Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials

Abe, O.; Abe, R.; Enomoto, K.; Kikuchi, K.; Koyama, H.; Masuda, H.; Nomura, Y.; Sakai, K.; Sugimachi, K.; Tominaga, T.; Uchino, J.; Yoshida, M.; Haybittle, J. L.; Davies, C.; Harvey, V. J.; Holdaway, T. M.; Kay, R. G.; Mason, B. H.; Forbes, J. F.; Wilcken, N.; Gnant, M.; Jakesz, R.; Ploner, M.; Yosef, H. M. A.; Focan, C.; Lobelle, J. P.; Peek, U.; Oates, G. D.; Powell, J.; Durand, M.; Mauriac, L.; Di Leo, A.; Dolci, S.; Piccart, M. J.; Masood, M. B.; Parker, D.; Price, J. J.; Hupperets, P. S. G. J.; Jackson, S.; Ragaz, J.; Berry, D.; Broadwater, G.; Cirrincione, C.; Muss, H.; Norton, L.; Weiss, R. B.; Abu-Zahra, H. T.; Portnoj, S. M.; Baum, M.; Cuzick, J.; Houghton, J.; Riley, D.; Mansel, R. E.; Gordon, N. H.; Davis, H. L.; Beatrice, A.; Mihura, J.; Naja, A.; Lehingue, Y.; Romestaing, P.; Dubois, J. B.; Delozier, T.; Mace Lesec'h, J.; Rambert, P.; Petruzelka, L.; Pribylova, O.; Owen, J. R.; Harbeck, N.; Jänicke, F.; Meisner, C.; Meier, P.; Howell, A.; Ribeiro, G. C.; Swindell, R.; Burrett, J.; Clarke, M.; Collins, R.; Darby, S.; Davies, C.; Elphinstone, P.; Evans, V.; Godwin, J.; Gray, R.; Harwood, C.; Hicks, C.; Jackson, D.; James, S.; Mackinnon, E.; Mcgale, P.; Mchugh, T.; Mead, G.; Morris, P.; Oulds, J.; Peto, R.; Taylor, C.; Wang, Y.; Albano, J.; De Oliveira, C. F.; Gervásio, H.; Gordilho, J.; Johansen, H.; Mouridsen, H. T.; Gelman, R. S.; Harris, J. R.; Henderson, I. C.; Shapiro, C. L.; Christiansen, P.; Ejlertsen, B.; Mouridsen, H. T.; Møller, S.; Overgaard, M.; Carstensen, B.; Palshof, T.; Trampisch, H. J.; Dalesio, O.; De Vries, E. G. E.; Rodenhuis, S.; Van Tinteren, H.; Comis, R. L.; Davidson, N. E.; Gray, R.; Robert, N.; Sledge, G.; Tormey, D. C.; Wood, W.; Cameron, D.; Chetty, U.; Forrest, P.; Jack, W.; Rossbach, J.; Klijn, J. G. M.; Treurniet-Donker, A. D.; Van Putten, W. L. J.; Costa, A.; Veronesi, U.; Bartelink, H.; Duchateau, L.; Legrand, C.; Sylvester, R.; Van Der Hage, J. A.; Van De Velde, C. J. H.; Cunningham, M. P.; Catalano, R.; Creech, R. H.; Bonneterre, J.; Fargeot, P.; Fumoleau, P.; Kerbrat, P.; Namer, M.; Jonat, W.; Kaufmann, M.; Schumacher, M.; Von Minckwitz, G.; Bastert, G.; Rauschecker, H.; Sauer, R.; Sauerbrei, W.; Schauer, A.; Schumacher, M.; De Schryver, A.; Vakaet, L.; Belfiglio, M.; Nicolucci, A.; Pellegrini, F.; Sacco, M.; Valentini, M.; Mcardle, C. S.; Smith, D. C.; Galligioni, E.; Boccardo, F.; Rubagotti, A.; Dent, D. M.; Gudgeon, C. A.; Hacking, A.; Erazo, A.; Medina, J. Y.; Izuo, M.; Morishita, Y.; Takei, H.; Fentiman, I. S.; Hayward, J. L.; Rubens, R. D.; Skilton, D.; Scheurlen, H.; Kaufmann, M.; Von Fournier, D.; Dafni, U.; Fountzilas, G.; Klefstrom, P.; Blomqvist, C.; Saarto, T.; Margreiter, R.; Asselain, B.; Salmon, R. J.; Vilcoq, J. R.; Arriagada, R.; Hill, C.; Laplanche, A.; M. G., Lê; Spielmann, M.; Bruzzi, P.; Montanaro, E.; Rosso, R.; Sertoli, M. R.; Venturini, M.; Amadori, D.; Benraadt, J.; Kooi, M.; Van De Velde, A. O.; Van Dongen, J. A.; Vermorken, J. B.; Castiglione, M.; Cavalli, F.; Coates, A.; Collins, J.; Forbes, J.; Gelber, R. D.; Goldhirsch, A.; Lindtner, J.; Price, K. N.; Rudenstam, C. M.; Senn, H. J.; Bliss, J. M.; Chilvers, C. E. D.; Coombes, R. C.; Hall, E.; Marty, M.; Borovik, R.; Brufman, G.; Hayat, H.; Robinson, E.; Wigler, N.; Bonadonna, G.; Camerini, T.; De Palo, G.; Del Vecchio, M.; Formelli, F.; Valagussa, P.; Martoni, A.; Pannuti, F.; Cocconi, G.; Colozza, A.; Camisa, R.; Aogi, K.; Takashima, S.; Abe, O.; Ikeda, T.; Inokuchi, K.; Kikuchi, K.; Sawa, K.; Sonoo, H.; Korzeniowski, S.; Skolyszewski, J.; Ogawa, M.; Yamashita, J.; Bonte, J.; Christiaens, R.; Paridaens, R.; Van Den Bogaert, W.; Martin, P.; Geniez, ROMAIN SYLVAIN JEAN; Hakes, T.; Hudis, C. A.; Norton, L.; Wittes, R.; Giokas, G.; Kondylis, D.; Lissaios, B.; De La Huerta, R.; Sainz, M. G.; Altemus, R.; Cowan, K.; Danforth, D.; Lichter, A.; Lippman, M.; O'Shaughnessy, J.; Pierce, L. J.; Steinberg, S.; Venzon, D.; Zujewski, J. A.; Paradiso, A.; De Lena, M.; Schittulli, F.; Myles, J. D.; Pater, J. L.; Pritchard, K. I.; Whelan, T.; Nomura, Y.; Anderson, S.; Bass, G.; Brown, A.; Bryant, J.; Costantino, J.; Dignam, J.; Fisher, B.; Redmond, C.; Wieand, S.; Wolmark, N.; Baum, M.; Jackson, I. M.; Palmer, M. K.; Ingle, J. N.; Suman, V. J.; Bengtsson, N. O.; Jonsson, H.; Larsson, L. G.; Lythgoe, J. P.; Swindell, R.; Kissin, M.; Erikstein, B.; Hannisdal, E.; Jacobsen, A. B.; Varhaug, J. E.; Erikstein, B.; Gundersen, S.; Hauer-Jensen, M.; Høst, H.; Jacobsen, A. B.; Nissen-Meyer, R.; Blamey, R. W.; Mitchell, A. K.; Morgan, D. A. L.; Robertson, J. F. R.; Di Palma, M.; Mathé, G.; Misset, J. L.; Clark, R. M.; Levine, M.; Pritchard, K. I.; Whelan, T.; Morimoto, K.; Sawa, K.; Takatsuka, Y.; Crossley, E.; Harris, A.; Talbot, D.; Taylor, M.; Cocconi, G.; Di Blasio, B.; Ivanov, V.; Semiglazov, V.; Brockschmidt, J.; Cooper, M. R.; Ueo, H.; Falkson, C. I.; A'Hern, R.; Ashley, S.; Powles, T. J.; Smith, I. E.; Yarnold, J. R.; Gazet, J. C.; Corcoran, N.; Deshpande, N.; Di