Cserni, Gábor

Royce, Melanie

Storme, Guy

Tai, Patricia

Van de Steene, Jan

Verschraegen, Claire

Vinh-Hung, Vincent

Vlastos, Georges

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CORRESPONDENCERe: Breast-Conserving SurgeryWith or Without Radiotherapy:Pooled-Analysis for Risks ofIpsilateral Breast TumorRecurrence and MortalityIn a recent article in the Journal,Vinh-Hung and Verschraegen (1) pro-vided a valuable pooled analysis ofrandomized trials of postoperative ra-diotherapy after breast-conserving sur-gery. They reported a small increase inbreast cancer mortality and a substan-tial risk of local recurrence from theomission of breast radiotherapy. Theseimportant observations should not beinterpreted to imply that all patientsrequire breast radiotherapy afterbreast-conserving surgery and appro-priate systemic therapy. We believe,however, that in contrast to youngerpatients, there are insufficient data todraw this conclusion in older patients.Indeed, the U.S. National Institutes ofHealth, in its 2000 consensus state-ment for breast cancer (2), makes nospecific recommendation on adjuvanttherapy for patients aged 70 years orolder because of the paucity of data forthis group of patients. Of the 15 ran-domized trials assessing the role ofbreast radiotherapy or its omission in-cluded in the pooled analysis by Vinh-Hung (1), only three (Uppsala-Orebro,Tokyo, and the Cancer and LeukemiaGroup B [CALGB]) included patientsover age 70. In this older group ofpatients, there are competing risks ofmortality from predominantly vascularcomorbidity. In addition, a body ofdata from both randomized and non-randomized trials suggests that therisks of local recurrence decrease withage (3). This observation reflects,in part, the increasing proportion ofolder patients with good prognosticcharacteristics.Large, adequately powered trialswith older patients are needed to as-sess the role of breast radiotherapy inlocal recurrence and breast cancermortality. The dramatic impact of thecompeting risks of non– breast cancermortality in the elderly is shown in theCALGB 9343 trial (4), cited in table 1of Vinh-Hung and Verschraegen (1),which randomly assigned patients withT1, node-negative, ER-positive tumorsto breast radiotherapy or no furthertreatment after breast-conserving ther-apy and tamoxifen. Of the 39 deathsamong the 647 patients in the trial,only one was due to breast cancer.Ongoing trials, such as the Post-operative Radiotherapy In Minimum-risk Elderly (PRIME) trial (5), are ad-dressing issues of local control,morbidity, and quality of life in older,low-risk patients to establish a firmbasis for the selection of patients forradiotherapy in this age group. We feelthat until the results of randomizedtrials focused on evaluating breast ra-diotherapy in the elderly are available,the role of breast radiotherapy in thisage group remains uncertain. Formany such women, their informed re-cruitment into appropriately designed,randomized, controlled trials may bethe most ethical way of determiningtreatment.IAN KUNKLERLINDA WILLIAMSROBIN PRESCOTTCELIA KINGREFERENCES(1) Vinh-Hung V, Verschraegen C. Breast-conserving surgery with and without radio-therapy: pooled-analysis for risks of ipsilateralbreast tumor recurrence and mortality. J NatlCancer Inst 2004;96:115–21.(2) Consensus statement: treatment of early-stagebreast cancer. National Institutes of HealthConsensus Development Panel. J Natl CancerInst Monogr 1992;(11):1–5.(3) Kunkler IH, King CC, Williams LJ, PrescottRJ, Jack W. What is the evidence for a re-duced risk of local recurrence with age amongolder patients treated by breast conservingtherapy? Breast 2001;10:464–9.(4) Hughes KS, Schnaper L, Berry D, CirrincioneC, McCormick B, Shank B, et al. Comparisonof lumpectomy plus tamoxifen with and with-out radiotherapy (RT) in women 70 years ofage or older who have clinical stage I, estro-gen receptor positive (ER) breast carcinoma[abstract 93]. Proc ASCO 2001;20:24a.(5) National Cancer Research Network (NCRN).Trials portfolio. Available at: http://www.ncrn.org.uk/portfolio/dbase.asp. Details onPRIME II can be found by selecting “PRIMEII” from the Find Acronym pulldown menu.