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Effects of chemotherapy and hormonal therapy for early breast cancer on 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 and Tominaga, T, et al. (2005) In The Lancet 365(9472). p.1687-1717
Abstract
Background Quinquennial overviews (1985-2000) of the randomised trials in early breast cancer have assessed the 5-year and 10-year effects of various systemic adjuvant therapies on breast cancer recurrence and survival. Here, we report the 10-year and 15-year effects. Methods Collaborative meta-analyses were undertaken of 194 unconfounded randomised trials of adjuvant chemotherapy or hormonal therapy that began by 1995. Many trials involved CMF (cyclophosphamide, methotrexate, fluorouracil), anthracycline-based combinations such as FAC (fluorouracil, doxombicin, cyclophosphamide) or FEC (fluorouracil, epirubicin, cyclophosphamide), tamoxifen, or ovarian suppression: none involved taxanes, trastuzumab, raloxifene, or modem aromatase... (More)
Background Quinquennial overviews (1985-2000) of the randomised trials in early breast cancer have assessed the 5-year and 10-year effects of various systemic adjuvant therapies on breast cancer recurrence and survival. Here, we report the 10-year and 15-year effects. Methods Collaborative meta-analyses were undertaken of 194 unconfounded randomised trials of adjuvant chemotherapy or hormonal therapy that began by 1995. Many trials involved CMF (cyclophosphamide, methotrexate, fluorouracil), anthracycline-based combinations such as FAC (fluorouracil, doxombicin, cyclophosphamide) or FEC (fluorouracil, epirubicin, cyclophosphamide), tamoxifen, or ovarian suppression: none involved taxanes, trastuzumab, raloxifene, or modem aromatase inhibitors. Findings Allocation to about 6 months of anthracycline-based polychemotherapy (eg, with FAC or FEC) reduces the annual breast cancer death rate by about 38% (SE 5) for women younger than 50 years of age when diagnosed and by about 20% (SE 4) for those of age 50-69 years when diagnosed, largely irrespective of the use of tamoxifen and of oestrogen receptor (ER) status, nodal status, or other tumour characteristics. Such regimens are significantly (2p=0 . 0001 for recurrence, 2p<0 . 00001 for breast cancer mortality) more effective than CMF chemotherapy. Few women of age 70 years or older entered these chemotherapy trials. For ER-positive disease only, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% (SE 3), largely irrespective of the use of chemotherapy and of age (<50, 50-69, &GE; 70 years), progesterone receptor status, or other tumour characteristics. 5 years is significantly (2p<0 . 00001 for recurrence, 2p=0 . 01 for breast cancer mortality) more effective than just 1-2 years of tamoxifen. For ER-positive tumours, the annual breast cancer mortality rates are similar during years 0-4 and 5-14, as are the proportional reductions in them by 5 years of tamoxifen, so the cumulative reduction in mortality is more than twice as big at 15 years as at 5 years after diagnosis. These results combine six meta-analyses: anthracycline-based versus no chemotherapy (8000 women); CMF-based versus no chemotherapy (14 000); anthracycline-based versus CMF-based chemotherapy (14 000); about 5 years of tamoxifen versus none (15 000); about 1-2 years of tamoxifen versus none (33 000); and about 5 years versus 1-2 years of tamoxifen (18 000). Finally, allocation to ovarian ablation or suppression (8000 women) also significantly reduces breast cancer mortality, but appears to do so only in the absence of other systemic treatments. For middle-aged women with ER-positive disease (the commonest type of breast cancer), the breast cancer mortality rate throughout the next 15 years would be approximately halved by 6 months of anthracycline-based chemotherapy (with a combination such as FAC or FEC) followed by 5 years of adjuvant tamoxifen. For, if mortality reductions of 38% (age <50 years) and 20% (age 50-69 years) from such chemotherapy were followed by a further reduction of 31% from tamoxifen in the risks