confidence in employing local therapies which conserve the breast. Finally, where doubt exists, the inclusion of patients in an appropriate randomized multicentre trial should be encouraged. This is the only valid way to ensure non-biased evaluation of methods of selection and treatment. REFERENCES 1 Taylor GW. Artificial menopause in carcinoma of the breast. N Engl J Mcd (1934); 211: Kennedy BJ, Meiklc PW, Fortuny IE. Therapeutic castration versus prophylactic castration in breast cancer. Surg Gyncc Obstet 1964; 118: Cole MP. Prophylactic compared with therapeutic X-ray artificial menopause. In: Joslin & Gleave, eds. Second Tenovus Workshop, The clinical management of advanced breast cancer. Cardiff: Tenovus Workshop Publications, Cole MP. A clinical trial of an artificial menopause in carcinoma of the breast. INSERM 1975; 55: Early- Breast Cancer Trialists' Collaborative Group. Worldwide evidence: Treatment of early breast cancer, Vol. 1, Oxford: Oxford Medical Publications Anon. Review of mortality results in randomised trials in early breast cancer. Lancet 1984; ii: Early Breast Cancer Trialists' Collaborative Group. Effects of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer. N Engl J Med 1988; 319: Fisher B, Redmond C, Fisher ER, Redmond C, Caplan R. Relative worth of estrogen or progesterone receptor and pathologic characteristics of differentiation as indicators of prognosis in node negative breast cancer patients: find-

14 356 BREAST DISEASE ings from National Surgical Adjuvant Breast and Bowel Project Protocol B-06. J Clin Oncol 1988; 6: Goldie JH, Codman AJ. The genetic origin of drug resistance in neoplasms: implications for systemic therapy. Cancer Res 1984; 44: Nolvadcx Adjuvant Trial Organisation. Controlled trial of tamoxifen as a single adjuvant agent in the management of early breast cancer. Br J Cancer 1988; 57: Daehnfeldt JL, Briand P, Palshof T, Mouridsen HT. Oestrogen and progesterone receptors in 701 breast cancer biopsies. Rev Endocrine-Related Cancer 1978; October Suppl: Stewart HJ. Scottish Adjuvant Breast Cancer Trials: Results in Pre-menopausal patients. In: Senn, Goldhirsch, Gelber, Osterwalder, eds. Recent results in cancer research, 115. Berlin-Heidelberg: Springer-Verlag, Breast Cancer Trials Committee (SCTO). Adjuvant tamoxifen in the management of operable breast cancer: the Scottish Trial. Lancet 1987; ii: Fisher B, Costantino J, Redmond, C. et al. A randomised clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med 1989; 320: Jordan VC. Long-term adjuvant tamoxifen therapy for breast cancer. Breast Cancer Res Treatment 1990; 15: Fornander T, Rutqvist LE, Cedermark B. et al. Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet 1989; ii: Stewart HJ. The Scottish node negative adjuvant tamoxifen trial. Proceedings of the consensus development conference on the treatment of early breast cancer, Bethesda, NCI Monograph, 1991 (in press) 18 McDonald C, Stewart HJ. Fatal myocardial infarction in the Scottish adjuvant tamoxifen trial (Submitted) 19 Fisher B, Redmond C, Dimitrov NV et al. A randomised clinical trial evaluating sequential methotrcxate and fluorouracil in the treatment of patients with nodenegative breast cancer who have estrogen-receptor-negative tumours. N Engl J Med 1989; 320: Fisher B, Brown A, Wolmark N. et al. Prolonging tamoxifen therapy for primary breast cancer. Findings from the National Surgical Adjuvant Breast and Bowel Project Clinical Trial. Ann Intern Med 1987; 106: