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Review Article
Adjuvant Hormone Therapy in Breast Cancer Carl P. Blomqvist, lnkeri Elomaa and Pentti Rissanen
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Recent results from controlled trials of adjuvant tamoxifen and oophorectomy in early breast cancer are reviewed.The results of the statistical overview performed by the Early Breast Cancer Trialists Collaborative Group are summarised, and some important questions left open by this overview are discussed.These include the choice of patients for adjuvant endocrine treatment, long term results of tamoxifen, interaction with postoperativeradiotherapy,theeffect of tamoxifen on non-cancer deaths,and interaction of the adjuvant effect of tamoxifen with concentrationsof oestrogen receptor levels in the tumour. Key words: breastcancer; adjuvant theraby; tamoxfen; oophorectomy. (Annals of Medicine 24: 91-96, 1992)
Introduction Numerous controlled studies have assessed the effects of adjuvant oophorectomy and tamoxifen in breast cancer. This article reviews current evidence of the beneficial effects of these treatments, the choice of patients for adjuvant endocrine treatment, potential long term toxicity, interaction with local treatment,and some aspects of the mechanism of the reduction in breast cancer deaths by the use of adjuvant endocrine intervention among patients with breast cancer. In 1984, an effort to do a statistical overview of trials investigatingadjuvanttreatment in breast cancer was started at a meeting in the United Kingdom. Data on results from all controlled trials studying adjuvant treatment in breast cancer were collected. The aim was to combine the results of these studies by means of a so-called overview analysis or meta-analysis, which it was hoped would produce more reliable data than single trials on the effects of various adjuvant therapies on the prognosis of breast cancer. The first scientific report was published in the New England Journal of Medicine in 1988 (1). In 1990, a more detailed report on the results was published in the form of a monograph (2). A second overview analysis extending the follow-up time to 10 years after randomisationwas started in 1990 and has recently been published (3). These reports are based on trials conducted all over the world with the exception of the USSR.
Meta Analysis of the Results of Adjuvant Hormone Therapy In this section where reference is made to reduced mortality From the Department of Radiotherapy and Oncology, Helsinki University Central Hospital, Helsinki, Flnland. Address and reprint request: Carl Blomqvist,M.D., Department of Radiotherapy and Oncology, Helsinki University Central Hospital, Haartmaninkatu 4. SF-00290 Helsinki, Finland.
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and recurrence rate, the percentagesgiven refer to relative and not to an absolute fall in mortality rates. If, for example, in a given untreated patient group, mortality is 50 %and the relative reduction of mortality by treatment is 25 Yo,this results in a final mortality of 37.5 o/o and not 25 Yo.Thus, the smaller the original mortality is the smaller will be the absolute reduction in mortality for a given relative mortality reduction.
Adjuvant Tamoxifen Therapy The latest meta-analysisof adjuvant tamoxifen therapy was done on 40 controlled studies involving 29 892 women (3). The analysis included studies in which adjuvant tamoxifen was compared with a control group and studies in which tamoxifen was combined with another adjuvant treatment the rest of the treatment being the same in both groups. Tamoxifen treatment reduced mortality overall by 17 % (SD 2) ( P < 0.00001) and recurrence of breast cancer by 25 Yo (SD 2) ( P < 0.00001); in women over 50, mortality was reduced by 20 O h (SD 2) and recurrence by 29 'A (SD 2). In patients under 50 there was a non-significant reduction in mortality (6 %, SD 5). Nevertheless, the rate of recurrence in women under 50 years was cut by 12 Yo(4) ( P= 0.001) (3). The reductionin mortalitywas similar regardlessof whether tamoxifen was used alone (19 %, SD 3) or combined with chemotherapy (16 %, SD 3). In most studies in women under 50 tamoxifen was combinedwith adjuvantchemotherapy(n= 6386), whileasmaller number had received tamoxifen alone (n = 2226). Mortality reduction was 17 % (SD10) with tamoxifen alone and only 3 % (SD 5) with tamoxifen added to cytotoxic agents in women under 50 years of age. In women over 50, however, mortality reduction was almost identical with tamoxifen alone (19 %, SD 3) and combined with cytotoxic agents (20 Yo,SD 4). Since no statistically significant overall interaction between tamoxifen and chemotherapy was found the rele-
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Blomqvist 9 Elomaa Rissanen
Although the meta-analysis has provided much new vance of these figures remains unclear. It means, however, that the results from the overview analysis cannot be used information about the significance of adjuvant hormone as astrong argumentagainst the eff icacy of tamoxifen alone therapy and its effects on the prognosis of patients with as adjuvant treatment in women younger than 50. In breast cancer, many problems remain unsolved. Extensive postmenopausal women the confidence interval of the further research is needed before adjuvant hormone theestimated effect of combiningtamoxifen with chemotherapy rapy establishes its position in the treatment of breast is fairly narrow and indicate that the effects of the two cancer. Some important issues which remain unclear are treatment modalities are relatively independent. In patients briefly summarised in Table 1. The rest of this review deals mainly with these questions younger than 50 years, however, the confidence intervals are quite large and the estimates of possible interactions in the light of recently published controlled studies. between cytotoxic and endocrine adjuvant therapy therefore still quite uncertain. Longer duration of adjuvant tamoxifen therapy was assoCombination of Adjuvant Tamoxifen ciated with a highly significantly ( P < 0.00001) greater reTherapy and Radiotherapy. Effect of duction of recurrence,while the association between treatAdjuvant Tamoxifen on Local and Distant ment duration and mortality was only modestly significant Recurrences ( P < 0.01). Reductionof recurrence was 16 o/o (SD 3), 28 o/o (SD 2), and 39 (SD 4) with tamoxifen for5 1 year, 2 years So far, only a few detailed results have been published and > 2 years, while the mortality reduction was 11 Yo (SD showing what kinds of recurrenceadjuvant tamoxifen ther4), 19 Yo(SD 3) and 24 % (SD 6), respectively. The dosage apy is capable of preventing. Rutqvist et al. have published did not seem to be of great importance in the ranges of results obtained in Stockholm in a controlled study on doses studied: mortality was reduced by 17 Yowith a daily tamoxifen adjuvant treatment. The study involved 1,429 dose of 20 mg, and by 15 Yowith a daily dose of 30 to 40 mg women (4, 5); patients with a high risk of recurrence were (difference not significant). randomizedto either postoperative radiotherapy or adjuvant The interaction between oestrogen receptor content of cytotoxic therapy (cyclophosphamide, methotrexate, the tumour and mortality was not statistically significant: fluorouracil, CMF). No statistically significant effect of mortality was reduced by 11 O h (SD 5) in receptor-negative tamoxifen was seen in terms of total survival rates after a 10 patients and by 21 Yo (SD 3) in cases with receptor