Clinical Characteristics of Patients with Metastatic Breast Cancer with Complete Remission Following Systemic Treatment

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1 Jpn J Clin Oncl8;8()8- Clinical Characteristics f Patients with Metastatic Breast Cancer with Cmplete Remissin Fllwing Systemic Treatment Nbru Yamamt, Nriyuki Katsumata, Tru Watanabe, Yasushi Omur, Masashi And, Masaru Narabayashi and Isamu Adachi Department f Medical Onclgy, Natinal Cancer Center Hspital, Tky, Japan Backgrund: Patients with metastatic breast cancer (MBC) have variable clinical curses. The purpse was t describe the clinical characteristics f MBC patients with cmplete remissins (CR) fllwing systemic treatment. Methds: We analyzed cnsecutive MBC patients treated with several types f systemic treatments at the Natinal Cancer Center Hspital between January 88 and December. Results: The median survival time (MST) and median prgressin-free survival were 8.0 and. mnths, respectively. Frty patients weredefined as 'first-cr' fllwing initial r secnd-line systemic treatment and the majrity f them had a gd perfrmance status, lw number f metastatic sitesand lw incidence f liverinvlvement. Ninef 0 patients withfirst-cr cntinued prgressin-free yearsafterbeginning systemic treatments. The majrsitesf metastasis were the lung and bneand thereweren cases with livermetastasis. Fivepatients received standard dxrubicin-cntaining cmbinatin chemtherapy with r withut tamxifen. Tw f these nine patients remain prgressin free in first-cr. Threef them remained in first-cr after yearsand diedf prgressive breastcancer andtw thers diedf unrelated causes. Tw patients relapsed after btaining a first-cr fr at least years and remain alivewith active metastatic disease. The MSTand median prgressin-free survival f ninepatients were 0.and.0 years, respectively. These nine patients represented.% f all first-cr patients and.% f the ttal patients. Cnclusins: Althugh MBC is cmmnly recgnized t be an incurable disease, a small percentage f patients clearly are alive and prgressin free fr prlnged perids after initiatin f systemic treatments. Key wrds: metastatic breastcancer- clinicalcharacteristics - cmplete remissin - survival INTRODUCTION Breast cancer is the secnd mst frequently diagnsed cancer after gastric cancer amng Japanese wmen, with apprximately 000 cases and 800 deaths in. Althugh these figures are much lwer cmpared with Western cuntries, the incidence f breast cancer in Japan is increasing and the number f newly diagnsed cases in the year 0 is predicted t exceed0 000 (). Cmbinatin chemtherapy is the mst effective mdality f treatment fr the majrity f patients with metastatic breast cancer (MBC). Overall respnse rates f -80% have been Received January, 8; accepted March, 8 Fr reprints and all crrespndence: Trn Watanabe, Department f Medical Onclgy, Natinal Cancer Center Hspital, -, Tsukiji -chme, Chu-ku, Tky 0, Japan. twatanab@gan.res.ncc.g.jp Abbreviatins: MBC, metastatic breast cancer; CR, cmplete remissin; PR partial remissin; NC, n change; PD, prgressive disease; first-ck, first cmplete remissin; MST, median survival time; DFI, disease-free interval reprted cnsistently ver the last few years and the duratin f survival after chemtherapy has ranged frm 8 t mnths (). Hwever, MBC is cmmnly recgnized t be an incurable disease and even thugh systemic treatments such as chemtherapy and endcrinetherapy can induce impressive respnses, their use in treating metastatic disease is usually limited t palliative rather than curative purpses. Thus, even thugh lng-term survivrs exist, their extended survival is thught t be attributed t the indlent nature f their disease rather than the treatments (-8). On the ther hand, MBC patients wh achieve cmplete remissin have a lnger duratin f remissin and lnger survival and a fractin f them are ptentially curable (-). A careful study f the quality and length f cmplete remissins in MBC is essential in rder t estimate the verall impact f systemic treatment n the survival f MBC patients. We have analyzed ur experience with cnsecutive MBC patients treated at the Natinal Cancer Center Hspital in recent years. The purpse f ur retrspective analysis was t describe the clinical characteristics f patients wh had cmplete remissins (CR) t the treatment fsystemic chemtherapy with r withut endcrinetherapy. Dwnladed frm n 0 December 0

