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A correction has been published: N Engl J Med 1996;334(15):1003.
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Background Randomized trials of radiotherapy and surgery for early breast cancer may have been too small to detect differences in long-term survival and recurrence reliably. We therefore performed a systematic overview (meta-analysis) of the results of such trials.
Methods Information was sought on each subject from investigators who conducted trials that began before 1985 and that compared local therapies for early breast cancer. Data on mortality were available from 36 trials comparing radiotherapy plus surgery with the same type of surgery alone, 10 comparing more-extensive surgery with less-extensive surgery, and 18 comparing more-extensive surgery with less-extensive surgery plus radiotherapy. Information on mortality was available for 28,405 women (97.4 percent of the 29,175 women in the trials).
Results The addition of radiotherapy to surgery resulted in a rate of local recurrence that was three times lower than the rate with surgery alone, but there was no significant difference in 10-year survival; among a total of 17,273 women enrolled in such trials, mortality was 40.3 percent with radiotherapy and 41.4 percent without radiotherapy (P = 0.3). Radiotherapy was associated with a reduced risk of death due to breast cancer (odds ratio, 0.94; 95 percent confidence interval, 0.88 to 1.00; P = 0.03), which indicates that, after 10 years, there would be about 0 to 5 fewer deaths due to breast cancer per 100 women. However, there was an increased risk of death from other causes (odds ratio, 1.24; 95 percent confidence interval, 1.09 to 1.42; P = 0.002). This, together with the age-specific death rates, implies, after 10 years, a few extra deaths not due to breast cancer per 100 older women or per 1000 younger women. During the first decade or two after diagnosis, the excess in the rate of such deaths that was associated with radiotherapy was much greater among women who were over 60 years of age at randomization (15.3 percent vs. 11.1 percent [339 vs. 249 deaths]) than among those under 50 (2.5 percent vs. 2.0 percent [62 vs. 49 deaths]). Breast-conserving surgery involved some risk of recurrence in the remaining tissue, but no significant differences in overall survival at 10 years were found in the studies of mastectomy versus breast-conserving surgery plus radiotherapy (4891 women), more-extensive surgery versus less-extensive surgery (4818 women), or axillary clearance versus radiotherapy as adjuncts to mastectomy (4370 women).
Conclusions Some of the local therapies for breast cancer had substantially different effects on the rates of local recurrence — such as the reduced recurrence with the addition of radiotherapy to surgery — but there were no definite differences in overall survival at 10 years.
Methods
The procedures for identifying trials and checking data have been described previously.1,2,3 Data on age, menopausal status, nodal status, and treatment assignment were sought for each woman (including patients entered later into trials begun before 1985). Dates of randomization, second primary cancer in the contralateral breast, first recurrence, first distant recurrence, and last known vital status were also sought. Causes of death were sought only for those who died without a recorded recurrence of breast cancer. After extensive checks for consistency, various tabulations and data listings (together with any queries) were sent back to the original trialists for them to review and correct. As a final check, a draft of this report was circulated for comment to all whose trial results were incorporated and the manuscript was revised in response to their suggestions and criticisms.
Statistical Analysis
Some comparisons are illustrated by pairs of survival curves, but others involve odds reductions (or, equivalently, odds ratios; an odds ratio of 0.9 implies an odds reduction of 10 percent). A persistent 10 percent reduction in the annual odds of death would eventually, when about half the subjects had died, produce a survival difference of about 4 percent (for example, 46 percent instead of 50 percent mortality).1 Likewise, a persistent annual odds reduction of 5 percent would eventually produce a difference of about 2 percent in the absolute risk of death.1 Two-sided P values are reported.
The main statistical methods we used for combining information from different trials are described elsewhere.1,2,3 Analyses were conducted on an intention-to-treat basis.6,7 Crude unstratified totals are provided for descriptive purposes, but in the main analyses we have adapted log-rank methods for analyses of cause-specific mortality (deaths from all causes, from breast cancer, and from causes other than breast cancer) and of the site of the first recurrence (any, isolated local, or other). Within each trial, the number of events observed in the group assigned to one treatment (O) is compared with the number of events that would be expected (E) if the probability of death were unrelated to treatment, a number that reflects the average experience of both treatment groups in that trial. The difference between the observed number and the expected number (O - E) and its variance yield the log-rank statistic for that one trial. Finally, the values for O - E from several different trials are simply added together to get an appropriately stratified overview of the results. To obtain the variance of this overall result, the separate variances are likewise summed. From these two totals, the odds ratio and its standard deviation can be calculated.1,2,3 Because the number of possible statistical comparisons is large, conventional 95 percent confidence intervals are generally not reported. Instead, we have reported either 99 percent confidence intervals (to limit the number of false positive comparisons) or, more compactly, standard deviations.
Deaths attributed to causes other than breast cancer with no reported recurrence of breast cancer are described as "non–breast-cancer deaths," and all other deaths are described as "breast-cancer deaths"; the latter includes not only the deaths attributed to breast cancer but also deaths from unknown causes without reported recurrence and deaths from any cause after recurrence. These conventions necessitate the use of special statistical methods to avoid bias. These special methods compensate for the fact that if someone who would otherwise have had a recurrence of breast cancer before dying of an unrelated cause were to be given a treatment that had no effect on the time or cause of death but merely prevented the recurrence from preceding it, then instead of being categorized as due to breast cancer, that death would be recategorized as a "non–breast-cancer death."