Martino, L.; Douglas, P.; Hacking, A.; Høst, H.; Lindtner, A.; Notter, G.; Bryant, A. J. S.; Ewing, G. H.; Firth, L. A.; Krushen-Kosloski, J. L.; Nissen-Meyer, R.; Foster, L.; George, W. D.; Stewart, H. J.; Stroner, P.; Malmström, P.; Möller, T. R.; Rydén, S.; Tengrup, I.; Tennvall-Nittby, L.; Carstenssen, J.; Dufmats, M.; Hatschek, T.; Nordenskjöld, B.; Söderberg, M.; Carpenter, J. T.; Albain, K.; Crowley, J.; Green, S.; Martino, S.; Osborne, C. K.; Ravdin, P. M.; Glas, U.; Johansson, U.; Rutqvist, L. E.; Singnomklao, T.; Wallgren, A.; Castiglione, M.; Goldhirsch, A.; Maibach, R.; Senn, H. J.; Thürlimann, B.; Brenner, H.; Hercbergs, A.; Yoshimoto, M.; Deboer, G.; Paterson, A. H. G.; Pritchard, K. I.; Meakin, J. W.; Panzarella, T.; Pritchard, K. I.; Shan, Y.; Shao, Y. F.; Wang, X.; Zhao, D. B.; Chen, Z. M.; Pan, H. C.; Bahi, J.; Reid, M.; Spittle, M.; Deutsch, G. P.; Senanayake, F.; Kwong, D. L. W.; Bianco, A. R.; Carlomagno, C.; De Laurentiis, M.; De Placido, S.; Buzdar, A. U.; Smith, T.; Bergh, J.; Holmberg, L.; Liljegren, G.; Nilsson, J.; Seifert, M.; Sevelda, P.; Zielinsky, C. C.; Buchanan, R. B.; Cross, M.; Royle, G. T.; Dunn, J. A.; Hills, R. K.; Lee, M.; Morrison, J. M.; Spooner, D.; Litton, A.; Chlebowski, R. T.; Caffier, H.

doi:10.1016/S0140-6736(05)67887-7

Background: In early breast cancer, variations in local treatment that substantially affect the risk of locoregional recurrence could also affect long-term breast cancer mortality. To examine this relationship, collaborative meta-analyses were undertaken, based on individual patient data, of the relevant randomised trials that began by 1995. Methods: Information was available on 42 000 women in 78 randomised treatment comparisons (radiotherapy vs no radiotherapy, 23 500; more vs less surgery, 9300; more surgery vs radiotherapy, 9300). 24 types of local treatment comparison were identified. To help relate the effect on local (ie, locoregional) recurrence to that on breast cancer mortality, these were grouped according to whether or not the 5-year local recurrence risk exceeded 10% (<10%, 17 000 women; >10%, 25 000 women). Findings: About three-quarters of the eventual local recurrence risk occurred during the first 5 years. In the comparisons that involved little (<10%) difference in 5-year local recurrence risk there was little difference in 15-year breast cancer mortality. Among the 25 000 women in the comparisons that involved substantial (>10%) differences, however, 5-year local recurrence risks were 7% active versus 26% control (absolute reduction 19%), and 15-year breast cancer mortality risks were 44.6% versus 49.5% (absolute reduction 5.0%, SE 0.8, 2p<0.00001). These 25 000 women included 7300 with breast-conserving surgery (BCS) in trials of radiotherapy (generally just to the conserved breast), with 5-year local recurrence risks (mainly in the conserved breast, as most had axillary clearance and node-negative disease) 7% versus 26% (reduction 