2 Jpn J Clin OncI8;8().. ".0 :~ ~ 0.8 u: "" ".. <I e 0. ~ "E e 0. --Overall survival (n=) -- Prgressin-free survival (n=0) CR (n=) Unknwn Initial systemic treatment---, respnse status n=l '" " 'fg, 0. E '" Mnths CR(n=) Failed n=8 Figure. Prgressin-free and verall survival curves f the ttal MBC patients. PATIENTS AND METHODS Between January 88 and December, cnsecutive MBC patients were treated with several types f systemic treatments at the Natinal Cancer Center Hspital. Thirty-six patients were excluded wing t inapprpriate data with respect t medical recrds and patients had insufficient data t determine respnse status but were assumed nt t have achieved cmplete remissin. Therefre, the data fr the remaining (8%) MBC patients were used fr further analysis. Respnses were evaluated after the first tw r three cycles (r - mnths) f systemic treatments. Standard Internatinal Unin Against Cancer (UICC) criteria were used t determine respnses t treatment (). A cmplete remissin (CR) was defined as the disappearance f all clinical evidence f an active tumr fr a minimum perid f weeks. In the case f bne metastases, CR was determined by clear evidence f cmplete bne recalcificatin with attainment f near-nrmal bne architecture r a nrmal bne scan. Partial remissin (PR) was defined as a 0% r greater decrease in the sum f prducts f the largest perpendicular diameters f measurable lesins, prvided that n lesins increased in size and n new lesins appeared fr a minimum f weeks. N change (NC) was defined as n change in tumr dimensins fr a minimum f weeks. Prgressive disease (PD) was defined as an unequivcal % increase in the size f any measurable lesins r the appearance f new lesins. In this analysis, bth patients wh achieved CR after initial systemic treatment and thse wh failed initial treatment but achieved CR n secnd-line treatment, were defined as 'firstcmplete remissin' (first-cr). The extent f metastatic invlvement was determined by physical examinatin, bichemical analyses and rutine imaging prcedures befre systemic treatment began. Bne invlvement was determined by lytic r blastic lesins shwn n radigraphs. Bne scans alne were nt cnsidered diagnstic. Abnrmalities shwn n bne scans had t be cnfirmed by radigraphy. Liver invlvement was determined by cmputed tmgraphy r ultrasund cnsistent with the lcatin f the metastases. Pleural r peritneal invlvement was determined by psitive cytlgy Relapsed during first years ~ Dead with Alive with Secnd CR metastasis metastasis n= n= n= ~ Alive NED n= Still in first-cr n= Alive witb metastasis n= Dead witb metastasis n= Dead NED after yrs n= Figure. Flw chart describing the clinical curse f 0 MBC patients wh achieved first-cr n initial r secnd-line systemic treatments. NED; n evidence f disease. fr tumr cells in the effusin fluid and by apprpriate imaging studies. Lymph nde invlvement was classified int tw categries; reginal and distant lymph nde metastases based n the VICC criteria. Reginal lymph nde metastasis included ipsilateral axillary, interpectral, supraclavicular and internal mammary lymph nde invlvement, while any ther lymph nde invlvement was classified as distant lymph nde metastasis, including cervical and cntralateral internal mammary lymph nde invlvement. The fllwing parameters were analyzed: age, menpausal status, estrgen (ER) receptr status, prgesterne (PgR) receptr status, ECOG perfrmance status (PS), number f metastatic sites, dminant metastatic sites, dcumented metastatic sites, types f adjuvant