positive year follow up. However, the disease free period was tumours. Recurrence was, however, significantly statistically significantly longer if the patient had received ( P < 0.00001) more effectively reducedin oestrogen receptor adjuvant tamoxifen. Disease free survival rates at ten years positive (32 %, SD 3) than in oestrogen receptor-negative in the four treatment groups of the high risk patients are tumours (13 %, SD 4). shown in Table 2. A significantly better recurrence free The relative reduction in mortality was the same and survival rate was seen after postoperative radiotherapy statisticallysignificant in all groups regardlessof the extent compared to CMF. No differences in terms of local recurof lymph node invasion: 17 Yo (SD 5) in lymph node nega- rence rate, distant metastases or death were reportedwhen tives (NO)and 18Yo(SD 2) cases with lymphnode metastases tamoxifen treatment was added to radiotherapy. (NI). The absolute reduction of mortality was, however, Treatment with tamoxifen significantly reducedthe number naturally less in the prognosticallymore favourable NO (3.5 of local recurrences but not the occurrence of distant recurYoat 10 years) than in N1 patients (8.2 "A). rence or death (4) (Table 3). Two studies by the Ludwig group, Ludwig Ill and IV, a Oophorectomy comparison between 681 patients randomised between adjuvant tamoxifen and prednisonetreatment, no adjuvant The two last reports on the meta-analysis(2,3) also includ- therapy also showed asignificantfallinthe riskof locoregional ed an analysis of the effects of adjuvant oophorectomy on recurrence but not in distant relapse (6). A predominant breast cancer mortality in the light of randomised studies. effect of tamoxifen on locoregional recurrence has also The latest analysis involvedten controlledstudies and 3014 been reported from the NATO study comprising 1,285 prewomen. In patients younger than 50 years ovarian ablation and postmenopausal patients (7). reduced recurrence by 26 Yo6 ( P = 0.00007) and mortality by 25 Yo (SD 7) (P=O.O004). There was no statistically significant reduction in either recurrence (6 %, SD 7) or Table 2. The Stockholm adjuvant study. Recurrence free surat 10 years in breast cancer patients with high risk of mortality (3 Yo,SD 7) in women older than 50 by ovarian vival disease randomised to radiotherapy and adjuvant treatment. ablation. Therapeutic group Table 1. Tamoxifen adjuvant treatment in breast cancer. Unsettled issues. *
* *
*
Role of ajuvant therapy in patients with no lymph node spread Effect of adjuvant tamoxifen on local recurrences The role of postoperative radiotherapy combined with adjuvant tamoxifen therapy The reason for apparent lack of effect of adjuvant tamoxifen on mortality in premenopausal women The lack of association between tumour oestrogen receptor content and effect of adjuvant tamoxifen on mortality The role of combinations of tamoxifen and adjuvant chemotheraPY
Radiotherapy Radiotherapy and tamoxifen CMF CMF and tamoxifen
n
Recurrence free survival ("A)
90 100 114 123
57 63 31 47
CMF: Cyclophosphamide 100 mg/m2 orally day 1-14; Methotrexate 450 mg /m2 IV day 1 and 8; 5-fluorouracil600 mg/mzday 1 and 8, 12 cycles with 28 days interval Tamoxifen: 40 mg daily 2 years Radiotherapy: 46 GY113 fractions to chest wall, axilla, supraclavicular fossa and internal mammary nodes
Adjuvant Hormone in Breast Cancer
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Table 3. The Stockholm adjuvant study. Effect of adjuvant tamoxifen therapy on local and distant recurrences.
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Local recurrences Distant recurrence Death
Tamoxifen (%) (n = 71 1)
Control (%) (n = 696)
8 17 18
13 20 20
The Danish Breast Cancer Group (DBCG) has conducted a series of randomised studies on the combined effects of adjuvant drug therapy and radiotherapy (8,9). In an early trial 1,716 postmenopausal women with a high risk of recurrence were randomised to adjuvant tamoxifen or no adjuvant tratment. All patients receiver postoperative radiation. Tamoxifen significantly reducedthe number of recurrences and deaths (8). In a subsequent study 1,202 postmenopausal women with large tumours or axillary metastaseswere randomisedbetween radiotherapyand no further local therapy: adjuvant tamoxifen was administered to all patients. Local recurrences and survival rates at five years are shown in Table 4 (9). These results suggest that tamoxifen adjuvanttreatment, although exerting its greatest impact on locoregional disease, does not always ensure adequate local control, at least not in patients with a high risk of recurrence, and that radiotherapy still has a role in this respect. On the other hand, postoperative radiotherapy does not seem to have a significant effecton survival rate when it is added to adjuvant tamoxifen therapy (5, 9).
Adjuvant Tamoxifen Therapy in Lymph Node-negative Patients Meta-analysessuggest that tamoxifen was equally effective in reducing recurrencesand deaths in women with no lymph node involvementand those with a spread to axillary nodes, and statistically significant in both. However, since there were fewer deaths in the former than in the latter group, the absolute reduction in women with no lymph node involvement was far less (3). No single randomised study has yet yielded a statistically improved survival by tamoxifen in women with no lymph node involvement. The first results from a controlled study by the NSABP group of tamoxifen adjuvant treatment in women with no lymph node involvement was publishedin the New England Journal of Medicine in 1989 (10); 2,644 postmenopausal, oestrogen receptor-positive women with node negative breast cancer were randomised to tamoxifen treatment or control. At the 4-year follow up tamoxifen had statistically significantly improved the disease free survival rate (83 Yo
P c 0.01
NS NS
Table 4. The Danish Breast Cancer Group trial DBCG 82. Postoperative radiotherapycombined with adjuvanttamoxifen therapy in postmenopausal breast cancer and a high risk of recurrence. 5 years results
Control group (%)
Radiotherapy (%)
36 61
6 62
Local recurrences Survival
versus 77 ”/.). On the other hand, there was no significant difference between the total survival rates (92 versus 93 YO). Varying opinions have been expressed as to the therapeutic significance of these results, including those of two respectedAmerican cancer experts in the same issue of the New England Journal of Medicine (11, 12). Vincent de Vita stated that these results “show an impressive reduction in the risk of recurrence among patients with node-negative disease” and that “the failure to observe a difference in overall survival is almost certainly a matter of timing”. He then recommends that apart from minimal and non-invasive tumors “all women with newly diagnosed localized invasive breast cancer can and should be offered some form of systemic treatment”. William McGuire,on the other hand, commentedthat “the cost considerably outweighs the benefits of treating all node-negative patients, especially in the absence of a proved survival benefit”. McGuire recommended further research on new prognostic factors, saying “that clinicians use the individual patient’s risk factors - to weight the probability of benefit against the patient’s total risk profile and overall clinical conditions”. At present, the opinions of the oncological community of adjuvant treatment in women with no node involvement are divided, and the issue will probably remainopen until further evidencefrom randomised trials emerges.
