Articles @*s erties Setar Ci re ics ob covets ocak a Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100 000 women in 123 randomised trials Eales Cancers’ Calleboatine Grup (EBCTEG) Summary Background Moderate differences in efficacy between adjuvant chemotherapy regimens for breast cancer are plausible, and could affect treatment choices. We souight any such differences Methods We undertook individualpatientdata metasanalyses of the randomised trials comparing: any taxane-phis anthracycline-based regimen versus the same, of more, non-axane chemotherapy (n=44000); one anthracycline: based regimen versus another (n=7000) or versus cyclophosphamide, methotrexate, and fluorouracil (CMF;n=18 000); and polychemotherapy versus no chemotherapy (n=32000). The scheduled dosages ofthese three drugs and of the amracyclines doxorubicin (A) and epirubicin (E) were used to define standard CME, standard 4AC, and CAF and CCEF. Logerank breast cancer mortality rate ratio (RRs) are reported. Findings In trials adding four separate cycles of a taxane to a fixed anthracycline-based control regimen, extending treatment duration, breast cancer mortality was reduced (RR 0-86, SE 0-04, two-sided significance [2p]+0-0005). In trials with four such extra cycles ofa taxane counterbalanced in controls by extra cycles of other cytotoxic drugs, roughly doubling non-taxane dosage, there was no significant difference (RR 0-94, SE 0-06, 2p=0-:33). Teals with CMF-teated controls showed that standard 4AC and standard CMF were equivalent (RR 0-98, SE 0-05, 2p-0-67), but that line-based regimens with substantially higher cumulative dosage than standard 4AC (eg, CAF or CEF) were to standard CMF (RR 0-78, SE 0:06, 2p=0.0004). Trials versus no chemotherapy also suggested greater 'mortality reductions with CAF (RR 0-64, SE 0-09, 2p<0-0001) than with standard 4AC (RR 0-78, SE 0-09, 2p=0-01) or standard CMF (RR 0-76, SE 0-05, 2p<0-0001). In all meta-analyses involving taxane-based or anthracyeline-based regimens, proportional risk reductions were litle affected by age, nodal status, tumour diameter or differentiation (moderate or poor; few were well differentiated), oestrogen receptor status, or tamoxifen use. Hence, largely independently of age (up to at least 70 years) or the tumour characteristics currently available to us for the patients selected to be in these trials, some taxane-plus-anthracycline-based or higher-cumulativedosage anthracycline-based regimens (not requiring stem cells) reduced breast cancer mortality by, on average, about one-third. 10-year overall ‘mortality differences paralleled breast cancer morality differences, despite taxane, anthracycline, and other toxicities. Interpretation 10-year gains from a one-third breast cancer morality reduction depend on absolute risks without chemotherapy (which, for oestrogen-receptorpostive disease, are the risks remaining with appropriate endocrine therapy). Low absolute risk implies low absolute benefit, but information was lacking about tumour gene expression, ‘markers or quantitative immunohistochemistry that might help to predict risk, chemosensitivity or both. Funding Cancer Research UK; British Heart Foundation; UK Medical Research Council Introduction ‘The Barly Breast Cancer Tralists’ Collaborative Group (EBCTCG) was established in 1985 to coordinate individuak-patient-level meta-analyses ofall randomised twials of adjuvant treatments." A previous report on the ‘vials that had begun by 1995 reviewed polychemotherapy versus no adjuvant chemotherapy and anthracycline- based chemotherapy (with doxorubicin or epirubicin) versus CMF (cyclophosphamide, methotrexate, fluorour- acl), but did not take dosage into account and did not review taxanes, “The present