treatments, types f initial (first-line) systemic treatments, respnses t initial systemic treatment and diseasefree interval (DFI) frm the time f initial diagnsis. Calculatin f the number f metastatic sites did nt distinguish between single and multiple metastasis in a given rgan in patients with the metastatic disease; fr example, a multiple bne metastasis, multiple pulmnary metastasis r multiple skin metastasis was cunted as ne site. Estimates f prgressin-free and verall survival were based n the Kaplan-Meier methd (). All deaths were cnsidered as events regardless f their cause. Each patient was cnsidered t be alive at the time f her last evaluatin unless death had been dcumented and censred data were taken int accunt (). The differences between pairs f curves were tested fr statistical significance by a stratified lg-rank test. Differences with a P value <0.0 were cnsidered significant. All P values were tw-sided. All analyses were perfrmed using SPSS Ver.. statistical sftware. Dwnladed frm n 0 December 0

3 0 Characteristics fmetastatic breast cancer patients with cmplete remissin Table. Clinical characteristics f patients with CR cmpared with the thers Table. Prfile f initial systemic treatment Patient characteristics CR patients Others Types f initial treatment CR patients Others N. f patients Median age (range) (years) Median disease-free interval (mnths) Menpausal status Premenpausal Pstmenpausal Unknwn Estrgen receptr status Negative Psitive Unknwn Prgesterne receptr status Negative Psitive Unknwn Perfrmance status Number f metastatic sites I Dminant disease site Bne Sft tissue Visceral Dcumented disease site Bne Reginal lymph ndes Distant lymph ndes Lung Skin Liver Pleura Pericardium Brain Adjuvant treatment Nne Chemtherapy (CT) alne Raditherapy (RT) alne Endcrinetherapy (ET) alne CT+RT RT+ET CT+ET CT+ET+RT N. % N. % N. % N. % 88 Anthracycline-cntaining regimen 0 8 (-) (8-8) Nn-anthracycline-cntaining regimen I 0..8 Oral -FU alne 0 Oral CPA alne 8 8 Investigatinal new agent* 0 Endcrinetherapy alne Ttal IS FU, flururacil; CPA, cyclphsphamide. *MXII, vinrelbine, dcetaxel. RESULTS Figure shws prgressin-free and verall survival curves f the ttal MBC patients. The estimated median prgressin-free survival was. mnths [% cnfidence interval (Cl) =.0-. mnths]. The median survival time (MST) was 8.0 mnths (% Cl =.-.0 mnths) and the, and 0 year survival rates were.8,. and.%, respectively. Figure shws a flw chart describing the clinical curse f 0 MBC patients wh were defmed as 'frrst-cr' n initial r secnd-line systemic treatments ( patients achieved CR n initial treatment and seven patients, wh failed initial treatment, achieved CR n secnd-line treatment). Thirty-ne f 0 patients develped a prgressive disease during the first years; died f metastatic breast cancer, ne remains alive with metastasis and anther remains in unmaintained secnd CR after retreatment. Nine patients wh achieved a frrst-cr cntinued prgressin-free years after beginning systemic treatments. Tw f these nine patients remain prgressin-free in frrst-cr at this time. Three f them wh remained in frrst-cr at years died f prgressive breast cancer and tw thers died f unrelated causes (infectin and mycardial infarctin). In additin, tw patients wh relapsed after btaining a first-cr fr at least years remain alive with an active metastatic disease. At the time f this analysis, these nine patients wh remained in frrst-cr fr mre than years represented.% f all frrst-cr patients and.% f the ttal patient ppulatin. Table lists the clinical characteristics f patients wh achieved CR n initial systemic treatment cmpared with all the ther patients. Several factrs were mre frequently present in patients with CR cmpared with the thers. Fr example, althugh 8% f CR patients were PS 0, 0% f the thers were in this categry. On the ther hand, althugh nly % f CRs had livermetastases, % f the thers had liver metastases. The number f different metastatic sites was lwer fr CR patients than fr the thers. Table lists the prfile f initial systemic treatment fr the MBC patients. The majrity f patients received standard anthracycline-cntaining chemtherapy with r withut endcrinetherapy and (0%) f CR patients received it. On the ther hand, (0%) f the ttal patients received a nn-anthracyclinecntaining regimen, ral flururacil (-FU) r cyclphspha- Dwnladed frm n 0 December 0