19%), and 15-year breast cancer mortality risks 30.5% versus 35.9% (reduction 5.4%, SE 1.7, 2p=0.0002; overall mortality reduction 5.3%, SE 1.8, 2p=0.005). They also included 8500 with mastectomy, axillary clearance, and node-positive disease in trials of radiotherapy (generally to the chest wall and regional lymph nodes), with similar absolute gains from radiotherapy; 5-year local recurrence risks (mainly at these sites) 6% versus 23% (reduction 17%), and 15-year breast cancer mortality risks 54.7% versus 60.1% (reduction 5.4%, SE 1.3, 2p=0.0002; overall mortality reduction 4.4%, SE 1.2, 2p=0.0009). Radiotherapy produced similar proportional reductions in local recurrence in all women (irrespective of age or tumour characteristics) and in all major trials of radiotherapy versus not (recent or older; with or without systemic therapy), so large absolute reductions in local recurrence were seen only if the control risk was large. To help assess the life-threatening side-effects of radiotherapy, the trials of radiotherapy versus not were combined with those of radiotherapy versus more surgery. There was, at least with some of the older radiotherapy regimens, a significant excess incidence of contralateral breast cancer (rate ratio 1.18, SE 0.06, 2p=0.002) and a significant excess of non-breast-cancer mortality in irradiated women (rate ratio 1.12, SE 0.04, 2p=0.001). Both were slight during the first 5 years, but continued after year 15. The excess mortality was mainly from heart disease (rate ratio 1.27, SE 0.07, 2p=0.0001) and lung cancer (rate ratio 1.78, SE 0.22, 2p=0.0004). Interpretation: In these trials, avoidance of a local recurrence in the conserved breast after BCS and avoidance of a local recurrence elsewhere (eg, the chest wall or regional nodes) after mastectomy were of comparable relevance to 15-year breast cancer mortality. Differences in local treatment that substantially affect local recurrence rates would, in the hypothetical absence of any other causes of death, avoid about one breast cancer death over the next 15 years for every four local recurrences avoided, and should reduce 15-year overall mortality.

Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials

Abe, O.;Abe, R.;Enomoto, K.;Kikuchi, K.;Koyama, H.;Masuda, H.;Nomura, Y.;Sakai, K.;Sugimachi, K.;Tominaga, T.;Uchino, J.;Yoshida, M.;Haybittle, J. L.;Davies, C.;Harvey, V. J.;Holdaway, T. M.;Kay, R. G.;Mason, B. H.;Forbes, J. F.;Wilcken, N.;Gnant, M.;Jakesz, R.;Ploner, M.;Yosef, H. M. A.;Focan, C.;Lobelle, J. P.;Peek, U.;Oates, G. D.;Powell, J.;Durand, M.;Mauriac, L.;Di