report reviews the preliminary taxane tral results and updates the other chemotherapy tral results, assessing the relevance of scheduled drug dosage and investigating whether any of the available patient or tumour characteristics (eg, age, nodal status, tumour differentiation, oestrogen receptor [ER] status, use of tamoxifen) affect the proportional reductions with modern chemotherapy in breast cancer recurrence and death Methods Trials Methods of trial identification, data checking, analysis, and involvement of tialists in the interpretation of resultsare as in previous EBCTCG reports." Information about each individual patient was sought during 2005-10 from all randomised trials begun during 1973-2003 of (0) taxane-based versus non-taxane-based regimens (data for 33 trials, begun in 1994-2003); (2) any anthracycline based regimen versus standard or nearstandard CMF wth com Yola79 Febuary 4, 2012(see table for the terminology used for these and selected other regimens; 20 trials, begun in 1978-97); (3) higher versus lower amtracycline dosage (six trials, begun in 1985-94); and (4) polychemotherapy versus no adjuvant chemotherapy (64 trials, begun in 1973-96, including 22 of various anthracycline-based regimens and 12 of standard or near-standard CME) “Teale of intensive chemotherapy with stem-cell rescue or of variation only in dose-density are not included, Datasets from taxane trials had to await trial publication, so they arrived from 2005 to 2010; although 33 are included (n=45000), three are not (n=7000; started by 2003 and unreported before mid-2010; see forest plot in \webappendix p 23). Otherwise, all main analyses include 9086 or more of all relevant patients in closed trials. Statistical analysis For each main chemotherapy comparison, forest plots (webappendix pp 21-62) describe the separate trials and their results, graphs illustrate absolute risks in various circumstances, and detailed subgroup analyses explore whether proportional risk reductions depend on patient or tumour characteristics. All text figures plus many more detailed analyses, and trial references, are in the ‘webappendix (which needs magnified viewing) Recurrence, ER, and nodal status are defined as before Statistical analyses ate stratified as before by trial, age, ER status, and, except in neoadjuvant trials, nodal status If log-rank statistic (o-e) has variance v, then, defining ze(o-e)/w and b=(0~e)/v, the event rate ratio (RR, newer treatment vs control) is estimated as exp(}) with standard error SE~(RR1)/z. Ether RR and its SE are Cited, or confidence limits for RR are derived from those for b (by normal approximations). 2p indicates two-sided significance, and n the number of patients to the nearest 500 or 1000 (with, for balance, control groups that were compared with more than one active group double- counted or triple-counted), ‘Breast cancer morality rate in each year is the overall mortality rate among all women minus that among women without recurrence. Breast cancer mortality RRS te estimated from the corresponding log-rank analyses of mortality with recurrence (obtained by subtracting log-rank analyses of mortality without recurrence lie, censored at recurrence] ftom those of overall ‘morality; webappendix p 1). For indirect comparisons between different regimens, effects on early recurrence rates (years 0-4) might be more sensitive than effects on other outcomes, because they are substantial and not materially affected by differences in follow-up duration (or chance effects on recurrence rates in later years when proportional reductions might be less extreme than in ‘yeats O-d), so the webappendix reports effects on early recurrence, any recurrence, and morality. For at least some major