Depencence of Adjuvant Tamoxifen Effect on Oestrogen Receptor Content of the Tumour Rutqvist et al. have published an analysis of the influence of oestrogen receptorstatus on the risk of recurrencefollowing
Table 5. The Stockholm adjuvant study. Effect of oestrogen receptor content and adjuvant tamoxifen therapy in frequency of recurrences. Oestrogen receptor content c 0.05 fmollyg DNA 0.05-0.08 fmol/yg DNA > 0.88 fmol/pg DNA
Recurrences controls (%) (n = 387)
Recurrences tamoxifen (%) (n = 363)
30 22 26
38 16 11
P NS NS P < 0.01
Note: 158 patients with high risk tumours also received posoperative radiation and 108 patients were also given adjuvant chemotherapy.
Blomqvist Elomaa Rissanen
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adjuvant tamoxifen therapy in the light of the Stockholm study (4). Table 5 shows the frequency of recurrences in various oestrogen receptor content categories, the median follow-up time being 6.5 years. The most pronounced therapeutic effect was seen in patients with tumours having high receptor contents, while no statistically significant effect was detected in patients with receptor negative tumors. Rose et al. have published a preliminary analysis of the effects of oestrogen receptor content on the efficacy of adjuvant tamoxifen therapy (13) in the DBCG study. In this study also, inhibition of recurrences seemed restricted to tumours with high receptor contents. In later reports by the same group the correlation between receptor values and tamoxifen was confirmed (8, 14). Furthermore, postmenopausalpatients with especially high receptor values (more than 200 fmol/mg protein) were found to carry a dismal prognosis of not given adjuvant treatment, while the prognosiswas improvedaftertamoxifen adjuvant treatment (14). Like the DBCG and Stockholm studies a report from the Ludwig studies Ill and IV also showed endocrine treatment in postmenopausalpatients only benefittedthose with oestrogen-receptor positive tumours (6). In contrast to these studies the NATOtrial did not show any interactionbetween oestrogen receptor status and recurrence free or overall survival rates (7).The results in the Stockholm, DBCG and Ludwig studies seem to contradict the results of the metaanalysis. However, a clear correlation was found between the receptor content of the tumour and reduction of recurrence in the overview analysis as well. Only with respect to overall mortality was the correlation between the effect of tamoxifenand oestrogen receptor status lacking. The metaanalysis did not include any analysis on causes of death, and thus left unsettled whether the reduction in death rate by tamoxifen adjuvant therapy was consequent on breast cancer only, or whether adjuvant therapy also affected other causes of death. Little is known on this subject so far, although a preliminaryanalysis on causes of deaths recently published from the so called Scottish trial may provide addditional information (15). In astudy on causes of deaths in this trial some extremely interesting findings were reported (15). The Scottish trial involved a total of 1,323 pre-, peri- and postmenopausal women randomised to receive adjuvant tamoxifen therapy or tamoxifen only after recurrence (15). The study showed a statistically significant reductionin the risk of death among the patients as a whole. As in the overview analysis, risk of death was more or less the same in all oestrogen receptor strata, and in post- as well as in premenopausal patients. However, just as in the Stockholm and the Danish studies there was a statistically significantly larger reduction of recurrence in patients whose tumours had high oestrogen receptor contents.
The analysis of causes of deaths provided some surprising findings (Table 6) (15). Deaths from breast cancer were considerably reduced in premenopausal patients receiving tamoxifen but very little in postmenopausalpatients.Among the latter, cardiovascular mortality was reduced after tamoxifen therapy, and this explained almost all the difference between the numbers of deaths of postmenopausal patients in the control group and in the group receiving tamoxifen. Calculation of the statistical significance of this finding was not provided. If tamoxifen shows other beneficial “side effects” (e.g. reduced risk of cardiovascular death and prevention of contralateral breast cancer) in older patients, in particular,it could at least partly explain the better effect of adjuvant tamoxifen in postmenopausalpatients. Results on causes of death from most other randomised tamoxifen trials is still lacking. In the NATO study, however, non-cancer deaths were also reduced (34 versus 43 deaths) in the tamoxifen group (7). In the Ludwig trials 111 and IV, on the other hand, there were more non-cancer deaths (15 %) in the patients treated with tamoxifen and prednisonecomparedwith those who had no adjuvant treatment (5 O h ) (6).