Leo, A.;Dolci, S.;Piccart, M. J.;Masood, M. B.;Parker, D.;Price, J. J.;Hupperets, P. S. G. J.;Jackson, S.;Ragaz, J.;Berry, D.;Broadwater, G.;Cirrincione, C.;Muss, H.;Norton, L.;Weiss, R. B.;Abu-Zahra, H. T.;Portnoj, S. M.;Baum, M.;Cuzick, J.;Houghton, J.;Riley, D.;Mansel, R. E.;Gordon, N. H.;Davis, H. L.;Beatrice, A.;Mihura, J.;Naja, A.;Lehingue, Y.;Romestaing, P.;Dubois, J. B.;Delozier, T.;Mace Lesec'h, J.;Rambert, P.;Petruzelka, L.;Pribylova, O.;Owen, J. R.;Harbeck, N.;Jänicke, F.;Meisner, C.;Meier, P.;Howell, A.;Ribeiro, G. C.;Swindell, R.;Burrett, J.;Clarke, M.;Collins, R.;Darby, S.;Davies, C.;Elphinstone, P.;Evans, V.;Godwin, J.;Gray, R.;Harwood, C.;Hicks, C.;Jackson, D.;James, S.;MacKinnon, E.;McGale, P.;McHugh, T.;Mead, G.;Morris, P.;Oulds, J.;Peto, R.;Taylor, C.;Wang, Y.;Albano, J.;De Oliveira, C. F.;Gervásio, H.;Gordilho, J.;Johansen, H.;Mouridsen, H. T.;Gelman, R. S.;Harris, J. R.;Henderson, I. C.;Shapiro, C. L.;Christiansen, P.;Ejlertsen, B.;Mouridsen, H. T.;Møller, S.;Overgaard, M.;Carstensen, B.;Palshof, T.;Trampisch, H. J.;Dalesio, O.;De Vries, E. G. E.;Rodenhuis, S.;Van Tinteren, H.;Comis, R. L.;Davidson, N. E.;Gray, R.;Robert, N.;Sledge, G.;Tormey, D. C.;Wood, W.;Cameron, D.;Chetty, U.;Forrest, P.;Jack, W.;Rossbach, J.;Klijn, J. G. M.;Treurniet-Donker, A. D.;Van Putten, W. L. J.;Costa, A.;Veronesi, U.;Bartelink, H.;Duchateau, L.;Legrand, C.;Sylvester, R.;Van Der Hage, J. A.;Van De Velde, C. J. H.;Cunningham, M. P.;Catalano, R.;Creech, R. H.;Bonneterre, J.;Fargeot, P.;Fumoleau, P.;Kerbrat, P.;Namer, M.;Jonat, W.;Kaufmann, M.;Schumacher, M.;Von Minckwitz, G.;Bastert, G.;Rauschecker, H.;Sauer, R.;Sauerbrei, W.;Schauer, A.;Schumacher, M.;De Schryver, A.;Vakaet, L.;Belfiglio, M.;Nicolucci, A.;Pellegrini, F.;Sacco, M.;Valentini, M.;McArdle, C. S.;Smith, D. C.;Galligioni, E.;Boccardo, F.;Rubagotti, A.;Dent, D. M.;Gudgeon, C. A.;Hacking, A.;Erazo, A.;Medina, J. Y.;Izuo, M.;Morishita, Y.;Takei, H.;Fentiman, I. S.;Hayward, J. L.;Rubens, R. D.;Skilton, D.;Scheurlen, H.;Kaufmann, M.;Von Fournier, D.;Dafni, U.;Fountzilas, G.;Klefstrom, P.;Blomqvist, C.;Saarto, T.;Margreiter, R.;Asselain, B.;Salmon, R. J.;Vilcoq, J. R.;Arriagada, R.;Hill, C.;Laplanche, A.;Lê, M. G.;Spielmann, M.;Bruzzi, P.;Montanaro, E.;Rosso, R.;Sertoli, M. R.;Venturini, M.;Amadori, D.;Benraadt, J.;Kooi, M.;Van De Velde, A. O.;Van Dongen, J. A.;Vermorken, J. B.;Castiglione, M.;Cavalli, F.;Coates, A.;Collins, J.;Forbes, J.;Gelber, R. D.;Goldhirsch, A.;Lindtner, J.;Price, K. N.;Rudenstam, C. M.;Senn, H. J.;Bliss, J. M.;Chilvers, C. E. D.;Coombes, R. C.;Hall, E.;Marty, M.;Borovik, R.;Brufman, G.;Hayat, H.;Robinson, E.;Wigler, N.;Bonadonna, G.;Camerini, T.;De Palo, G.;Del