For the log-rank analysis of mortality from all causes, O - E and its variance are calculated in the usual unbiased way, which ignores recurrences. However, to prevent delayed recurrences from biasing the analyses of cause-specific mortality, the log-rank analysis of non–breast-cancer mortality covers only the period before recurrence (i.e., data are censored at the first recurrence) and is therefore unbiased. Finally, an unbiased — although potentially diluted — log-rank analysis of breast-cancer mortality is obtained indirectly by subtracting the log-rank statistic for non–breast-cancer mortality from the log-rank statistic for mortality from all causes (i.e., the two observed values are subtracted from each other, the two expected values are subtracted from each other, and the two variances are subtracted from each other).
Table 1 lists three main types of unconfounded comparison (comparisons in which no aspects of management other than the treatments directly compared were affected by randomization): studies of radiotherapy plus surgery versus the same surgery alone, involving 17,273 women for whom data on mortality were available in 36 trials; studies of more-extensive surgery versus less-extensive surgery, involving 4818 women in 10 trials; and studies of more-extensive surgery versus less-extensive surgery plus additional radiotherapy, involving 9891 women in 18 trials. Appendix 2 describes these and other trials of local therapy.
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Results
Trials of Radiotherapy
The 36 trials of radiotherapy can be subdivided according to the type of surgery that was common to both groups, and the type of surgery influenced the type of radiotherapy that was tested (Figure 1 and Appendix 2A). When both groups underwent full mastectomy, the trial radiotherapy included the axillary and supraclavicular fossa and usually also the chest wall and internal mammary chain. When surgery involved breast conservation, radiotherapy included the breast and chest wall (plus, in one study, the axilla), but no other sites.
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Overall mortality was 40.3 percent with radiotherapy and 41.4 percent without it (Figure 1), corresponding to a nonsignificant reduction (±SD) of 2.6±2.5 percent in the odds of death. The reduction that is produced by radiotherapy in the odds of death appeared slightly larger after mastectomy with axillary sampling (Figure 1b) (odds reduction, 14±7 percent) or after breast-conserving surgery (Figure 1d) (odds reduction, 12±9 percent) than after mastectomy alone (Figure 1a) (odds reduction, 3±4 percent) or after mastectomy with axillary clearance (Figure 1c) (odds reduction, -3±4 percent [a negative number indicates an increase in the odds of death]). There is no significant heterogeneity, however, among these four subgroups — or among the 36 trials — and hence no good statistical evidence that radiotherapy helped in some surgical subgroups and not others. (Tests for heterogeneity, however, generally have low sensitivity.3)
Figure 2 shows survival among the approximately 16,000 women in the 35 trials of radiotherapy for whom individual data on survival were collected, categorized according to nodal status. There was no statistically significant effect of radiotherapy in women with node-positive or node-negative cancer.
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Data were available from 28 trials, involving 13,627 women, on causes of death among women who died without a recurrence of breast cancer. Of the 986 such deaths, 93 percent (918) were from known causes other than breast cancer; the remaining 7 percent of deaths, from unknown causes, are included with the deaths due to breast cancer. Table 2 shows the numbers of non–breast-cancer deaths plus the numbers of breast-cancer deaths according to the type of surgery, nodal status, age at diagnosis, and length of time to death.
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There was no significant heterogeneity among the proportional increases in non–breast-cancer mortality among the different trials, among different types of surgery, or among different nodal-status categories. Radiotherapy generally included the internal mammary chain (Figure 1 and Appendix 2A), but when this was not included the proportional increase in non–breast-cancer mortality still appeared to be at least as great as when the internal mammary chain was included (odds ratios, 1.54±0.32 vs. 1.22±0.08).
The proportional increase in non–breast-cancer mortality appeared to be about as great in the trials in which at least some orthovoltage radiotherapy was used (odds ratio, 1.28±0.10) as in the trials in which all women received megavoltage therapy (odds ratio, 1.23±0.12); in this analysis, the study by Høst et al.,9 which included both orthovoltage and megavoltage radiotherapy, was included as two separate trials (Oslo X-ray and Oslo Co-60). In only one trial10 was the increase in non–breast-cancer mortality significant, and it had used some orthovoltage and some megavoltage therapy.
Mortality Excluding Non–Breast-Cancer Deaths
In the 28 trials that supplied data on causes of death, 34.1 percent of the women assigned to radiotherapy (2325 of 6811 women) died of breast cancer, as compared with 36.9 percent of the controls (2512 of 6816), but a small part of this difference is artifactual. When, as described in the Methods section, non–breast-cancer deaths are subtracted from deaths from all causes, an unbiased analysis remains of deaths from breast cancer, indicating an odds ratio of 0.94±0.03 (95 percent confidence interval, 0.88 to 1.00; P = 0.03) (Table 2). The lower confidence limit for this result corresponds to about twice as much benefit as the point estimate of 0.94 suggests, but the upper limit corresponds to about zero benefit. Hence, although such radiotherapy may well produce a moderate reduction in deaths due to breast cancer, the findings are also statistically consistent with a negligibly small effect from radiotherapy. These uncertainties cannot be resolved by subgroup analyses. Whether or not there is any real effect of radiotherapy on mortality due to breast cancer, chance may make it seem that there is benefit in some subgroups and none in others. Such patterns (Table 2) are untrustworthy, especially since rates of local recurrence were reduced substantially in all subgroups.