subgroup analyses to be statistically seliable, the overall x2, forthe RR (treatment vs control) in all subgroups together should generally be vtec com Yola79 Febuary 4, 2012 large (eg, at least 25, but preferably 50, or even 100). For, if there is little real heterogeneity between the RRS, this overall x2 (plus the small x¢ for heterogeneity between treatment RRs in different subgroups) gels partitioned between the subgroups in approximate proportion to numbers of events, to yield 2, in each, If 2, in a major subgroup should be only about 10 or less after such a split, chance could well make it non-significant or null For, a subgroup-specifc treatment effect that, given the overall findings, should be about 3 SE (yielding 32-9, 2p-0003) could easily by chance be less than 2SE {and hence not significant). Statistical analyses utilised programs written by the EBCTCG in FORTRAN. Seen ort Role of the funding sources The funders had no role in study design, conduct, or reporting. The Secretariat had full access to all data. The decision to publish was by the writing committe, after circulation to all collaborators. Results Taxane-based regimens versus active controls For each trial of taxane-based versus non-taxane-based chemotherapy, forest plots (webappendix pp 21-26) give results for early recurrence (years 0-4), any recurrence, breast cancer mortality (movtality with recurrence, by log-rank subtraction), mortality without recurrence (first year only, all years) and overall mortality. Each forest plot gives one line per tial: year stated, study name, regimens ‘compared, results, and log-rank analyses, Treatment comparisons varied greatly, which compli cates meta-analyses, All but two trials (excluded from the meta-analyses) compared a taxane-plus-anthracycline- based regimen versus an anthracycline-based control regimen with the same or more of each nontaxane component, Averaging the results for all such trals to test for some taxane effec (by summing the trial specific log- rank statistics; webappendix pp 7-8 and 21-26; n=44000), the RRs were 0-87 (SE 0-03) for distant recurrence, 0-86 {SE 0-02, 2,=47-7, 20-0001) for any recurrence, 0-87 (SE 0-03, }2;=22-0, 2p<0.00001) for breast cancer ‘mortality, 0-99 (SE0-08, no net hazard) for other mortality, and 0-89 (SE 0-03, 2p<0-00001) for overall morality. Articles ‘Scheduled nomberofcyls nd etotancteatnent perce StundadOMF——— Gecenof Cone Mn Fito, gen 4 ely wey sid NesrstandidOMP 612s wth same doses as standard CMF andr én epcing034 Sud 4NC Ace Aol hv 3-ey wielystid Stan aC “ceo Eon he 3 ey or Gocesofciba4 na Fizoa, enw a Saerof 4 Fanon, gen wey red dose msec prove drys 1-28 Tabs eet ‘hie dona neat appre ca oa dos ncn eo ope Menaiovente Fb! ede Adam) Empat atau {abe Teminlogy—standd eg ad igh coltve-done ginsArticles 12167 wenn cnt ‘ese may csr Peano 3a aerate: eosa(gsucio7e0m) sgt spocn Robs won ctl MORE mane henry et) Ahan e086 (9sxcloa.00) Lege ooun ow Er 5 Presta erty) z ction ow Mion nw 8 ‘tras anak ans Semoun Beoargnees9) }apsADgA) vetseooe” oasseoar ‘sss sume brestance meaty "ity meme (gent apcoumes 2a Tatar ‘atte ea tl e-em into andl karl Jasco 24850, jsBse0n ——dowseou8 Sewaws = “nui walinrtay 12367 women sno as gsec079-059 spent omer Be TESTIS eather onkarsons Yomo-t ‘ears denesnetsn) dre uselzis) Saco “aaarye enrages {ar as59665) Senta 506 Dasseo0s Seams Hor asasoe) dean roseons raise Legenapo0ot Syorouni anon) a ‘oes Dutt jor tae wit core rig ki Borseons Bsto2 aooseour basso pote worn meegogucioasoa7) sgt 08 thc cnt Tame antag oft Destroy niger 2Hoarasoon Jes ceusssm) Deine) Guausams) ‘These varied treatment comparisons can be grouped by hhow the chemotherapy regimen in the contol group compared withthe non-tnane chemotherapy in