Vecchio, M.;Formelli, F.;Valagussa, P.;Martoni, A.;Pannuti, F.;Cocconi, G.;Colozza, A.;Camisa, R.;Aogi, K.;Takashima, S.;Abe, O.;Ikeda, T.;Inokuchi, K.;Kikuchi, K.;Sawa, K.;Sonoo, H.;Korzeniowski, S.;Skolyszewski, J.;Ogawa, M.;Yamashita, J.;Bonte, J.;Christiaens, R.;Paridaens, R.;Van Den Bogaert, W.;Martin, P.;GENIEZ, ROMAIN SYLVAIN JEAN;Hakes, T.;Hudis, C. A.;Norton, L.;Wittes, R.;Giokas, G.;Kondylis, D.;Lissaios, B.;De La Huerta, R.;Sainz, M. G.;Altemus, R.;Cowan, K.;Danforth, D.;Lichter, A.;Lippman, M.;O'Shaughnessy, J.;Pierce, L. J.;Steinberg, S.;Venzon, D.;Zujewski, J. A.;Paradiso, A.;De Lena, M.;Schittulli, F.;Myles, J. D.;Pater, J. L.;Pritchard, K. I.;Whelan, T.;Nomura, Y.;Anderson, S.;Bass, G.;Brown, A.;Bryant, J.;Costantino, J.;Dignam, J.;Fisher, B.;Redmond, C.;Wieand, S.;Wolmark, N.;Baum, M.;Jackson, I. M.;Palmer, M. K.;Ingle, J. N.;Suman, V. J.;Bengtsson, N. O.;Jonsson, H.;Larsson, L. G.;Lythgoe, J. P.;Swindell, R.;Kissin, M.;Erikstein, B.;Hannisdal, E.;Jacobsen, A. B.;Varhaug, J. E.;Erikstein, B.;Gundersen, S.;Hauer-Jensen, M.;Høst, H.;Jacobsen, A. B.;Nissen-Meyer, R.;Blamey, R. W.;Mitchell, A. K.;Morgan, D. A. L.;Robertson, J. F. R.;Di Palma, M.;Mathé, G.;Misset, J. L.;Clark, R. M.;Levine, M.;Pritchard, K. I.;Whelan, T.;Morimoto, K.;Sawa, K.;Takatsuka, Y.;Crossley, E.;Harris, A.;Talbot, D.;Taylor, M.;Cocconi, G.;Di Blasio, B.;Ivanov, V.;Semiglazov, V.;Brockschmidt, J.;Cooper, M. R.;Ueo, H.;Falkson, C. I.;A'Hern, R.;Ashley, S.;Powles, T. J.;Smith, I. E.;Yarnold, J. R.;Gazet, J. C.;Corcoran, N.;Deshpande, N.;Di Martino, L.;Douglas, P.;Hacking, A.;Høst, H.;Lindtner, A.;Notter, G.;Bryant, A. J. S.;Ewing, G. H.;Firth, L. A.;Krushen-Kosloski, J. L.;Nissen-Meyer, R.;Foster, L.;George, W. D.;Stewart, H. J.;Stroner, P.;Malmström, P.;Möller, T. R.;Rydén, S.;Tengrup, I.;Tennvall-Nittby, L.;Carstenssen, J.;Dufmats, M.;Hatschek, T.;Nordenskjöld, B.;Söderberg, M.;Carpenter, J. T.;Albain, K.;Crowley, J.;Green, S.;Martino, S.;Osborne, C. K.;Ravdin, P. M.;Glas, U.;Johansson, U.;Rutqvist, L. E.;Singnomklao, T.;Wallgren, A.;Castiglione, M.;Goldhirsch, A.;Maibach, R.;Senn, H. J.;Thürlimann, B.;Brenner, H.;Hercbergs, A.;Yoshimoto, M.;DeBoer, G.;Paterson, A. H. G.;Pritchard, K. I.;Meakin, J. W.;Panzarella, T.;Pritchard, K. I.;Shan, Y.;Shao, Y. F.;Wang, X.;Zhao, D. B.;Chen, Z. M.;Pan, H. C.;Bahi, J.;Reid, M.;Spittle, M.;Deutsch, G. P.;Senanayake, F.;Kwong, D. L. W.;Bianco, A. R.;Carlomagno, C.;De Laurentiis, M.;De Placido, S.;Buzdar, A. U.;Smith, T.;Bergh, J.;Holmberg, L.;Liljegren, G.;Nilsson, J.;Seifert, M.;Sevelda, P.;Zielinsky, C. C.;Buchanan, R. B.;Cross, M.;Royle, G. T.;Dunn, J. A.;Hills, R. K.;Lee, M.;Morrison, J. M.;Spooner, D.;Litton, A.;Chlebowski, R. T.;Caffier, H.