Rates of Recurrence
Dates of first recurrence were available from 35 studies, of which 32 specified whether the recurrence was local, distant, or both (but not the exact site). Overall, 38.1 percent of the women assigned to radiotherapy and 45.9 percent of those not assigned to radiotherapy had reported recurrences (odds ratio, 0.76±0.02). The reduction in the rates of recurrence was significant in each subgroup used in Table 2 (data not shown; P<0.001 for each comparison). As expected, radiotherapy produced an even greater reduction in the rate of isolated local recurrences (6.7 percent [501 of 7473 women] vs. 19.6 percent [1480 of 7570]; odds ratio, 0.33) (Table 2). The size of this protective effect was not significantly affected by the type of axillary surgery, nodal status, or age at diagnosis.
Because radiotherapy reduced the rate of local recurrence by about two thirds, many patients whose first recurrence would have been local had distant recurrences instead as a first event. Hence, because the risks of local recurrence and of other recurrences are correlated,11,12 radiotherapy was artifactually associated with an apparent increase in non-local recurrences as first events (odds ratio, 1.13±0.04). This made it impossible to assess, on the basis of the data currently available, whether radiotherapy had any protective effect against distant recurrence.
Trials Comparing More Extensive with Less Extensive Surgery
The 10 trials comparing more extensive with less extensive surgery can be subdivided according to the extent of surgery among controls — radical or total mastectomy, simple mastectomy, or breast conservation — yielding three types of surgical comparison (Figure 3 and Appendix 2B).
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Overall, 48.0 percent of the women assigned to more extensive surgery and 50.1 percent of those assigned to less extensive surgery died (Figure 3); this corresponds to a nonsignificant reduction of 3 percent in the odds of death. There was no significant heterogeneity among the 10 trials or among the three types of surgical comparison. Data on causes of death were available for only 53 percent of the women who died without a recurrence of breast cancer; these data also showed no significant differences.
Figure 4 shows survival according to nodal status for the approximately 3400 women in trials comparing more extensive with less extensive surgery. The less extensive surgery was total or radical mastectomy in some of these trials (Figure 3a) and simple mastectomy in all the others (Figure 3b), since data on individual patients were not yet available from the trial of breast-conserving surgery (Figure 3c). No difference in survival was apparent among either women with node-positive cancer or those with node-negative disease.
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Among the women whose outcomes are summarized in Figure 4, more-extensive surgery involved a nonsignificant reduction in the rate of recurrence; 48.8 percent of those treated with more-extensive surgery and 50.3 percent of those with less-extensive surgery had a reported recurrence (odds ratio, 0.98±0.05, with no significant heterogeneity among different trials or among different types of surgery). For isolated local recurrence, the odds ratio of 0.89±0.12 was also not significant.
Trials of Breast-Conserving Surgery
In the nine trials of mastectomy versus breast-conserving surgery plus radiotherapy (Figure 3d and Appendix 2C), there was no apparent difference in total mortality (22.9 percent vs. 22.9 percent) and little information on the causes of death. For six studies (involving 3107 women) in which data on recurrence were available, there were fewer recurrences with mastectomy, but the difference was not significant (odds ratio, 0.96±0.08). Few local recurrences were recorded, and the definition of local recurrence varied, particularly for recurrences in the remaining breast tissue (which, even with radiotherapy, may affect a substantial minority of women, and which some trials ignore in counting "local recurrences"). Once again there was no significant difference (6.2 percent had local recurrences with mastectomy, as compared with 5.9 percent with breast conservation). As Figure 5 shows, no difference in survival was apparent between mastectomy and breast-conserving therapy plus radiotherapy in seven trials.
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In the eight trials of axillary clearance versus radiotherapy (Figure 3e and Appendix 2C), there was no apparent difference in total mortality (54.7 percent vs. 54.9 percent) or in recurrence as a first event (odds ratio, 1.01), but radiotherapy was associated with fewer isolated local recurrences (odds reduction, 15±8 percent; P = 0.06).
Trials Involving Other Comparisons
Of the remaining comparisons of mortality, only one was statistically significant (Figure 3f and Appendix 2C); in this trial mastectomy plus axillary clearance plus some radiotherapy appeared to be better than breast-conserving surgery without axillary clearance but with additional radiotherapy. The difference in mortality (64 percent vs. 72 percent; P = 0.01) was greater than would be expected from the other results presented here. This may reflect the particular treatments used in this study13 or the effects of chance, as is possible in any trial. Analyses of mortality in various other trials of local therapy are listed in Appendix 2d.