the taxane group: the same (ie, unconfounded trials ofthe effects of adding four separate cycles just of a taxane to a constant background chemotherapy regimen, theteby prolonging tecatment duration; n-I1000), double (ie, strongly con founded trials in which the effects of adding four separate cycles of a taxane to an anthracyline-hased regimen were counterbalanced in conteols by roughly doubling the number of eyles of nonaxane chemotherapy; 10000), or intermediate (2300). Oniyin some ofthe tis with fn intermediate control Fegimen was the taxane given concurrently with any other ototoxic agents Tn the ‘unconfounded taxane trials, which all began in 1994-99, litle followup beyond year 8 is yet available; figure I lefthand side) gives absohute effects on Syear recurrence, breast mortality and overall morality in these trials, Effects were moderate for recureence, and slightly smaller (but still highly significant) for breast cancer mortality and overall mortality 8 year breast cancer morality was 21-19% for the taxane groups versus 23:9% for the conteol groups {absolute gain 28%, SE 0; RR 0-86, SE 0:04, 2p-0:0005); fr overall mortality the absolute gain was Similar. By contrast, in the wials of adding four cycles of a taxane versus roughly doubling the non-taxane chemotherapy, there as litle net difference in recurrence, breast cancer mortality foot of figure 24; n=10000; RR 0-94, SE 0-06, 2p=0-16), or overall mortality (webappendix pp 7-8 and 21-26) agnin, however, comparisons varied, and follow-up was shor. Figure 1 (righthand side) describes these and all other trials in which the effects of the taxane were counterbalanced by giving the controls more non-taxane chemotherapy (2~33000 with data on numbers dead in each treatment group, only 30004 of whom had data on the times to any deaths: webappendix p 23) In these confounded tazane tals, lite follow-up beyond 5 years is yet available, but on average their Sear findings again Show small but significant reductions in recurrence, breast cancer mortality, and overall mortality. Chemo therapy regimens varied greatly, so real teatment effects in different tals could well difer, even though chance ‘makes it dificult to asses this reliably, particularly with short follow-up and some trials not yet available. Only one ‘vial (GEICAM9906) involved weekly pacitanel Figure 2 shows selected subgroup analyses for breast cancer moraltyinall 44000 women. Its first three sections g70up the treatment comparisons in various ways, without gure 1Time to recaence, east cancer meray and overall meray fErtmane ploantacyine bad egimen axa verona ith lf these or (ght) more on tacanechemathe apy “ak vrssthoare on acne chratherapy sy aC) see four oartatane ory jes ari 95% c-eventate t,o Summed atts allie Pods caned Gln its Snasoledifereceetacnehsof gaps er tes, en ae lowe y(t evetwoman yan) ror show #15 wth com Yola79 Febuary 4, 2012Articles finding clear evidence of differences in the average confounded, as above (for the trial-specific details treatment effect. Its first section groups the taxane corresponding to these groupings sce webappendix: comparisons as unconfounded, intermediate, or strongly pp 21-26) and the next two sections group the treatment Desthire — tee ets ‘aetinan Aicaedvortame TopauO# WeiorioOETaanetionnaee (0) seroma rene 28-065) ‘Same (12) Ge, necnfounded) “1269/5590 (20-98) 1306/5577034%) 798 S708 = (086 (5E 004) tta9) sanecsy amenesy 333 mm3 = —_otagrom tt 29 Semmes sro) 3m eg ABE BOO) Sauonasaesm — snsneeaas) ses Asn) (€) tan a dle 9-088) sO-oept fsistomsy smisosesry ses gL omnscoun Cert nsmnk@esn | ttwncoos) sts 3659 | oastoon soa ropes) Samir) ones E00 ep Sonmaaaas) Sssnscem) 309m] era (0) cont ena ery 02 968) te ‘race saramoy a7 aes