that remain, the final mortality reductions would be 57% and 45%, respectively (and, the trial results could well have been somewhat stronger if there had been full compliance with the allocated treatments). Overall survival would be comparably improved, since these treatments have relatively small effects on mortality from the aggregate of all other causes. Interpretation Some of the widely practicable adjuvant drug treatments that were being tested in the 1980s, which substantially reduced 5-year recurrence rates (but had somewhat less effect on 5-year mortality rates), also substantially reduce 15-year mortality rates. Further improvements in long-term survival could well be available from newer drugs, or better use of older drugs. (Less)
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The Lancet
volume
365
issue
9472
pages
1687 - 1717
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Elsevier Limited
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  • WOS:000229082300022
  • Scopus:19344364880
ISSN
1474-547X
DOI
10.1016/S0140-6736(05)66544-0
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English
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@misc{f44fbf14-97ee-4bb3-ab34-14b5246b5cfe,
  abstract     = {Background Quinquennial overviews (1985-2000) of the randomised trials in early breast cancer have assessed the 5-year and 10-year effects of various systemic adjuvant therapies on breast cancer recurrence and survival. Here, we report the 10-year and 15-year effects. Methods Collaborative meta-analyses were undertaken of 194 unconfounded randomised trials of adjuvant chemotherapy or hormonal therapy that began by 1995. Many trials involved CMF (cyclophosphamide, methotrexate, fluorouracil), anthracycline-based combinations such as FAC (fluorouracil, doxombicin, cyclophosphamide) or FEC (fluorouracil, epirubicin, cyclophosphamide), tamoxifen, or ovarian suppression: none involved taxanes, trastuzumab, raloxifene, or modem aromatase inhibitors. Findings Allocation to about 6 months of anthracycline-based polychemotherapy (eg, with FAC or FEC) reduces the annual breast cancer death rate by about 38% (SE 5) for women younger than 50 years of age when diagnosed and by about 20% (SE 4) for those of age 50-69 years when diagnosed, largely irrespective of the use of tamoxifen and of oestrogen receptor (ER) status, nodal status, or other tumour characteristics. Such regimens are significantly (2p=0 . 0001 for recurrence, 2p&lt;0 . 00001 for breast cancer mortality) more effective than CMF chemotherapy. Few women of age 70 years or older entered these chemotherapy trials. For ER-positive disease only, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% (SE 3), largely irrespective of the use of chemotherapy and of age (&lt;50, 50-69, &amp;GE; 70 years), progesterone receptor status, or other tumour characteristics. 5 years is significantly (2p&lt;0 . 00001 for recurrence, 2p=0 . 01 for breast cancer mortality) more effective than just 1-2 years of tamoxifen. For ER-positive tumours, the annual breast cancer mortality rates are similar during years 0-4 and 5-14, as are the proportional reductions in them by 5 years of tamoxifen, so the cumulative reduction in mortality is more than twice as big at 15 years as at 5 years after diagnosis. These results combine six meta-analyses: anthracycline-based versus no chemotherapy (8000 women); CMF-based versus no chemotherapy (14 000); anthracycline-based versus CMF-based chemotherapy (14 000); about 5 years of tamoxifen versus none (15 000); about 1-2 years of tamoxifen versus none (33 000); and about 5 years versus 1-2 years of tamoxifen (18 000). Finally, allocation to ovarian ablation or suppression (8000 women) also significantly reduces breast cancer mortality, but appears to do so only in the absence of other systemic treatments. For middle-aged women with ER-positive disease (the commonest type of breast cancer), the breast cancer mortality rate throughout the next 15 years would be approximately halved by 6 months of anthracycline-based chemotherapy (with a combination such as FAC or FEC) followed by 5 years of adjuvant tamoxifen. For, if mortality reductions of 38% (age &lt;50 years) and 20% (age 50-69 years) from such chemotherapy were followed by a further reduction of 31% from tamoxifen in the risks that remain, the final mortality reductions would be 57% and 45%, respectively (and, the trial results could well have been somewhat stronger if there had been full compliance with the allocated treatments). Overall survival would be comparably improved, since these treatments have relatively small effects on mortality from the aggregate of all other causes. Interpretation Some of the widely practicable adjuvant drug treatments that were being tested in the 1980s, which substantially reduced 5-year recurrence rates (but had somewhat less effect on 5-year mortality rates), also substantially reduce 15-year mortality rates. Further improvements in long-term survival could well be available from newer drugs, or better use of older drugs.},
  author       = {Abe, O and Abe, R and Enomoto, K and Kikuchi, K and Koyama, H and Masuda, H and Nomura, Y and Sakai, K and Sugimachi, K and Tominaga, T and Uchino, J and Yoshida, M and Haybittle, JL and Davies, C and Harvey, VJ and Holdaway, TM and Kay, RG and Mason, BH and Forbes, JF and Wilcken, N and Gnant, M and Jakesz, R and Ploner, M and Yosef, HMA and Focan, C and Lobelle, JP and Peek, U and Oates, GD and Powell, J and Durand, M and Mauriac, L and Di Leo, A and Dolci, S and Piccart, MJ and Masood, MB and Parker, D and Price, JJ and Hupperets, PSGJ and Jackson, S and Ragaz, J and Berry, D and Broadwater, G and Cirrincione, C and Muss, H and Norton, L and Weiss, RB and Abu-Zahra, HT and Portnoj, SM and Baum, M and Cuzick, J and Houghton, J and Riley, D and Gordon, NH and Davis, HL and Beatrice, A and Mihura, J and Naja, A and Lehingue, Y and Romestaing, P and Dubois, JB and Delozier, T and Mace-Lesec'h, J and Rambert, P and Andrysek, O and Barkmanova, J and Owen, JR and Meier, P and Howell, A and Ribeiro, GC and Swindell, R and Alison, R and Boreham, J and Clarke, M and Collins, R and Darby, S and Davies, C and Elphinstone, P and Evans, V and Godwin, J and Gray, R and Harwood, C and Hicks, C and James, S and MacKinnon, E and McGale, P and McHugh, T and Mead, G and Peto, R and Wang, Y and Albano, J and de Oliveira, CF and Gervasio, H and Gordilho, J and Johansen, H and Mouridsen, HT and Gelman, RS and Harris, JR and Henderson, IC and Shapiro, CL and Andersen, KW and Axelsson, CK and Blichert-Toft, M and Moller, S and Mouridsen, HT and Overgaard, J and Overgaard, M and Rose, C and Cartensen, B and Palshof, T and Trampisch, HJ and Dalesio, O and de Vries, EGE and Rodenhuis, S and van Tinteren, H and Comis, RL and Davidson, NE and Gray, R and Robert, N and Sledge, G and Tormey, DC and Wood, W and Cameron, D and Chetty, U and Forrest, P and Jack, W and Rossbach, J and Klijn, JGM and Treurniet-Donker, AD and van Putten, WLJ and Costa, A and Veronesi, U and Bartelink, H and Duchateau, L and Legrand, C and Sylvester, R and van der Hage, JA and van de Velde, CJH and Cunningham, MP and Catalano, R and Creech, RH and Bonneterre, J and Fargeot, P and Fumoleau, P and Kerbrat, P and Namer, M and Jonat, W and Kaufmann, M and Schumacher, M and von Minckwitz, G and Bastert, G and Rauschecker, H and Sauer, R and Sauerbrei, W and Schauer, A and Schumacher, M and de Schryver, A and Vakaet, L and Belfiglio, M and Nicolucci, A and Pellegrini, F and Sacco, M and Valentini, M and McArdle, CS and Smith, DC and Galligioni, E and Boccardo, F and Rubagotti, A and Dent, DM and Gudgeon, CA and Hacking, A and Erazo, A and Medina, JY and Izuo, M and Morishita, Y and Takei, H and Fentiman, IS and Hayward, JL and Rubens, RD and Skilton, D and Graeff, H and Janicke, F and Meisner, C and Scheurlen, H and Kaufmann, M and von Fournier, D and Dafni, U and Fountzilas, G and Klefstrom, P and Blomqvist, C and Saarto, T and Margreiter, R and Asselain, B and Salmon, RJ and Vilcoq, JR and Arriagada, R and Hill, C and Laplanche, A and Le, MG and Spielmann, M and