Discussion
Some of the local therapies for breast cancer had substantially different effects on the rates of local recurrence, but there were no definite differences in overall 10-year survival. It has long been accepted that radiotherapy can delay or prevent local or regional recurrence in women with early breast cancer, as may more extensive surgery. More recently, it has appeared that radiotherapy can also produce a small increase in the rate of death from causes other than breast cancer.4 In this extensive overview, we confirmed these findings, but we could not assess separately the effects of treatment on deaths from cardiovascular or other specific causes or the relevance of particular details of radiologic or surgical technique. Our findings indicate, however, that the absolute excess rate of non–breast-cancer mortality during the first decade or so after radiotherapy is strongly related to age. Among women who were under 50 when they underwent irradiation, the apparent excess is just a few deaths not due to breast cancer per 1000 women, whereas among women who were 60 or older at the time of radiotherapy, it is a few per 100. As Table 2 suggests, the excess may persist for more than 10 years. If such a proportional excess persists indefinitely, the absolute excess might become appreciable even among women who were under 50 when they received radiotherapy. Although the radiotherapy techniques differed substantially among the studies, the overall result still provides a valid measure of the value of such treatment.
A central question about local therapy for early breast cancer is whether more-extensive treatment significantly reduces long-term mortality from breast cancer. The current analyses show that any reduction cannot be large, at least during the first decade. But even a small difference could be important, especially if any hazards of the treatment could be limited. With radiotherapy, there is a small, marginally significant (P = 0.03) reduction in mortality due to breast cancer but not in overall mortality. However, because the "breast-cancer" deaths do include some deaths from other causes, the effect could be somewhat larger than the 6 percent reduction seen in this overview. In the comparisons of different types of surgery, no significant differences in survival were found.
The National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-06 is the largest trial of surgical strategies included in this overview.14 After 12 years of follow-up in Protocol B-06, no significant differences in survival have been found in it between women treated with total mastectomy and those treated with lumpectomy, with or without irradiation, as reported in this issue of the Journal.14 Information from this trial on the length of time to death was not included in this overview, so, although Figure 1 and Figure 3 include the overall results from Protocol B-06 (with the analyses of all available data on mortality among all randomized patients), the survival curves in Figure 2 and Figure 5 do not include data from this study. The analyses in Figure 5 are therefore independent of (and strongly supportive of) the conclusion from the NSABP trial that, in suitable patients, survival is about as good with appropriate breast-conserving surgery plus radiotherapy as with mastectomy. When one combines the results from Protocol B-06 and Figure 5, the evidence that 10-year survival is approximately equivalent with these two strategies is therefore now based on a total of almost 5000 women (Figure 3d).
Survival differences are not the only factors influencing choices about surgery and radiotherapy for the treatment of early breast cancer, but if any such differences could be reliably demonstrated they would be important. Any differences between these local therapies do not involve large effects on 10-year survival, but they could still involve worthwhile effects on longer-term survival. As follow-up continues, an increasing proportion of the natural history of the disease becomes accessible to study. The next five-yearly analysis of the Early Breast Cancer Trialists' Collaborative Group will include trials that began during 1985 through 1989, plus five additional years of follow-up on the present trials and (for some studies) more details of sites of recurrence and causes of death.
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Supported by a special grant from the Imperial Cancer Research Fund to the Clinical Trial Service Unit in the Nuffield Department of Clinical Medicine, University of Oxford.
We are indebted to the many thousands of women who took part in these trials and thus helped determine how best to treat breast cancer, and to the many medical, statistical, and administrative investigators who carefully answered our questions and provided details on their trials.
Source Information
The Early Breast Cancer Trialists' Collaborative Group Secretariat (Mike Clarke, Rory Collins, Jon Godwin, Richard Gray, and Richard Peto) assumes full responsibility for the overall content and integrity of this manuscript.
Address reprint requests to the EBCTCG Secretariat, ICRF/MRC Clinical Trial Service Unit, Nuffield Department of Clinical Medicine, Radcliffe Infirmary, Oxford OX2 6HE, United Kingdom.