Long Term Effects of Adjuvant Tamoxifen on Other than Breast Cancer Morbidity The Stockholm study has produced several reports on the log term effects of adjuvant tamoxifen. In a study of the effects on the occurrenceof new primarytumours tamoxifen adjuvant therapy wasshown to reducethe riskof contralateral new primary breast cancers (18 in the tamoxifen group and 32 in the control group) (16). As far as other primary tumours were concerned, differenceswere onlyseen in cancer of the uterine corpus, in that their occurrence seemed to increase after treatment with tamoxifen (13 versus 2) (16). In the Stockholm study, the daily dose of tamoxifen was 40 mg, and no cancer of the uterus was recorded earlier than after two years’ treatment with tamoxifen. A preliminary analysis on the Scottish trial published by Stewart did not show similar increases in the number of carcinomasof the corpus uteri (14). Stewart, however, also found a reduction in the number of new primary breast cancers (15). In the “Scottish study”, the daily tamoxifen (20 mg) dose was only half that used in the Stockholm study. Tamoxifen’s effects on serum lipid metabolism have been the subject of several studies (15, 17, 18, 19). These have generally shown that serum lipids are modified in a way that tends to reduce cardiovascularmorbidity,an effect which mimics the effect of oestrogen and which may explain the connection between adjuvant tamoxifen treatment and the reduction in cardiovascular mortality. Tamoxifen has in rare cases been associated with ocular complications. In a few patients, especially those receiving
Table 6. The Scottish trial. Causes of deaths in pre- and postmenopausal patients with breast cancer receiving adjuvant tamoxifen and controls. Cause of death
Breast cancer Myocardial infarction All causes
Prernenop. tarnoxifen (n = 108)
Prernenop. controls (n = 106)
Prernenop. tarnoxifen (n = 266)
Prernenop. controls (n = 267)
12 -
21 22
43 5
45
68
79
14
15
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Adjuvant Hormone in Breast Cancer high cumulative tamoxifen doses, complications have occurred in the retina, cornea or optic nerve, athough most of these have been reversible (20). In any case, this side effect is very rare and its exact incidence is unknown. The Stockholm group and others have published results on the effects of tamoxifen on skeletal mass (21, 22,23). In the Stockholm study using an isotopic bone measuring technique adjuvant tamoxifen therapy did not increase the risk of osteoporosis even when treatment had lasted for five years (21). Consequently, it seems that in certain organs tamoxifen acts not only as an oestrogen antagonist but as an oestrogen agonist as well. The agonist effect seems to be stronger in the uterus and possibly in the skeleton, and the antagonist effect in the mammary tissue. This might explain why tamoxifen does not induce osteoporosis although lack of oestrogen certainly does. As far as lipid metabolism is concerned, tamoxifen’s agonist effect seems to be the prevailing one. So far, the rare occurrence of eye complications and the possible induction of carcinoma of the uterus seem to be the only demonstrated severe side effects caused by long term tamoxifen therapy.
Conclusions Adjuvant tamoxifen therapy clearly reduces recurrence of breast cancer and deaths in postmenopausal patients with axillary node spread. In premenopausal patients the effect on the risk of death remains unclear. The proportional reduction in mortality is the same in women with no lymph node involvement and those with a spread to axillary nodes, but the absolute difference is much less in the former due to the substantially better prognosis of women with no lymph node involvement. Adjuvant tamoxifen treatment for two years or longer seems to ensure a greater reduction of recurrence and mortality than shorter treatment, while the dose of tamoxifen is less important and a daily dose of 20 m g seems to be adequate. The overview analysis on adjuvant oophorectomy showed that both surgical oophorectomy and castration by radiation may reduce mortality in early breast cancer. The magnitude of the effect was similar to that obtained with tamoxifen therapy. As expected, the effect of oophorectomy was evident only in patients aged under 50. Adjuvant tamoxifen does not seem to induce osteoporosis but it does reduce the occurrence of new primary breast cancers. Long term adjuvant tamoxifen treatment-at least in a high dosage - may increase the risk of corpus uteri carcinomas. The possibility of tamoxifen induced eye complications should be borne in mind when using adjuvant tamoxifen therapy, although the risk of this side effect seems minor. One study has shown that adjuvant tamoxifen therapy reduced the risk of cardiovascular deaths, which could, at least in part, explain the better effect of adjuvant therapy in postmenopausal women. This may be connected with the favourable effects of tamoxifen on lipid metabolism. Despite the fact that adjuvant tamoxifen therapy seems most effective against local recurrences, the risk of local recurrences continues to be great in patients with more advanced breast cancer receiving adjuvant therapy. This risk may be reduced by postoperative ratiotherapy, which therefore still has to be considered as an option in at least
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certain subsets of patients given adjuvant endocrine therapy. Tamoxifen therapy seems to be most effective in preventing the recurrence of breast cancer if the tumour has a high receptor content. The correlation between the oestrogen receptor content and the reduction in mortality is less obvious; this may be explained in part by the fact that tamoxifen also affects mortality from causes other than breast cancer. The authors wish to thank ICI Pharmaceuticalsfor help in preparing the manuscript.
References 1. EBCTCG. Effects of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer. An overview of 61 randomizedtrials of 28,896 women. N EnglJ Med 1988; 319: 1681-92. 2. EBCTCG. Treatment of early breast cancer. Worldwide evidence 1985-1 990. Oxford: Oxford University Press, 1990: 209. 3. EBCTCG. Systemic treatment of early breast cancer by hormonal, cytotocis, or immune therapy. 133 randomised trials involving31 000 recurrences and 24 000 deaths among 75 000 women. Lancet1992; i: 1-15,71-85. 4. Rutqvist LE, Cedermark 8, FornanderT, et al. The relation-
ship between hormone receptor content and the effect of adjuvant tamoxifen in operable breast cancer. J Clin Oncol 1989; 7: 1474-84. 5. Rutqvist LE, Cedermark8, Glas U, et al. Randomizedtrial of
adjuvant tamoxifen combined with postoperative radiation therapy or adjuvant chemotherapy in postmenopausalbreast cancer. Cancer 1990; 66: 89-96. 6. Goldhirsch A, Gelber R. Adjuvant treatment for early breast cancer: The Ludwig breast cancer studies. NCI Monograph 1986; 55-70. 7. Controlled trial of tamoxifen as a single agent in the manage-
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9. 10.
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ment of early breastcancer.Analysis of eight years by ‘Nolvadex’ adjuvant trial organisation. Br J Cancer 1988; 57: 608-1 1. Mouridsen HT, Rose C, Overgaard M, et al. Adjuvant treatment of postmenopausal patients with high risk primary breast cancer. Results from the Danish adjuvant trials DBCG 77 C and DBCG 82 C. Acta Oncoll988; 27: 699-705. Mouridsen H, Overgaard M. The role of adjuvant radiotherapy added to systemic therapy. Hamburg: 15th International Cancer Congress, 1990: 1123 (abstract). Fisher B, Constantino J, Redmond C, et al. A randomized trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptorpositive tumors. N EnglJ Med 1989; 320: 479-84. DeVita VT. Breast cancer therapy: Exercising all our options.