gf Nayidalnedy ster dumcbgyeda ISRIASCON) TemMH) 83 ue] owrscoey (0) trae tnd 35 29-086 one msnocure matsimasr) 367 ates Lose sine Semoaesy sormotny vara an) eoan Saye rersnnne) — erismmm 0365] ota EOOD Sones sine) wanaves) tia tag et (RCE) cst renee) wmseey 25 ae tof (©) Neste etn e006) none Dimes —mameay 400 osigcon m3 Seno4) —Ssesrr@en) nies] E000) ne mrmacsen esomnem) mos ne Lamon Chet uiimesinsan) elanacrsy ba sae LF] onser00p (6) eraam-oar 078) pe sys) upwayeuy) ee ge) a o tmiaiaersers) nownrm@m) orks areons Surocon sossrason susnsasis) 89 os HL omzonn eer anise) reese as mL secon ees enrecoos) anomen) 62 aes pL — encore roe op08 Gsemeton —raummaey ara bean tans topae sion) aainaom sats ah tera Cts pty etn fomo(sm stanton wea Ta teneeone (asta tied Tasso susie te use| a | onretoan tte ‘aisno2 — mgesm) an 387 —= Eb oeaeon Bw Mummnioy woman a0 ues | omatoan apeocon Scateicge 07 Se, “rst tpt gr: subgroup analyse east cancer mortality (ora with ecurenc by lg ak subtraction for axane pls anthaeyie based regimens ‘ers the sae, or mores than dbl roughly dbl), non-taxaneoetonk chemother (tant Pepa (0) ower deseo deta 100mg’ ainsi 3 wes. 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"ist ou ibgoups aes inte ors ts nebppendnp 2.26) hl gees ears feta regen. ane cone ont onelap ther chemotherapy une ate gen concert anes tlt com Wol379 Febuary 2012 2sArticles "5 woe emt carte tain songe SNS} RCM 38% Pease eos g5nc.082-096) Togancay-o0ca roheagane om10) Storer stant AC stan ayy “ fax een (gssclogoc tegeantop76 oye gan 855) eat ona moray (8) Sat er S6420079 zona) Ln As) Gir taetesanaean2oniaao4s nee 195 ret cnr nrg ‘5 women em (9901072088) lograntap00003 osu gan 43605810) ett eo tl Crastoat —oesseouy Ove ray R084 95.c1076092) togeantap09002 Iejegan sen 20) rare ts xenon abs Fostemeys) seston Leena Scuasarnenraanaes) Laue mene otiseo2 Dette yen alg kara “Geers “pany cone tsp an ok anys Sexebminns) eons 1876s) s2zmomer 2098 91089108) (ogrankae 6) ohpargino S14) OMe ne thats eee alate nee vet ens) lg ar meos7sxcioesson Uopankaeass on roagentzscer | Mh Aion uth er andlg kann engaiauss) Tactermse Teyana) arscoos” oescoen.” iaito, comparisons in other ways, Later sections, again without clear evidence of heterogeneity of treatment effect, subdivide by age (finding significant benefit even at ages 55-69 years; few were older, but their results suggest favourable effects of taxanes even in old age), nodal status before chemotherapy (4000 had node-negative disease), and ER status, Results are also given for subsets of ER- positive disease by HERZ status (generally by immune. histochemistry, classified where possible by standard criteria for definite positivity), age, and differentiation (with a tend towards greater taxane benefit in well differentiated [RR 0-68, SE 0-16, 2p=0-04, n=3000] or moderately differentiated [RR 0-77, SE 0-07, 2p=0-001, 000] ER positive tumoursthan in poorly differentiated ER-positive tumours). Mostofthe women with ER-positve disease had endocrine therapy after their chemotherapy. More detailed subgroup analyses of recurrence and breast cancer mortality (webappendix pp 7-8) found no consistent heterogeneity of the proportional risk reductions by age, nodal staus, ER status, progesterone receptor status, tumour differentiation (although only 4000 were well differentiated; webappendix p 8), tumour diameter, or combinations of these. Proportional risk reductions appeared similar in years 0-1, 2-4, and (provisionally) 5+ after entry, so the indirect treatment comparisons in figure 2 should not have been materially affected by differences between taxane trials in follow up duration. If there is real heterogeneity between effects in different subgroups, this should be clearer