References
Appendix 1. Members of the Early Breast Cancer Trialists' Collaborative Group
The following investigators were members of the Early Breast Cancer Trialists' Collaborative Group: Adjuvant Chemo-Endocrine Trials in Breast Cancer: O. Abe, R. Abe, K. Asaishi, K. Enomoto, T. Hattori, Y. Iino, K. Kikuchi, H. Koyama, K. Sawa, J. Uchino, M. Yoshida; Integraal Kankercentrum: A.O. van de Velde, J.B. Vermorken; Metaxas Memorial Cancer Hospital: P. Foroglou, G. Giokas, B. Lissaios; Auckland Breast Cancer Study Group: V.J. Harvey, T.M. Holdaway, R.G. Kay, B.H. Mason; Australian–New Zealand Breast Cancer Trials Group: J.F. Forbes; Instituto Policlinico: A. Milla, F. Sanchiz; Belgian Adjuvant Breast Cancer Project: C. Focan, J.P. Lobelle; Berlin–Buch, Akademie der Wissenschaften: U. Peek; Birmingham General Hospital: G.D. Oates, J. Powell; Bundesminsterium für Forschung und Technologie: G. Bastert, H. Rauschecker, R. Sauer, W. Sauerbrei, A. Schauer, M. Schumacher; Fondation Bergonié: M. Durand, L. Mauriac; Dana–Farber Cancer Institute: R.S. Gelman, I.C. Henderson, C.L. Shapiro; Bradford Royal Infirmary: A.K. Hancock; British Columbia Cancer Agency: S. Jackson, J. Ragaz; Centre Regional François Baclesse: T. Delozier, J. Mace-Lesec'h; Addenbrooke's Hospital: J.L. Haybittle; Cancer and Leukemia Group B: C. Cirrincione, I.C. Henderson, A. Korzun, R.B. Weiss, W.C. Wood; Cancer Research Campaign: M. Baum, J. Houghton, D. Riley; Groote Schuur Hospital: D.M. Dent, C.A. Gudgeon, A. Hacking; Cardiff Surgery Trialists: K. Horgan, L. Hughes, H.J. Stewart; Case Western Reserve University: N.H. Gordon; Central Oncology Group: H.L. Davis; Cheltenham General Hospital: J.R. Owen; University of Chicago: P. Meier; Christie Hospital and Holt Radium Institute: A. Howell, G.C. Ribeiro, R. Swindell; Coimbra Instituto de Oncologia: J. Albano, C.F. de Oliveira, H. Gervásio, J. Gordilho; Danish Cancer Registry: B. Carstensen, T. Palshof; Copenhagen Radium Centre: H. Johansen; Cracow Institute of Oncology: S. Korzeniowski, J. Skolyszewski; Danish Breast Cancer Cooperative Group: K.W. Andersen, C.K. Axelsson, M. Blichert-Toft, H.T. Mouridsen, M. Overgaard, C. Rose; Dublin St. Luke's Hospital: N. Corcoran; Düsseldorf University: H.J. Trampisch; Eastern Cooperative Oncology Group: M.D. Abeloff, P.C. Carbone, J. Glick, R. Gray, D.C. Tormey; European Organization for Research and Treatment of Cancer: H. Bartelink, I.S. Fentiman, R. Paridaens, O.J. Repelaer van Driel, R.J. Sylvester, C.J.H. van de Velde, E. van der Schueren, J.A. van Dongen, K. Welvaart; Evanston Hospital: E.F. Scanlon, S. Schurman; Ghent University Hospital: A. de Schryver; Glasgow Beatson Oncology Centre: H.M.A. Yosef; Glasgow Victoria Infirmary: C.S. McArdle, D.C. Smith; Granada University Hospital: P.C. Lara; Gruppo Ricerca Ormono Chemio Terapia Adiuvante: F. Boccardo; Gunma University: M. Izuo, Y. Morishita; Guy's Hospital: A. Bentley, Z. Doran, I.S. Fentiman, J.L. Hayward, R.D. Rubens; Gynecological Adjuvant Breast Group: M. Kaufmann, W. Jonat; Heidelberg University I: H. Scheurlen; Heidelberg University II: D. von Fournier, M. Kaufmann; Helsinki, Deaconess Medical Centre: P. Klefstrom; Imperial Cancer Research Fund: J. Cuzick; Innsbruck University: R. Margreiter; International Breast Cancer Study Group (Ludwig): M. Castiglione, F. Cavalli, J. Collins, R.D. Gelber, A. Goldhirsch, M.R. Isley, J. Lindtner, K.N. Price, C.M. Rudenstam, H.J. Senn; International Collaborative Cancer Group, Charing Cross Hospital: J.M. Bliss, C.E.D. Chilvers, R.C. Coombes, M. Marty; National Study for Adjuvant Treatment of Breast Cancer: G. Brufman, H. Hayat; Israel Technion, Rambam Medical Center: R. Borovik, G. Brufman, E. Robinson; Italian Cooperative Chemo-Radio-Surgical Group: F. Pannuti;Japanese National Hospitals Group Breast Cancer Study Group: S. Takashima, T. Yasutomi; Kawasaki Medical School: H. Sonoo; Kumamoto University Group: J. Yamashita, M. Ogawa; Kyushu National Cancer Center: Y. Nomura; Louvain, Academisch Ziekenhuis St. Rafael: J. Bonte; Lund University: I. Tengrup, L. Tennvall-Nittby; Laboratoire de Cancérologie Biologique APM: P. Martin, S. Romain; Mayo Clinic: D. Ahmann, D.J. Schaid; M.D. Anderson Cancer Center: A.U. Buzdar, T. Smith; Memorial Sloan-Kettering Cancer Center: T. Hakes, L. Norton, R. Wittes; Mexico, National Medical Centre: R. de la Huerta, M.G. Sainz; Milan Istituto Nazionale per lo Studio e la Cura dei Tumori: G. Bonadonna, M. del Vecchio, P. Valagussa, U. Veronesi; Montpellier Centre Paul Lamarque: J.B. Dubois; Naples University: A.R. Bianco; National Cancer Institute: M.E. Lippman, L.J. Pierce, R. Simon, S.M. Steinberg; National Surgical Adjuvant Breast and Bowel Project: A. Brown, B. Fisher, C. Redmond, N. Wolmark; Nolvadex Adjuvant Trial Organisation: M. Baum, I.M. Jackson, M.K. Palmer; North Central Cancer Treatment Group: J.N. Ingle, D.J. Schaid; North Sweden Breast Cancer Group: N.O. Bengtsson, L.G. Larsson; North-Western British Surgeons: J.P. Lythgoe, R. Swindell; Northwick Park Hospital: M. Kissin; Norwegian Breast Cancer Group: E. Hannisdal, J.E. Varhaug; Nottingham City Hospital: R.W. Blamey, A.K. Mitchell, J.F.R. Robertson; Oita Prefectural Hospital: Y. Nakamura; Oncofrance: G. Mathé, J.L. Misset; Ontario Cancer Treatment and Research Foundation: E.A. Clarke, J.R. McLaughlin; Ontario Clinical Oncology Group: R.M. Clark, M. Levine; Osaka City Medical School: K. Morimoto; Oslo Radium Hospital: S. Gundersen, M. Hauer-Jensen, H. Høst; Oxford Churchill Hospital: E. Crossley, K. Durrant, A. Harris; Imperial Cancer Research Fund–Medical Research Council Clinical Trial Service Unit: A. Beighton, D. Chadbon, M. Clarke, R. Collins, C. Davies, V. Evans, J. Godwin, R. Gray, E. Greaves, C. Harwood, S. James, G. Mead, A. Muldahl, R. Peto, A. Tooth, K. Wheatley; Centre René Huguenin, St. Cloud: P. Rambert; Institut Curie: B. Asselain, R.J. Salmon, J.R. Vilcoq; Institut Gustave-Roussy: R. Arriagada, C. Hill, A. Laplanche, M.G. Lê, M. Spielmann; Parma Hospital: G. Cocconi, B. di Blasio; Fox Chase Cancer Center: R. Catalano, R.H. Creech; Piedmont Oncology Association: J. Brockschmidt, M.R. Cooper; Charles University: O. Andrysek, J. Barkmanova; Rotterdam Radio-Therapeutic Institute: A.D. Treurniet-Donker, W.L.J. van Putten; Royal Marsden Hospital, Institute of Cancer Research: D. Easton, T.J. Powles; St. George's Hospital: J.C. Gazet; Petrov Research Institute of Oncology: V. Semiglazov; Sardinia, Oncology Hospital A. Businico: N. Deshpande, L. di Martino; Scandi-Afro-Swiss-Immuno-Breast International Trialists: P. Douglas, A. Hacking, H. Høst, A. Lindtner, G. Notter; Saskatchewan Cancer Foundation: A.J.S. Bryant, G.H. Ewing, J.L. Krushen; Scandinavian Adjuvant Chemotherapy Study Group: R. Nissen-Meyer; Scottish Cancer Trials Office: A.P.M. Forrest, W. Jack, C. McDonald, H.J. Stewart; South Swedish Breast Cancer Group: T.R. Möller, S. Rydén; South-East Sweden Breast Cancer Group: J. Carstensen, T. Hatschek, M. Söderberg; Southeastern Cancer Study Group and Alabama Breast Cancer Project: J.T. Carpenter; Southwest Oncology Group: K. Albain, J. Crowley, S. Green, C.K. Osborne; Stockholm Breast Cancer Study Group: L.E. Rutqvist, A. Wallgren; Karolinska Hospital: L.E. Holm; Swiss Group for Clinical Cancer Research and Working Party for Clinical Oncology in Eastern Switzerland (OSAKO): M. Castiglione, H. Flückiger, A. Goldhirsch, H.J. Senn, B. Thürlimann; Tel Aviv University: H. Brenner, A. Hercbergs; Tokyo, Cancer Institute Hospital: M. Yoshimoto; Toronto–Edmonton Breast Cancer Study Group: G. DeBoer, A.H.G. Paterson, K.I. Pritchard; Princess Margaret Hospital: J.W. Meakin, T. Panzarella, K.I. Pritchard; Toulouse Centre Claudius Regaud: A. Naja; Institut Salah Azaiz: J. Bahi; United Kingdom Multicentre Cancer Chemotherapy Study Group: M. Reid, M. Spittle; UK/Asia Collaborative Breast Cancer Group: F. Senanayake; Uppsala–Örebro Cancer Study Group: L. Holmberg; Vienna University Hospital: P. Sevelda, C.C. Zielinsky, R. Jakesz; Wessex Radiotherapy Centre: R.B. Buchanan, M. Cross; West Midlands Oncology Association: J.A. Dunn, W.M. Gillespie, K. Kelly, J.M. Morrison; West of Scotland Breast Trial: A. Litton; Western Cancer Study Group: R.T. Chlebowski; Witwatersrand University: W.R. Bezwoda; Wurzburg: H. Caffier.
Appendix 2. Randomized Trials of Radiotherapy and Surgery in the Treatment of Early Breast Cancer
For a complete list of the trials, listed alphabetically by their short names, see Appendix 3. This appendix contains some trials from which data on mortality were not available for analysis.