N Engl J Med 1989; 320: 527-9. 12. McGuire WL. Adjuvant therapy of node-negative breast cancer. N Engl J Med 1989; 320: 525-7. 13. Rose C, Thorpe SM, Andersen KW, et al. Beneficialeffect of 14. 15. 16. 17. 18.
adjuvant tamoxifen therapy in primary breast cancer patients with high oestrogen receptor values. Lancet 1985; 1: 16-1 9. Thorpe S. Prognosticvalue of hormone receptorsand adjuvant effect in the DBCG studies. Haikko: Fourth Scandinavian Breast Cancer Symposium, 199: 5 (abstract). Stewart HJ. The Scottishadjuvant tamoxifentrials. Treatment of early stage breast cancer. NIH Consensus Development Conference June 18-21, 1990: 65-70 (abstract). Fornander T, Cedermark B, Mattson A, et al. Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet 1989; 1: 1 17-9. Bagdade JD, Wolter J, Subbai.dh PV, Ryan W. Effects of tamoxifen treatment on plasma lipids and lipoprotein composition. J Clin EndocrinolMetab 1990; 70: 1132-5. BertelliG, PronzatoP, Amoroso D,et at. Adjuvant tamoxifen in primary breast cancer: influence on plasma lipids and antithrombin 111 levels. Breast Cancer Res Treat 1988; 12:
307-10. 19. Bruning PF, Bonfrer JM, Hart AA, et al. Tamoxifen, serum
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497-9. 20. Longstaff S,SigurdssonH, O’Keeffe M, Ogston S, Preece
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P. A controlled study of the ocular effects of tamoxifen in conventionaldosage in the treatment of breast carcinoma. Eur J Cancer Clin Oncoll989;25: 1805-8. 21. FornanderT, RutqvistLE,Sjoberg HE, BlomqvistL, Mattson A, Glas U. Long term adjuvant tamoxifen in early breast
cancer: Effect of bone mineral density in postmenopausal women. J Clin Oncoll980;8:1019-24. 22. Gotfredsen A, Christiansen C, Palshof T. The effect of tamoxifen on bone mineralcontent in premenopausal women with breast cancer. Cancer 1984;53:853-7. 23. Fentirnan IS, Caleffi M, Rodidn A, Murby B, Fogelman 1. Bone mineral content of women receiving tamoxifen for mastalgia. Br J Cancer 1989;60: 2 6 2 4 .
Review Article
Adjuvant Hormone Therapy in Breast Cancer Carl P. Blomqvist, lnkeri Elomaa and Pentti Rissanen
Ann Med Downloaded from informahealthcare.com by York University Libraries on 12/29/14 For personal use only.
Recent results from controlled trials of adjuvant tamoxifen and oophorectomy in early breast cancer are reviewed.The results of the statistical overview performed by the Early Breast Cancer Trialists Collaborative Group are summarised, and some important questions left open by this overview are discussed.These include the choice of patients for adjuvant endocrine treatment, long term results of tamoxifen, interaction with postoperativeradiotherapy,theeffect of tamoxifen on non-cancer deaths,and interaction of the adjuvant effect of tamoxifen with concentrationsof oestrogen receptor levels in the tumour. Key words: breastcancer; adjuvant theraby; tamoxfen; oophorectomy. (Annals of Medicine 24: 91-96, 1992)
Introduction Numerous controlled studies have assessed the effects of adjuvant oophorectomy and tamoxifen in breast cancer. This article reviews current evidence of the beneficial effects of these treatments, the choice of patients for adjuvant endocrine treatment, potential long term toxicity, interaction with local treatment,and some aspects of the mechanism of the reduction in breast cancer deaths by the use of adjuvant endocrine intervention among patients with breast cancer. In 1984, an effort to do a statistical overview of trials investigatingadjuvanttreatment in breast cancer was started at a meeting in the United Kingdom. Data on results from all controlled trials studying adjuvant treatment in breast cancer were collected. The aim was to combine the results of these studies by means of a so-called overview analysis or meta-analysis, which it was hoped would produce more reliable data than single trials on the effects of various adjuvant therapies on the prognosis of breast cancer. The first scientific report was published in the New England Journal of Medicine in 1988 (1). In 1990, a more detailed report on the results was published in the form of a monograph (2). A second overview analysis extending the follow-up time to 10 years after randomisationwas started in 1990 and has recently been published (3). These reports are based on trials conducted all over the world with the exception of the USSR.
Meta Analysis of the Results of Adjuvant Hormone Therapy In this section where reference is made to reduced mortality From the Department of Radiotherapy and Oncology, Helsinki University Central Hospital, Helsinki, Flnland. Address and reprint request: Carl Blomqvist,M.D., Department of Radiotherapy and Oncology, Helsinki University Central Hospital, Haartmaninkatu 4. SF-00290 Helsinki, Finland.
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and recurrence rate, the percentagesgiven refer to relative and not to an absolute fall in mortality rates. If, for example, in a given untreated patient group, mortality is 50 %and the relative reduction of mortality by treatment is 25 Yo,this results in a final mortality of 37.5 o/o and not 25 Yo.Thus, the smaller the original mortality is the smaller will be the absolute reduction in mortality for a given relative mortality reduction.