4 Jpn J Clin OncI8;8() CR(n=) -- PR(n=8) -- NC (n=iio) -- PD(n=8).. c.~ CR(n=) -PR(n=) -NC(n=0) -- PD(n=0) ] 0. c e f e Mnths Mnths Figure. Prgressin-free survivalcurvesf thettalpatientsfllwinginitial systemic treatmentaccrdingt the maximum respnsestatus. Figure. Overallsurvivalcurvesf the ttal patientsfllwing initialsystemic treatmentaccrdingt the maximumrespnse status. mide alne. Hwever, nly three (%) patients achieved CR and n CR was bserved in patients wh received ral -FU alne. At the time f this analysis, (%) MBC patients achieved CR while receiving initial systemic treatments (described earlier). Seventy-tw patients (%) achieved PR, (%) had n change in their tumr dimensins and develped PD (%). The verall respnse rate was % (% CI =.-.0%). The prgressin-free survival curves f the ttal patients, accrding t the maximum respnse status achieved fllwing initial systemic treatment, are shwn in Fig.. Eleven patients whse respnse status was nt determined were excluded frm Figs and (described belw). The estimated median prgressin-free survival f the patients with CR, PR, NC and PD were.8,.,. and. mnths, respectively. The verall survival curves f the ttal patients, accrding t the maximum respnse status achieved fllwing initial systemic treatment, are shwn in Fig.. MSTs f the patients with CR, PR, NC and PD were.,., 8.0 and. mnths, respectively. Table shws the individual characteristics f the nine patients wh remained in first-cr fr mre than years. All f these patients had gd PS and the majrity f them had received adjuvant chemtherapy with a lnger DFI. The majr sites f metastasis were the lung and bne and there were n cases with liver metastasis. Five patients received standard dxrubicincntainingcmbinatinchemtherapy with r withut tamxifen (ACT r AC). Median prgressin-free survival f these cases and MST were. (range.-.) and 0. (range.-.) years, respectively. Althugh three patients were died f MBC, tw patients remain prgressin-free in first-cr at the time f this analysis. DISCUSSION Mst patients with breast cancer are diagnsed at an early stage, when ptentially curative treatment strategies are pssible. Hwever, 0-8% f these patients, depending n the initial stage and the treatment strategy fllwed, will develp distant metastases within years f their initial diagnsis (). It is cmmnly recgnized that the great majrity f MBC patients will eventually die f their disease, usually within a few years f relapse. On the ther hand, it is less recgnized that a small fractin f patients treated with systemic treatment will remain alive and prgressin-free fr prlnged perids after initiatin f systemic treatment (). Greenberg et al. () reprted that a small fractin (.%) f MBC patients remained alive and in CR fr mre than years and mre than half f these patients were alive and disease-free within a minimum 0 years fllw-up. Between January 88 and December, cnsecutive MBC patients were treated at the Natinal Cancer Center Hspital, generally with standard anthracycline-cntaining cmbinatin chemtherapy with r withut endcrinetherapy. Amng these patients, nine f 0 patients, wh achieved first-cr, remain disease-free fr mre than years fllwing systemic treatment. These nine patients represented.