The following abbreviations are used in this appendix: o denotes orthovoltage; f fractions; d days; m megavoltage; OvAbl ovarian ablation; IMC internal mammary chain; N nodal stage; R radiotherapy; Tam tamoxifen; CMF cyclophosphamide, methotrexate, and fluorouracil; OvIrr ovarian irradiation; CFP cyclophosphamide, fluorouracil, and prednisone; AC axillary clearance; MF methotrexate and fluorouracil; Mel melphalan; T tumor size; FAC fluorouracil, adriamycin, and cyclophosphamide; BCG bacille Calmette–Guérin; Pre premenopausal; Cyclo cyclophosphamide; Post postmenopausal; CMFP cyclophosphamide, methotrexate, fluorouracil, and prednisone; ER estrogen receptor; Pr prednisone; LMF chlorambucil, methotrexate, and fluorouracil; CAFt cyclophosphamide, doxorubicin, and futrofur; FMel fluorouracil and melphalan; M mastectomy; IMND internal mammary-node dissection; PME pectoral-muscle excision; AB axillary biopsy (sampling); BW breast or chest wall; Ooph oophorectomy; C breast conserving surgery; AF axilla and supraclavicular fossa; MThio methotrexate and thiotepa; MPA medroxyprogesterone acetate; ± not all patients; periop perioperative.
Appendix 2A. Randomized Trials Comparing Radiotherapy plus Surgery with the Same Surgery Alone
Appendix 2B. Randomized Trials Comparing More Extensive Surgery with Less Extensive Surgery
Appendix 2C. Randomized Trials Comparing More Extensive Surgery with Less Extensive Surgery plus Radiotherapy
Appendix 2D. Other Randomized Trials for Which Data on Individual Patients Were Available
Appendix 3. Randomized Trials of Local Therapy for Breast Cancer
The trials included in this overview are listed below with a short name (as used in Figure 1 and Figure 3 and Appendix 2; an asterisk indicates that data on causes of death were supplied); the full name of the trial, if different; the year in which the trial was begun (in parentheses); and the name or location of the institution or study group.
Addenbrooke's* (1958): Addenbrooke's Hospital, Cambridge, United Kingdom.
Alabama BCP* (1975): Alabama Breast Cancer Project, Birmingham, Ala.
BCCA Vancouver,* BCCA G1 Trial (1978): British Columbia Cancer Agency, Vancouver, B.C., Canada.
Berlin MQ (1976): Berlin–Buch Akademie der Wissenschaften, Berlin, Germany.
Berlin–Buch, CMEA Multicentre Trial (1976): Berlin–Buch Akademie der Wissenschaften, Berlin, Germany.
Berlin–Buch ABC (1962): Berlin–Buch Akademie der Wissenschaften, Berlin, Germany.
BMFT 01 Germany,* GBSG Protocol 01 (1983): Bundesminsterium für Forschung und Technologie, Freiburg, Germany.
BMFT 03 Germany,* GBSG Protocol 03 (1984): Bundesminsterium für Forschung und Technologie, Freiburg, Germany.
Bradford RI (1974): Bradford Royal Infirmary, Bradford, United Kingdom.
Cardiff (1967): Cardiff Surgery Trialists, Cardiff, United Kingdom.
Charing Cross, Hammersmith Trial (1965): Charing Cross Hospital, London.
Chicago U* (1973): University of Chicago, Chicago.
Coimbra* (1979): Coimbra Instituto de Oncologia, Coimbra, Portugal.
Cologne (1976): Cologne, Germany.
Copenhagen* (1951): Copenhagen Radium Center, Copenhagen, Denmark.
CRC UK,* CRC Breast Conservation Trial (1982): Cancer Research Campaign, London.
CRC UK, Elderly Trial (1984): Cancer Research Campaign, London.
Danish BCG 82b pre,* DBCG 82b premenopausal (1982): Danish Breast Cancer Cooperative Group, Copenhagen, Denmark.
Danish BCG 82c post,* DBCG 82b postmenopausal (1982): Danish Breast Cancer Cooperative Group, Copenhagen, Denmark.
Danish BCG 82TM,* DBCG 82TM (1983): Danish Breast Cancer Cooperative Group, Copenhagen, Denmark.
DFCI Boston,* DFCI 74-063/75-122 (1976): Dana–Farber Cancer Institute, Boston.
Düsseldorf U (1977): Düsseldorf University, Düsseldorf, Germany.
ECOG EST3181 (1982): Eastern Cooperative Oncology Group, Boston.
Edinburgh,* Edinburgh Surgery Trial (1980): Edinburgh, United Kingdom.
Edinburgh I,* Edinburgh Radiotherapy Trial I (1974): Edinburgh, United Kingdom.
EORTC 10801 (1980): European Organisation for Research and Treatment of Cancer, Brussels, Belgium.
Glasgow,* Victoria-Gartnavel Study (1976): Victoria Infirmary, Glasgow, United Kingdom.
Groote Schuur,* (1967): Groote Schuur Hospital, Cape Town, South Africa.
Guy's London, Guy's Surgery I and II Trials (1961): Guy's Hospital, London.
Heidelberg XRT,* Heidelberg Radiotherapy Trial (1969): Heidelberg University, Heidelberg, Germany.
Helsinki* (1980): Helsinki University, Helsinki, Finland.
Huguenin France, Fédération Nationale des Centres de Lutte contre le Cancer Trial (1974): Centre René Huguenin, St. Cloud, France.