Adjuvant Tamoxifen Therapy The latest meta-analysisof adjuvant tamoxifen therapy was done on 40 controlled studies involving 29 892 women (3). The analysis included studies in which adjuvant tamoxifen was compared with a control group and studies in which tamoxifen was combined with another adjuvant treatment the rest of the treatment being the same in both groups. Tamoxifen treatment reduced mortality overall by 17 % (SD 2) ( P < 0.00001) and recurrence of breast cancer by 25 Yo (SD 2) ( P < 0.00001); in women over 50, mortality was reduced by 20 O h (SD 2) and recurrence by 29 'A (SD 2). In patients under 50 there was a non-significant reduction in mortality (6 %, SD 5). Nevertheless, the rate of recurrence in women under 50 years was cut by 12 Yo(4) ( P= 0.001) (3). The reductionin mortalitywas similar regardlessof whether tamoxifen was used alone (19 %, SD 3) or combined with chemotherapy (16 %, SD 3). In most studies in women under 50 tamoxifen was combinedwith adjuvantchemotherapy(n= 6386), whileasmaller number had received tamoxifen alone (n = 2226). Mortality reduction was 17 % (SD10) with tamoxifen alone and only 3 % (SD 5) with tamoxifen added to cytotoxic agents in women under 50 years of age. In women over 50, however, mortality reduction was almost identical with tamoxifen alone (19 %, SD 3) and combined with cytotoxic agents (20 Yo,SD 4). Since no statistically significant overall interaction between tamoxifen and chemotherapy was found the rele-
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Blomqvist 9 Elomaa Rissanen
Although the meta-analysis has provided much new vance of these figures remains unclear. It means, however, that the results from the overview analysis cannot be used information about the significance of adjuvant hormone as astrong argumentagainst the eff icacy of tamoxifen alone therapy and its effects on the prognosis of patients with as adjuvant treatment in women younger than 50. In breast cancer, many problems remain unsolved. Extensive postmenopausal women the confidence interval of the further research is needed before adjuvant hormone theestimated effect of combiningtamoxifen with chemotherapy rapy establishes its position in the treatment of breast is fairly narrow and indicate that the effects of the two cancer. Some important issues which remain unclear are treatment modalities are relatively independent. In patients briefly summarised in Table 1. The rest of this review deals mainly with these questions younger than 50 years, however, the confidence intervals are quite large and the estimates of possible interactions in the light of recently published controlled studies. between cytotoxic and endocrine adjuvant therapy therefore still quite uncertain. Longer duration of adjuvant tamoxifen therapy was assoCombination of Adjuvant Tamoxifen ciated with a highly significantly ( P < 0.00001) greater reTherapy and Radiotherapy. Effect of duction of recurrence,while the association between treatAdjuvant Tamoxifen on Local and Distant ment duration and mortality was only modestly significant Recurrences ( P < 0.01). Reductionof recurrence was 16 o/o (SD 3), 28 o/o (SD 2), and 39 (SD 4) with tamoxifen for5 1 year, 2 years So far, only a few detailed results have been published and > 2 years, while the mortality reduction was 11 Yo (SD showing what kinds of recurrenceadjuvant tamoxifen ther4), 19 Yo(SD 3) and 24 % (SD 6), respectively. The dosage apy is capable of preventing. Rutqvist et al. have published did not seem to be of great importance in the ranges of results obtained in Stockholm in a controlled study on doses studied: mortality was reduced by 17 Yowith a daily tamoxifen adjuvant treatment. The study involved 1,429 dose of 20 mg, and by 15 Yowith a daily dose of 30 to 40 mg women (4, 5); patients with a high risk of recurrence were (difference not significant). randomizedto either postoperative radiotherapy or adjuvant The interaction between oestrogen receptor content of cytotoxic therapy (cyclophosphamide, methotrexate, the tumour and mortality was not statistically significant: fluorouracil, CMF). No statistically significant effect of mortality was reduced by 11 O h (SD 5) in receptor-negative tamoxifen was seen in terms of total survival rates after a 10 patients and by 21 Yo (SD 3) in cases with receptor positive year follow up. However, the disease free period was tumours. Recurrence was, however, significantly statistically significantly longer if the patient had received ( P < 0.00001) more effectively reducedin oestrogen receptor adjuvant tamoxifen. Disease free survival rates at ten years positive (32 %, SD 3) than in oestrogen receptor-negative in the four treatment groups of the high risk patients are tumours (13 %, SD 4). shown in Table 2. A significantly better recurrence free The relative reduction in mortality was the same and survival rate was seen after postoperative radiotherapy statisticallysignificant in all groups regardlessof the extent compared to CMF. No differences in terms of local recurof lymph node invasion: 17 Yo (SD 5) in lymph node nega- rence rate, distant metastases or death were reportedwhen tives (NO)and 18Yo(SD 2) cases with lymphnode metastases tamoxifen treatment was added to radiotherapy. (NI). The absolute reduction of mortality was, however, Treatment with tamoxifen significantly reducedthe number naturally less in the prognosticallymore favourable NO (3.5 of local recurrences but not the occurrence of distant recurYoat 10 years) than in N1 patients (8.2 "A). rence or death (4) (Table 3). Two studies by the Ludwig group, Ludwig Ill and IV, a Oophorectomy comparison between 681 patients randomised between adjuvant tamoxifen and prednisonetreatment, no adjuvant The two last reports on the meta-analysis(2,3) also includ- therapy also showed asignificantfallinthe riskof locoregional ed an analysis of the effects of adjuvant oophorectomy on recurrence but not in distant relapse (6). A predominant breast cancer mortality in the light of randomised studies. effect of tamoxifen on locoregional recurrence has also The latest analysis involvedten controlledstudies and 3014 been reported from the NATO study comprising 1,285 prewomen. In patients younger than 50 years ovarian ablation and postmenopausal patients (7). reduced recurrence by 26 Yo6 ( P = 0.00007) and mortality by 25 Yo (SD 7) (P=O.O004). There was no statistically significant reduction in either recurrence (6 %, SD 7) or Table 2. The Stockholm adjuvant study. Recurrence free surat 10 years in breast cancer patients with high risk of mortality (3 Yo,SD 7) in women older than 50 by ovarian vival disease randomised to radiotherapy and adjuvant treatment. ablation. Therapeutic group Table 1. Tamoxifen adjuvant treatment in breast cancer. Unsettled issues. *
* *
*
Role of ajuvant therapy in patients with no lymph node spread Effect of adjuvant tamoxifen on local recurrences The role of postoperative radiotherapy combined with adjuvant tamoxifen therapy The reason for apparent lack of effect of adjuvant tamoxifen on mortality in premenopausal women The lack of association between tumour oestrogen receptor content and effect of adjuvant tamoxifen on mortality The role of combinations of tamoxifen and adjuvant chemotheraPY
Radiotherapy Radiotherapy and tamoxifen CMF CMF and tamoxifen
n
Recurrence free survival ("A)
90 100 114 123
57 63 31 47
CMF: Cyclophosphamide 100 mg/m2 orally day 1-14; Methotrexate 450 mg /m2 IV day 1 and 8; 5-fluorouracil600 mg/mzday 1 and 8, 12 cycles with 28 days interval Tamoxifen: 40 mg daily 2 years Radiotherapy: 46 GY113 fractions to chest wall, axilla, supraclavicular fossa and internal mammary nodes
Adjuvant Hormone in Breast Cancer
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Table 3. The Stockholm adjuvant study. Effect of adjuvant tamoxifen therapy on local and distant recurrences.