[Last accessed: July 19, 2004.]NOTESAffiliations of authors: Edinburgh Cancer Centre,Western General Hospital, Edinburgh, U.K. (IK);Medical Statistics Unit, Medical School, Universityof Edinburgh, Edinburgh (LW, RP, CK).Correspondence to: Ian Kunkler, MBBChir,FRCP (Ed), Edinburgh Cancer Centre, WesternGeneral Hospital, Crewe Rd., Edinburgh, U.K.EH4 2XU (e-mail: i.kunkler@ed.ac.uk).DOI: 10.1093/jnci/djh245RESPONSEKunkler et al. address an importantissue: whether or not to continue ran-domized trials of postoperative radio-therapy after breast-conserving surgeryin selected patient subgroups such asthose in the Scottish Post-operative Ra-diotherapy In Minimum-risk Elderly II(PRIME II) and the Italian RT 55-75trials (1). We welcome the opportunityto analyze the additional data that thePRIME II and the RT 55-75 trials willprovide because we think these data willhelp patients make the best treatmentchoices.In 2003, the updated report (2) fromthe 2001 Cancer and Leukemia Group B(CALGB) 9343 trial (3) provided in-sight into several age-related issues. Oneissue is that the extreme difficulty infollowing up older patients may haveled earlier studies to mistakenly con-clude a lower risk of recurrence. Theupdated report revealed substantiallyimproved registration of deaths and re-currences—55 deaths were reported (30deaths with no radiotherapy, 25 deathswith radiotherapy, and a statisticallynonsignificant 19% excess relative riskof mortality from omitting radiother-apy). The updated report also showedstatistically significantly poorer in-breast and poorer locoregional recur-rence-free survivals in the absence ofradiotherapy (2).Although elderly patients are under-represented in clinical trials, the rela-tionship between age and survival inbreast cancer is now well established.All large studies concur that the effect ofage is biphasic: high mortality inyounger women, lowest in menopausalwomen, and then increasing again withage (Tai P: personal communication).To provide a concrete representation ofthe biphasic relationship and to obtainquantitative estimates of the risks asso-ciated with age, consider a cohort oflow-risk patients who have a primaryJournal of the National Cancer Institute, Vol. 96, No. 16, August 18, 2004 CORRESPONDENCE 1255breast carcinoma 2 cm or less in diam-eter, and a status of pN0 (axillary dis-section) selected from the Surveillance,Epidemiology, and End Results (SEER)database, for diagnostic years 1988 –1997 (4). Figure 1 shows counts andrates of death in this cohort as a func-tion of age. The average follow-upwas 7.8 years. Despite the short fol-low-up period and the overall lowbreast cancer–specific death rate, thebiphasic shape is immediately appar-ent: high breast cancer death rates inpatients younger than 50 years and asmall but steady increase in patientsaged 50 years or older (Fig. 1, D). Thisbiphasic relationship clarifies howbreast cancer can be misperceived asbeing indolent in older patients. Groupcomparisons indicate that postmeno-pausal patients, as a group, have alower risk of breast cancer death thanyounger premenopausal patients (Fig.1, D). But by each successive year ofage within their group, the older post-menopausal patients have a greaterrisk of dying of breast cancer than doyounger postmenopausal patients (Fig.1, D), which shows that older age isnot associated with lower risk.Should we infer from the unremittingrisk that all patients, regardless of age,should receive adjuvant radiotherapy?Kunkler et al. draw attention to the im-portance of competing risks of death.Figure 1, E, shows an exponential in-crease of non–breast cancer deaths withage. Figure 1, F, shows the correspond-ing odds of non–breast cancer death. Atage 60 years, the odds of death frombreast cancer versus other causes are1:2.5. At age 65 years, the odds are stillsubstantial: 1:3.5. At age 70 years, theodds are 1:5. At age 80 years, the oddsare 1:10. Considering mortality only,these odds suggest that it is reasonableto propose that low-risk older patientsparticipate in the PRIME II trial. Buttaking local recurrences into account, ifpatients are considered fit for surgery,then it is unclear why they should bedenied the chance to have radiotherapyto reduce their risk of recurrence. Theevidence of risk reduction is strong, andimprovements that will benefit low-riskand fragile patients are within reach (5).Shouldn’t the priority be to enroll thesepatients in trials of alternatives to con-ventional radiotherapy, whether it beshort-course (6) or intra-operative radio-therapy (7)?VINCENT VINH-HUNGCLAIRE VERSCHRAEGENMELANIE ROYCEJAN VAN DE STEENEFig. 