for recurrence (overall yi=48) than for breast cancer ‘mortality (overall x2=22), but neither x2 value is big enough for subgroup analyses to be wholly reliable. “Anthracycline-based regimens versus active controls For trials ofan anthracycline-based regimen versus CMF, forest plots for each of several different outcomes (webappendix pp 27-32) give one descriptive line per ‘rial: name, regimens compared, and results. The conteol regimen was generally standard CMF (otherwise it was nearstandard CMF; to challenge anthracyeline-based regimens rigorously, however, these analyses exclude CME regimens with the dose per eyele of any drug. less than that in nearstandard CMF; see table). Again, most of the women with FR-positive disease would have been given endocrine therapy after their chemotherapy. Figure 3 (lefthand side; n=9500) shows results from the trials with anthracycline dose per cycle at least {60:mgym? doxorubicin or 90 mg/m? epirubicin and with Figure 3: Time een breast cancer morality, and over moray for sted arthvacylie bse gimers ers tanardor ner turdarsC {et ganar with omage geaterthan 110mg deorbinor 20a ep on AEo CEP,ight taar 44 come donge 240 a evento Allgaps exe eens this than 6rgir ‘exon or 9 gi epn pe oe Rand 95%mever ate ‘allen amen sat for a ne pads corbin and "sseabsohte dane: between ens of gaps Aantal et ‘aes Seay afoot vetoes} SE wth com Yola79 Febuary 4, 2012cumulative anthracycline dosage more than 240 mg/m? doxorubicin or 360 mg/m? epirubicin (eg, CAF or CER), ‘The findings for recurrence, breast cancer morality, and overall mortality show a definite improvement over CME, ‘Averaging the results for all these trials, the RRs were (0-89 for recurrence (SE 0:04, 2p=,003; this included, ‘what might have been mainly a chance excess incidence of contralateral disease), 0-80 for breast cancer mortality (SE 0:05, 2p=0:00001), and 0-84 for overall mortality {SE0-04, y2,~9:9, 2p-0-0002). By contrast, standard AAC and standard CMF appeared equivalent (righthand side of figure 3; n=5000).. Dative Antrtine dts Raoult tn ‘ateandascine AecaICHF Logi mkO€ Warne oO AneagnecHE (A) carta aby dongs prc nt ast AE nd, 29-0005) ‘oot 09. Trineutm anes 901980 | _oraist000) rooms snes) aramearon 59H BL] oanto0 ‘oosanan) Minsescum) RIEOSIOK) — 8556.0 SEOON Deere sensmeaae) 2750.) 3H OL Eos E00) (8) oven in Fora -09;2-03:95) Cxeatonone ee |) Coser SsMnas4be) | BSUOCARS) 66 TS ANG STOOH (€) canst entone tp FER 00:20:85) Ye wens) Gasme) —a9 90 Nonyenncneonystectenctenyended) sHeMI(IN) nBeNSI) ams sire] —_o8acscoon (0) eager 0 :9-09:05) 100 finol/mg). This finding suggests that the Combination of the breast cancer mortality results for extreme RR in figure 4 for disease with ER greater than disease with ER greater than 100 fimol/mg for any 100 fmol/mg could be partly a chance subgroup finding, _anthracycline-based regimen versus no chemotherapy and Dest women Athyn dain ‘abot ith ‘ecttontnatne Ashen legit Veiner ere (A) camnoveantncyin doo ee persistent A502) soca Spans7/arsn) MOON) 53-803 osst009 sown tnt ac rngaee) rere) 356 tos ostomy Denna formats) steemtasen 90s enon (0) anna 9.370358 Downton) maser) ussaseu6m) 1061 ae e7sise005 peer Sevsinases) RNG4om) ese tssc00m awe snesarey skeen «BI ots ge0n) (© concent odoin they 6 02 29-06) we Soramacow) sexnoasen -st4 880 oncom Teeeyeameonysercenetayrone) asiEN3N) — SWTSEGGER) 492 aE 75000 fant aoamaa6r9 —aaunacres) 2a 66 r009 (0) nro 029-02: “spun 20369 —-umsI060%) 0 osnseon) ‘sire spiaiso099) —_ABMUSOS79 v8 orseoan Ss69y005 Yoanso00) sonsseasm) “8570 75005 on comsaoss) —tammes) ay see 365019 (€) nec na toeny 20.3909: ane amass) aso) nes ons stom) 2 snasry soma) 33 mat orase006 ke Smansuem) MAE) 7m orase006 Crlacun roe(aM) — mgco(ess) dO