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Local recurrences Distant recurrence Death
Tamoxifen (%) (n = 71 1)
Control (%) (n = 696)
8 17 18
13 20 20
The Danish Breast Cancer Group (DBCG) has conducted a series of randomised studies on the combined effects of adjuvant drug therapy and radiotherapy (8,9). In an early trial 1,716 postmenopausal women with a high risk of recurrence were randomised to adjuvant tamoxifen or no adjuvant tratment. All patients receiver postoperative radiation. Tamoxifen significantly reducedthe number of recurrences and deaths (8). In a subsequent study 1,202 postmenopausal women with large tumours or axillary metastaseswere randomisedbetween radiotherapyand no further local therapy: adjuvant tamoxifen was administered to all patients. Local recurrences and survival rates at five years are shown in Table 4 (9). These results suggest that tamoxifen adjuvanttreatment, although exerting its greatest impact on locoregional disease, does not always ensure adequate local control, at least not in patients with a high risk of recurrence, and that radiotherapy still has a role in this respect. On the other hand, postoperative radiotherapy does not seem to have a significant effecton survival rate when it is added to adjuvant tamoxifen therapy (5, 9).
Adjuvant Tamoxifen Therapy in Lymph Node-negative Patients Meta-analysessuggest that tamoxifen was equally effective in reducing recurrencesand deaths in women with no lymph node involvementand those with a spread to axillary nodes, and statistically significant in both. However, since there were fewer deaths in the former than in the latter group, the absolute reduction in women with no lymph node involvement was far less (3). No single randomised study has yet yielded a statistically improved survival by tamoxifen in women with no lymph node involvement. The first results from a controlled study by the NSABP group of tamoxifen adjuvant treatment in women with no lymph node involvement was publishedin the New England Journal of Medicine in 1989 (10); 2,644 postmenopausal, oestrogen receptor-positive women with node negative breast cancer were randomised to tamoxifen treatment or control. At the 4-year follow up tamoxifen had statistically significantly improved the disease free survival rate (83 Yo
P c 0.01
NS NS
Table 4. The Danish Breast Cancer Group trial DBCG 82. Postoperative radiotherapycombined with adjuvanttamoxifen therapy in postmenopausal breast cancer and a high risk of recurrence. 5 years results
Control group (%)
Radiotherapy (%)
36 61
6 62
Local recurrences Survival
versus 77 ”/.). On the other hand, there was no significant difference between the total survival rates (92 versus 93 YO). Varying opinions have been expressed as to the therapeutic significance of these results, including those of two respectedAmerican cancer experts in the same issue of the New England Journal of Medicine (11, 12). Vincent de Vita stated that these results “show an impressive reduction in the risk of recurrence among patients with node-negative disease” and that “the failure to observe a difference in overall survival is almost certainly a matter of timing”. He then recommends that apart from minimal and non-invasive tumors “all women with newly diagnosed localized invasive breast cancer can and should be offered some form of systemic treatment”. William McGuire,on the other hand, commentedthat “the cost considerably outweighs the benefits of treating all node-negative patients, especially in the absence of a proved survival benefit”. McGuire recommended further research on new prognostic factors, saying “that clinicians use the individual patient’s risk factors - to weight the probability of benefit against the patient’s total risk profile and overall clinical conditions”. At present, the opinions of the oncological community of adjuvant treatment in women with no node involvement are divided, and the issue will probably remainopen until further evidencefrom randomised trials emerges.
Depencence of Adjuvant Tamoxifen Effect on Oestrogen Receptor Content of the Tumour Rutqvist et al. have published an analysis of the influence of oestrogen receptorstatus on the risk of recurrencefollowing
Table 5. The Stockholm adjuvant study. Effect of oestrogen receptor content and adjuvant tamoxifen therapy in frequency of recurrences. Oestrogen receptor content c 0.05 fmollyg DNA 0.05-0.08 fmol/yg DNA > 0.88 fmol/pg DNA
Recurrences controls (%) (n = 387)
Recurrences tamoxifen (%) (n = 363)
30 22 26
38 16 11
P NS NS P < 0.01
Note: 158 patients with high risk tumours also received posoperative radiation and 108 patients were also given adjuvant chemotherapy.
Blomqvist Elomaa Rissanen
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adjuvant tamoxifen therapy in the light of the Stockholm study (4). Table 5 shows the frequency of recurrences in various oestrogen receptor content categories, the median follow-up time being 6.5 years. The most pronounced therapeutic effect was seen in patients with tumours having high receptor contents, while no statistically significant effect was detected in patients with receptor negative tumors. Rose et al. have published a preliminary analysis of the effects of oestrogen receptor content on the efficacy of adjuvant tamoxifen therapy (13) in the DBCG study. In this study also, inhibition of recurrences seemed restricted to tumours with high receptor contents. In later reports by the same group the correlation between receptor values and tamoxifen was confirmed (8, 14). Furthermore, postmenopausalpatients with especially high receptor values (more than 200 fmol/mg protein) were found to carry a dismal prognosis of not given adjuvant treatment, while the prognosiswas improvedaftertamoxifen adjuvant treatment (14). Like the DBCG and Stockholm studies a report from the Ludwig studies Ill and IV also showed endocrine treatment in postmenopausalpatients only benefittedthose with oestrogen-receptor positive tumours (6). In contrast to these studies the NATOtrial did not show any interactionbetween oestrogen receptor status and recurrence free or overall survival rates (7).The results in the Stockholm, DBCG and Ludwig studies seem to contradict the results of the metaanalysis. However, a clear correlation was found between the receptor content of the tumour and reduction of recurrence in the overview analysis as well. Only with respect to overall mortality was the correlation between the effect of tamoxifenand oestrogen receptor status lacking. The metaanalysis did not include any analysis on causes of death, and thus left unsettled whether the reduction in death rate by tamoxifen adjuvant therapy was consequent on breast cancer only, or whether adjuvant therapy also affected other causes of death. Little is known on this subject so far, although a preliminaryanalysis on causes of deaths recently published from the so called Scottish trial may provide addditional information (15). In astudy on causes of deaths in this trial some extremely interesting findings were reported (15). The Scottish trial involved a total of 1,323 pre-, peri- and postmenopausal women randomised to receive adjuvant tamoxifen therapy or tamoxifen only after recurrence (15). The study showed a statistically significant reductionin the risk of death among the patients as a whole. As in the overview analysis, risk of death was more or less the same in all oestrogen receptor strata, and in post- as well as in premenopausal patients. However, just as in the Stockholm and the Danish studies there was a statistically significantly larger reduction of recurrence in patients whose tumours had high oestrogen receptor contents.