ICCRSG Bologna (1975): Italian Cooperative Chemo-Radio-Surgical Group, Bologna, Italy.
Ins. Curie Paris, S4 Trial (1982): Institut Curie, Paris.
INT Milan1* (1973): Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy.
Int'l. Co-op.,* International Cooperative Study (1963): International Cooperative Study Trialists, Villejuif, France.
IT Naples (1977): Istituto Tumori, Naples, Italy.
Kings/Cambridge,* Cancer Research Campaign 1 (1970): Cancer Research Campaign, London.
Manchester RBS1,* Regional Breast Study 1 (1970): North-Western British Surgeons, Manchester, United Kingdom.
Manchester RBS2,* Regional Breast Study 2 (1970): North-Western British Surgeons, Manchester, United Kingdom.
Mayo Clinic,* Mayo 70-56-32 (1973): Mayo Clinic, Rochester, Minn.
MD Ander. 7730B,* M.D. Anderson Study 77-30B (1978): M.D. Anderson Cancer Center, Houston.
Metaxas Athens (1979): Metaxas Memorial Cancer Hospital, Athens, Greece.
Mexico* (1974): Mexican National Cancer Center, Mexico City, Mexico.
NCI Bethesda,* 79-C-111 (1979): National Cancer Institute, Bethesda, Md.
Northwest UK,* Lister Trial (1969): North-Western British Surgeons, Manchester, United Kingdom.
Nottingham City (1982): Nottingham City Hospital, Nottingham, United Kingdom.
NSABC Israel,* BR81 (1980): Israel National Study for Adjuvant Treatment of Breast Cancer, Israel.
NSABC Israel B (1977): Israel National Study for Adjuvant Treatment of Breast Cancer, Israel.
NSABP B-02 (1961): National Surgical Adjuvant Breast and Bowel Project, Pittsburgh.
NSABP B-04 (1971): National Surgical Adjuvant Breast and Bowel Project, Pittsburgh.
NSABP B-06 (1976): National Surgical Adjuvant Breast and Bowel Project, Pittsburgh.
Ontario COG (1984): Ontario Clinical Oncology Group, Toronto.
Oslo Co-60* (1967): Oslo Radium Hospital, Oslo, Norway.
Oslo X-ray* (1964): Oslo Radium Hospital, Oslo, Norway.
Piedmont OA,* POA 74176 (1975): Piedmont Oncology Association, Winston-Salem, N.C.
PMH Toronto* (1973): Princess Margaret Hospital, Toronto.
S Swedish BCG,* SB II (1978): South Swedish Breast Cancer Group, Lund, Sweden.
SASIB* (1971): Scandi-Afro-Swiss-Immuno-Breast International Trialists' Group, Cape Town, South Africa.
Scottish, Scottish Surgery Trial (1982) or Scottish Conservation Trial (1983): Scottish Cancer Trials Office, Edinburgh, United Kingdom.
Scottish D* (1980): Scottish Cancer Trials Office, Edinburgh, United Kingdom.
SE Scotland,* South-East Scotland Radiotherapy Trial (1964): Scottish Cancer Trials Office, Edinburgh, United Kingdom.
SECSG 1* (1976): Southeastern Cancer Study Group, Birmingham, Ala.
St George's,* T1/T2 study (1982): St George's Hospital, London.
St George's E (1982): St George's Hospital, London.
Stockholm (1976): Stockholm Breast Cancer Study Group, Stockholm, Sweden.
Stockholm A* (1971): Stockholm Breast Cancer Study Group, Stockholm, Sweden.
Toronto-Edmont.,* Toronto–Edmonton Radiotherapy Trial (1978): Toronto–Edmonton Breast Cancer Study Group, Toronto.
Tunisia (1977): Institut Salah Azaiz, Tunis, Tunisia.
Uppsala–Örebro* (1981): Uppsala–Örebro Cancer Study Group, Uppsala, Sweden.
Villejuif Paris* (1972): Institut Gustave-Roussy, Villejuif, France.
Wessex* (1973): Wessex Radiotherapy Centre, Southampton, United Kingdom.
WSSA Glasgow (1972): West of Scotland Surgery Trial, Glasgow, United Kingdom.
Wurzburg U., Trial 1 (1977): Wurzburg University, Wurzburg, Germany.
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Related Letters:
Radiotherapy and Surgery in Early Breast Cancer
Recht A., Peto R., Gray R., Collins R.
Extract |
Full Text
N Engl J Med 1996;
334:989, Apr 11, 1996.
Correspondence
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10 are based on the overall death rates in the 10th and subsequent years. The results are shown for women with node-negative cancer (as determined by dissection or by sampling) and for those with node-positive cancer (all other women, including the few with unrecorded nodal status) and are restricted to trials that supplied data on individual patients that included nodal status.
29 = 6.3. In this case the odds ratio shows the rate of death in the groups assigned to more-extensive surgery, as compared with the rate in the groups assigned to less-extensive surgery; the odds reduction represents the decrease in the risk of death among women treated with more-extensive surgery. For a list of the trials, see Appendix 3. AF denotes axilla or supraclavicular fossa, IMC internal mammary chain, and BW breast or chest wall.