ore} (0 eran 3-07 85) gee coumsase) esyroeisy sod ‘acoen in Enaieon6es) eaaITESS) Ss erri005 ko wmsseo) wana 97 otae03 Sut e Erdumstergmiinenedae — SEanGESIK) FANON 562 2070 40 st008 0 334mm awhmnooy —saneoar7 38285 oaasto0y too fatng raniescaae) aumisoaatsy 296 a6 815009 harp aneaseses) — menaeasy 394 tend onnceoon oS pm Senoiasas) ernessens 853 ose006 poy i sence) 4770529 8 onsen) {ml etd mnigaso3m) — aenosergy 8H orseoat Bow rnsins4e9%9 wournOss) -99 S19 orisistoean # soto aa ——e Gather gS 4 & 5 aoc Anant wane "watottcpc00001 igre Subgroup analy of reset cancermartalty (morality with recency lg ank subtraction foray anthracycline. aed gin vere rechemotherpy edb rane). Epi. ese ae cundate des) hafta my Aafo mans 0 an fine Songhai WS-ot sgn aoc eas fo ibd ae asin eos aehngep 3-8) ge detach as ‘tet inens inthe SMOG EL al of CAF pstnerspn saan aman atl anywho ft emote wth com Yola79 Febuary 4, 2012Articles versus CMF chemotherapy (figures 4 and 6) yields an RR of 0-77 (SE.0-07, 2p=0-002, n=3000), confirming atleast some benefit of antnracycline-based regimens in thishigh- [ER subgroup. Most women were aged 55-69 years at entry; results in the few who were older also suggest benefit (as im the taxane trial), but with wide uncertainty Figure 7 shows 10year breast cancer mortality in trials of anthracyline-based regimens by age and ER status. The lack of apparent relevance of age oF ER to the proportional risk reduction is somewhat confounded by regimen; almost half the evidence in older women with ER-pesitive disease (RR 0-78, $E0-06, 2p=0-0002, n=A)0)came from the one trial (SWOG88t4) of CAF in 1500 postmenopausal ‘women with tamenifenreated ER-pesitve disease, which showed that such chemotherapy substantially reduces breast cancer mortality in this major patient category In subgroup analyses for trials of standard or near standard CMF versus no chemotherapy (webappendix pp 13-14) the proportional risk reduction appeared inversely related to age and nodal status, but again appeared independent of ER status (RR for breast cancer ‘morblity 0-80, SE 0-10, 2p=0-05 for ER-poor disease and 0-74, SE 0-07, 2p-0:0002 for ER-psitve disease. ‘Among both older and younger women with ER-positive disease, the effects of chemotherapy added to those of ‘effective endocrine therapy. Combining (webappendix p 6, final section) these tials of CMF and the trials of anthracyline-based chemotherapy versus no chemo- therapy if both groups had 5 years of endocrine therapy then chemotherapy reduced breast cancer mortality both im women with entry age 55-69 years (chemoendocrine »s only endacrine therapy, RR 0:78, SE 0:07, 2p=0-001, 1n=3000) and in younger women (RR 0-72, SE 0-08, 2p-0002, n=2040), OF these younger women, half were ‘known to be premenopausal or perimenopausal (vith RR 0-76, SE 0-13, 2p-0-4, m=1000), but information about chemotherapy-induced amenorthoea was unavailable. ‘To help assess any lifeshreatening acute toxicity, the table on webappendix p 63 describes year mortality without recurrence. In trials comparing two active regimens, this early mortality depended lesson treatment troup than on age, and before age70 years itwas relatively low (eg, 59/19477 [0-33] for taxane-plus-anthracycline- based regimens » 40/1986 (0-2%| for anthracycline- based control regimens, 2p=0-06). In tials of chemotherapy versus no chemotherapy, these Lyear hhazards were notable only inthe 1970s trials of 12 cycles of CMF and in one ofthe two trials" of CAP. ‘There were also, as expected“ some deaths from acute myeloid leukaemia and anthracycline cardiotoxicity. gee Ales foureyerofany antral sed jie ithmean ‘ect ough as for standard 4A) vrs no ajovant chemotherapy. 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