2005-01-01

Abstract

Background: In early breast cancer, variations in local treatment that substantially affect the risk of locoregional recurrence could also affect long-term breast cancer mortality. To examine this relationship, collaborative meta-analyses were undertaken, based on individual patient data, of the relevant randomised trials that began by 1995. Methods: Information was available on 42 000 women in 78 randomised treatment comparisons (radiotherapy vs no radiotherapy, 23 500; more vs less surgery, 9300; more surgery vs radiotherapy, 9300). 24 types of local treatment comparison were identified. To help relate the effect on local (ie, locoregional) recurrence to that on breast cancer mortality, these were grouped according to whether or not the 5-year local recurrence risk exceeded 10% (<10%, 17 000 women; >10%, 25 000 women). Findings: About three-quarters of the eventual local recurrence risk occurred during the first 5 years. In the comparisons that involved little (<10%) difference in 5-year local recurrence risk there was little difference in 15-year breast cancer mortality. Among the 25 000 women in the comparisons that involved substantial (>10%) differences, however, 5-year local recurrence risks were 7% active versus 26% control (absolute reduction 19%), and 15-year breast cancer mortality risks were 44.6% versus 49.5% (absolute reduction 5.0%, SE 0.8, 2p<0.00001). These 25 000 women included 7300 with breast-conserving surgery (BCS) in trials of radiotherapy (generally just to the conserved breast), with 5-year local recurrence risks (mainly in the conserved breast, as most had axillary clearance and node-negative disease) 7% versus 26% (reduction 19%), and 15-year breast cancer mortality risks 30.5% versus 35.9% (reduction 5.4%, SE 1.7, 2p=0.0002; overall mortality reduction 5.3%, SE 1.8, 2p=0.005). They also included 8500 with mastectomy, axillary clearance, and node-positive disease in trials of radiotherapy (generally to the chest wall and regional lymph nodes), with similar absolute gains from radiotherapy; 5-year local recurrence risks (mainly at these sites) 6% versus 23% (reduction 17%), and 15-year breast cancer mortality risks 54.7% versus 60.1% (reduction 5.4%, SE 1.3, 2p=0.0002; overall mortality reduction 4.4%, SE 1.2, 2p=0.0009). Radiotherapy produced similar proportional reductions in local recurrence in all women (irrespective of age or tumour characteristics) and in all major trials of radiotherapy versus not (recent or older; with or without systemic therapy), so large absolute reductions in local recurrence were seen only if the control risk was large. To help assess the life-threatening side-effects of radiotherapy, the trials of radiotherapy versus not were combined with those of radiotherapy versus more surgery. There was, at least with some of the older radiotherapy regimens, a significant excess incidence of contralateral breast cancer (rate ratio 1.18, SE 0.06, 2p=0.002) and a significant excess of non-breast-cancer mortality in irradiated women (rate ratio 1.12, SE 0.04, 2p=0.001). Both were slight during the first 5 years, but continued after year 15. The excess mortality was mainly from heart disease (rate ratio 1.27, SE 0.07, 2p=0.0001) and lung cancer (rate ratio 1.78, SE 0.22, 2p=0.0004). Interpretation: In these trials, avoidance of a local recurrence in the conserved breast after BCS and avoidance of a local recurrence elsewhere (eg, the chest wall or regional nodes) after mastectomy were of comparable relevance to 15-year breast cancer mortality. Differences in local treatment that substantially affect local recurrence rates would, in the hypothetical absence of any other causes of death, avoid about one breast cancer death over the next 15 years for every four local recurrences avoided, and should reduce 15-year overall mortality.