The analysis of causes of deaths provided some surprising findings (Table 6) (15). Deaths from breast cancer were considerably reduced in premenopausal patients receiving tamoxifen but very little in postmenopausalpatients.Among the latter, cardiovascular mortality was reduced after tamoxifen therapy, and this explained almost all the difference between the numbers of deaths of postmenopausal patients in the control group and in the group receiving tamoxifen. Calculation of the statistical significance of this finding was not provided. If tamoxifen shows other beneficial “side effects” (e.g. reduced risk of cardiovascular death and prevention of contralateral breast cancer) in older patients, in particular,it could at least partly explain the better effect of adjuvant tamoxifen in postmenopausalpatients. Results on causes of death from most other randomised tamoxifen trials is still lacking. In the NATO study, however, non-cancer deaths were also reduced (34 versus 43 deaths) in the tamoxifen group (7). In the Ludwig trials 111 and IV, on the other hand, there were more non-cancer deaths (15 %) in the patients treated with tamoxifen and prednisonecomparedwith those who had no adjuvant treatment (5 O h ) (6).
Long Term Effects of Adjuvant Tamoxifen on Other than Breast Cancer Morbidity The Stockholm study has produced several reports on the log term effects of adjuvant tamoxifen. In a study of the effects on the occurrenceof new primarytumours tamoxifen adjuvant therapy wasshown to reducethe riskof contralateral new primary breast cancers (18 in the tamoxifen group and 32 in the control group) (16). As far as other primary tumours were concerned, differenceswere onlyseen in cancer of the uterine corpus, in that their occurrence seemed to increase after treatment with tamoxifen (13 versus 2) (16). In the Stockholm study, the daily dose of tamoxifen was 40 mg, and no cancer of the uterus was recorded earlier than after two years’ treatment with tamoxifen. A preliminary analysis on the Scottish trial published by Stewart did not show similar increases in the number of carcinomasof the corpus uteri (14). Stewart, however, also found a reduction in the number of new primary breast cancers (15). In the “Scottish study”, the daily tamoxifen (20 mg) dose was only half that used in the Stockholm study. Tamoxifen’s effects on serum lipid metabolism have been the subject of several studies (15, 17, 18, 19). These have generally shown that serum lipids are modified in a way that tends to reduce cardiovascularmorbidity,an effect which mimics the effect of oestrogen and which may explain the connection between adjuvant tamoxifen treatment and the reduction in cardiovascular mortality. Tamoxifen has in rare cases been associated with ocular complications. In a few patients, especially those receiving
Table 6. The Scottish trial. Causes of deaths in pre- and postmenopausal patients with breast cancer receiving adjuvant tamoxifen and controls. Cause of death
Breast cancer Myocardial infarction All causes
Prernenop. tarnoxifen (n = 108)
Prernenop. controls (n = 106)
Prernenop. tarnoxifen (n = 266)
Prernenop. controls (n = 267)
12 -
21 22
43 5
45
68
79
14
15
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Adjuvant Hormone in Breast Cancer high cumulative tamoxifen doses, complications have occurred in the retina, cornea or optic nerve, athough most of these have been reversible (20). In any case, this side effect is very rare and its exact incidence is unknown. The Stockholm group and others have published results on the effects of tamoxifen on skeletal mass (21, 22,23). In the Stockholm study using an isotopic bone measuring technique adjuvant tamoxifen therapy did not increase the risk of osteoporosis even when treatment had lasted for five years (21). Consequently, it seems that in certain organs tamoxifen acts not only as an oestrogen antagonist but as an oestrogen agonist as well. The agonist effect seems to be stronger in the uterus and possibly in the skeleton, and the antagonist effect in the mammary tissue. This might explain why tamoxifen does not induce osteoporosis although lack of oestrogen certainly does. As far as lipid metabolism is concerned, tamoxifen’s agonist effect seems to be the prevailing one. So far, the rare occurrence of eye complications and the possible induction of carcinoma of the uterus seem to be the only demonstrated severe side effects caused by long term tamoxifen therapy.
Conclusions Adjuvant tamoxifen therapy clearly reduces recurrence of breast cancer and deaths in postmenopausal patients with axillary node spread. In premenopausal patients the effect on the risk of death remains unclear. The proportional reduction in mortality is the same in women with no lymph node involvement and those with a spread to axillary nodes, but the absolute difference is much less in the former due to the substantially better prognosis of women with no lymph node involvement. Adjuvant tamoxifen treatment for two years or longer seems to ensure a greater reduction of recurrence and mortality than shorter treatment, while the dose of tamoxifen is less important and a daily dose of 20 m g seems to be adequate. The overview analysis on adjuvant oophorectomy showed that both surgical oophorectomy and castration by radiation may reduce mortality in early breast cancer. The magnitude of the effect was similar to that obtained with tamoxifen therapy. As expected, the effect of oophorectomy was evident only in patients aged under 50. Adjuvant tamoxifen does not seem to induce osteoporosis but it does reduce the occurrence of new primary breast cancers. Long term adjuvant tamoxifen treatment-at least in a high dosage - may increase the risk of corpus uteri carcinomas. The possibility of tamoxifen induced eye complications should be borne in mind when using adjuvant tamoxifen therapy, although the risk of this side effect seems minor. One study has shown that adjuvant tamoxifen therapy reduced the risk of cardiovascular deaths, which could, at least in part, explain the better effect of adjuvant therapy in postmenopausal women. This may be connected with the favourable effects of tamoxifen on lipid metabolism. Despite the fact that adjuvant tamoxifen therapy seems most effective against local recurrences, the risk of local recurrences continues to be great in patients with more advanced breast cancer receiving adjuvant therapy. This risk may be reduced by postoperative ratiotherapy, which therefore still has to be considered as an option in at least
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certain subsets of patients given adjuvant endocrine therapy. Tamoxifen therapy seems to be most effective in preventing the recurrence of breast cancer if the tumour has a high receptor content. The correlation between the oestrogen receptor content and the reduction in mortality is less obvious; this may be explained in part by the fact that tamoxifen also affects mortality from causes other than breast cancer. The authors wish to thank ICI Pharmaceuticalsfor help in preparing the manuscript.
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