1. Mortality as a func-tion of age for low-riskbreast cancer patients withthe following characteris-tics: primary breast carci-noma 2 cm, pN0, exclud-ing high-grade and estrogenreceptor–negative tumors,from the Surveillance, Epi-demiology, and End Results(SEER) Program 2004 data-base (9 registries), diagnos-tic years 1988–1997 (4), ir-respective of type ofsurgery or radiotherapy, age25 to 95 years; N  32 045.A) Counts of breast cancer–specific deaths. B) Countsof deaths from other causes.C) Total incidence counts.D) Crude rates of deathfrom breast cancer. E)Crude rates of death fromother causes. F) Odds ofdeath from other causesversus from breast cancer,based on a log scale (empir-ical logistic transform).1256 CORRESPONDENCE Journal of the National Cancer Institute, Vol. 96, No. 16, August 18, 2004PATRICIA TAIGA´ BOR CSERNIGUY STORMEGEORGES VLASTOSREFERENCES(1) Tinterri C, Gatzemeier W, Andreoli C, RegoloL, Zanini V, Giorgi I, et al. Breast conserva-tive surgery with and without radiotherapywith early stage breast cancer: a prospectiverandomised multi-centre trial [abstract 378].Eur J Cancer Suppl 2004;2(Suppl 3):166.(2) Kemeny M. Review of current surgical oncol-ogy trials. Advancing Cancer Care in the El-derly (ACCE), Geriatric Oncology Consor-tium Conference, September 18–20, 2003,Washington, DC. Available at http://www.thegoc.org/pdf/ppt/Kemeny_Margaret.pdf.[Last accessed: May 24, 2004.](3) Hughes KS, Schnaper L, Berry D, CirrincioneC, McCormick B, Shank B, et al. Comparisonof lumpectomy plus tamoxifen with and with-out radiotherapy (RT) in women 70 years ofage or older who have clinical stage I, estro-gen receptor positive (ER) breast carcinoma[abstract 93]. Proc ASCO 2001;20:24a. Avail-able at http://www.asco.org/ac/1,1003,_12-002643-00_18-0010-00_19-0093,00.asp.[Last accessed: July 7, 2004.](4) Surveillance, Epidemiology, and End Results(SEER) Program. SEER 1973–2001 Public-Use Data. Surveillance Research Program,Cancer Statistics Branch, Division of CancerControl and Population Sciences, NationalCancer Institute. Released April 2004, basedon the November 2003 submission. http://seer.cancer.gov/publicdata/.(5) Vallis KA, Tannock IF. Postoperative radio-therapy for breast cancer: growing evidencefor an impact on survival. J Natl Cancer Inst2004;96:88–9.(6) Whelan T, MacKenzie R, Julian J, Levine M,Shelley W, Grimard L, et al. Randomized trial ofbreast irradiation schedules after lumpectomyfor women with lymph node-negative breastcancer. J Natl Cancer Inst 2002;94:1143–50.(7) Vicini FA, Kestin L, Chen P, Benitez P, Gold-stein NS, Martinez A. Limited-field radiationtherapy in the management of early-stage breastcancer. J Natl Cancer Inst 2003;95:1205–10.NOTESAffiliations of authors: University of New Mex-ico, Cancer Research and Treatment Center, Al-buquerque, NM (MR, CV); Oncology Center,Vrije Universiteit Brussel, Jette, Belgium (GS,JVDS, VVH); University of Saskatchewan, Saska-toon, SK, Canada (PT); Gynecologic Oncologyand Senology, Geneva, Switzerland (GV); Surgi-cal Pathology, Ba´cs-Kiskun County TeachingHospital, Kecskemét, Hungary (GC).Correspondence to: Vincent Vinh-Hung, MD,Oncology Center, Academic Hospital, Vrije Uni-versiteit Brussel, 101 Laarbeeklaan, 1090 Jette,Belgium (e-mail: conrvhgv@az.vub.ac.be).DOI: 10.1093/jnci/djh246Journal of the National Cancer Institute, Vol. 96, No. 16, August 18, 2004 CORRESPONDENCE 1257

RESPONSE: Re: Breast-Conserving Surgery With or Without Radiotherapy: Pooled-Analysis for Risks of Ipsilateral Breast Tumor Recurrence and Mortality

RESPONSE: Re: Breast-Conserving Surgery With or Without Radiotherapy: Pooled-Analysis for Risks of Ipsilateral Breast Tumor Recurrence and Mortality

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