Bruzzi, P and Montanaro, E and Rosso, R and Sertoli, MR and Venturini, M and Amadori, D and Benraadt, J and Kooi, M and van de Velde, AO and van Dongen, JA and Vermorken, JB and Castiglione, M and Cavalli, F and Coates, A and Collins, J and Forbes, J and Gelber, RD and Goldhirsch, A and Lindtner, J and Price, KN and Rudenstam, CM and Senn, HJ and Bliss, JM and Chilvers, CED and Coombes, RC and Hall, E and Marty, M and Borovik, R and Brufman, G and Hayat, H and Robinson, E and Wigler, N and Bonadonna, G and Camerini, T and De Palo, G and Del Vecchio, M and Formelli, F and Valagussa, P and Martoni, A and Pannuti, F and Cocconi, G and Colozza, A and Camisa, R and Aogi, K and Takashima, S and Abe, O and Ikeda, T and Inokuchi, K and Kikuchi, K and Sawa, K and Sonoo, H and Korzeniowski, S and Skolyszewski, J and Ogawa, M and Yamashita, J and Bonte, J and Christiaens, R and Paridaens, R and Van den Boegart, W and Martin, P and Romain, S and Hakes, T and Hudis, CA and Norton, L and Wittes, R and Giokas, G and Kondylis, D and Lissaios, B and de la Huerta, R and Sainz, MG and Altemus, R and Cowan, K and Danforth, D and Lichter, A and Lippman, M and O'Shaughnessy, J and Pierce, LJ and Steinberg, S and Venzon, D and Zujewski, J and Paradiso, A and De Lena, M and Schittulli, F and Myles, JD and Pater, JL and Pritchard, KI and Nomura, Y and Anderson, S and Bass, G and Brown, A and Bryant, J and Costantino, J and Dignam, J and Fisher, B and Redmond, C and Wieand, S and Wolmark, N and Baum, M and Jackson, IM and Palmer, MK and Ingle, JN and Suman, VJ and Bengtsson, NO and Jonsson, H and Larsson, LG and Lythgoe, JP and Swindell, R and Kissin, M and Erikstein, B and Hannisdal, E and Jacobsen, AB and Varhaug, JE and Erikstein, B and Gundersen, S and Hauer-Jensen, M and Host, H and Jacobsen, AB and Nissen-Meyer, R and Blamey, RW and Mitchell, AK and Morgan, DAL and Robertson, JFR and Di Palma, M and Mathe, G and Misset, JL and Clark, RM and Levine, M and Morimoto, K and Sawa, K and Takatsuka, Y and Crossley, E and Harris, A and Talbot, D and Taylor, M and Cocconi, G and di Blasio, B and Ivanov, V and Semiglazov, V and Brockschmidt, J and Cooper, MR and Ueo, H and Falkson, CI and A'Hern, R and Ashley, S and Powles, TJ and Smith, IE and Yarnold, JR and Gazet, JC and Cocoran, N and Deshpande, N and di Martino, L and Douglas, P and Hacking, A and Host, H and Lindtner, A and Notter, G and Bryant, AJS and Ewing, GH and Firth, LA and Krushen-Kosloski, JL and Nissen-Meyer, R and Foster, L and George, WD and Stewart, HJ and Stroner, P and Malmström, Per and Möller, Torgil and Ryden, S and Tengrup, Ingrid and Tennvall-Nittby, L and Carstenssen, J and Dufmats, M and Hatschek, T and Nordenskjold, B and Soderberg, M and Carpenter, JT and Albain, K and Crowley, J and Green, S and Martino, S and Osborne, CK and Ravdin, PM and Glas, U and Johansson, U and Rutqvist, LE and Singnomklao, T and Wallgren, A and Castiglione, M and Goldhirsch, A and Maibach, R and Senn, HJ and Thurlimann, B and Brenner, H and Hercbergs, A and Yoshimoto, M and DeBoer, G and Paterson, AHG and Pritchard, KI and Meakin, JW and Panzarella, T and Pritchard, KI and Shan, Y and Shao, YF and Wang, X and Zhao, DB and Boreham, J and Chen, ZM and Pan, HC and Peto, R and Bahi, J and Reid, M and Spittle, M and Deutsch, GP and Senanayake, F and Kwong, DLW and Bianco, AR and Carlomagno, C and De Laurentiis, M and De Placido, S and Buzdar, AU and Smith, T and Bergh, J and Holmberg, L and Liljegren, G and Nilsson, J and Seifert, M and Sevelda, P and Zielinsky, CC and Buchanan, RB and Cross, M and Royle, GT and Dunn, JA and Hills, RK and Lee, M and Morrison, JM and Spooner, D and Litton, A and Chlebowski, RT and Caffier, H},
  issn         = {1474-547X},
  language     = {eng},
  number       = {9472},
  pages        = {1687--1717},
  publisher    = {ARRAY(0x8adf0c8)},
  series       = {The Lancet},
  title        = {Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials},
  url          = {http://dx.doi.org/10.1016/S0140-6736(05)66544-0},
  volume       = {365},
  year         = {2005},
}