% f the ttal patients and the results were similar t thse reprted by Greenberg et al. (). In ther wrds, we cnfirmed that a small fractin f Japanese MBC patients als remain alive and prgressin-free fr prlngedperids with CR fllwing systemic treatment. Hwever, it was difficult t determine frm ur data whether lng-term CRs result frm the treatment strategy r the underlying indlent nature f MBC in sme patients. Achieving CR is mre likely fr patients with a lw tumr burden and gd perfrmance status (,8). CRs were als mre cmmn amng patients with pulmnary and reginal lymph nde metastases and less cmmn in patients with bne metastases in ur study (shwn in Table ). This discrepancy may be partially caused by differences in the tumr burden and als differences in the ability t detect metastases in different rgan sites and by mnitring changes. Additinally, assessment f the respnses in bne metastases is based n indirect measurements, a factr that is prbably respnsible fr the difficulty f evaluating the respnse t therapy in these sites f the disease. In mst studies, visceral invlvement, especially liver invlvement, was a pr prgnstic factr (,0). Our data als shwed that patients with liver invlvement had a prer prgnsis than thse withut liver invlvement (MST;. vs. mnths, p < by lg-rank test) and nly ne (%) f the patients with liver invlvement achieved CR. Dwnladed frm n 0 December 0

5 Characteristics fmetastatic breast cancer patients with cmplete remissin Table. Individual characteristics f patients with first-cr after mre than years N. Stage* ER* PgR* Adj. DFI Age ] pst Menpausal Site f lst-iine PFS OS Present status treat. (yr) (yr) status'] metastasis treat. (yr) (yr) II UN UN CT.0 0 Pre. Lung, bne TAM.8 0. Dead with NED UN UN Nne. 8 Pst. Lung, DLNs ACT 8. l. Alive with metastasis IlIa UN UN CT+RT.8 0 Pre. Lung CPA.. Dead with metastasis II UN UN CT. 0 Pst. Skin CPA+TAM.. Alive with metastasis II + + CT. Pst. Bne TAM Dead with NED UN UN UN CT. 0 Pre. Pleura ACT.. Still in first-cr IlIb UN UN CT+ET. Pst. Skin AC.. Dead with metastasis 8 IV Nne 0 Pre. Lung, bne, pleura ACT.. Dead with metastasis UN UN CT. 8 0 Pre. Lung ACT Still in first-cr UN, unknwn; ER, estrgen receptr; PgR, prgesterne receptr; adj. treat., adjuvant treatment; DLNs, distant lymph ndes; NED, n evidence f disease; CT, chemtherapy; RT, raditherapy; ET, endcrinetherapy; TAM, tamxifen; CPA, cyclphsphamide; ACT, adriamycin + CPA + TAM; AC, adriamycin + CPA; DFI, disease-free interval; PFS, prgressin-free survival; OS, verall survival after diagnsis f MBC. *At the status f initial diagnsis. tat the status f diagnsis f MBC. The factr that appears t be mst imprtant is the initial achievement f a CR. Only five (.%) f patients with PR and (.%) f patients with NC remained prgressin-free beynd years because the respnse rate t salvage chemtherapy regimens, nce hrmnal and first-line chemtherapy have been exhausted, is extremely pr and shrt-lived (). Althugh cmbined chemtherapy and endcrinetherapy might result in lnger CRs, there is n evidence that the lng-term disease-free survival percentage is increased by this strategy. There is als n evidence t suggest that the additin f raditherapy increases the fractin f lng-term disease-free survivrs. Our data failed t shw the significant differences between patients wh received anthracycline-cntaining chemtherapy and thse wh did nt receive it with respect t nt nly verall survival but als prgressin-free survival (data nt shwn). One f the pssible reasns is the insufficient impact f tday's cmbinatin chemtherapy and the utcme fr MBC patients may be strngly influenced by the indlent nature f their disease. T break dwn the current status, it is necessary t develp new and better treatment strategies. One pssible strategy is high-dse chemtherapy with hematpietic stem cell supprt. When high-dse chemtherapy is used fr respnse cnslidatin, CR rates ranging frm t 80% have been reprted, with sme lasting lnger than years (,). In cnclusin, a small percentage f MBC patients clearly are alive and disease-free mre than years after initial relapse. The fractin may be small, but it might expand t the majrity fmbc patients by sme treatment strategy cmpletely different frm tday's cmbinatin chemtherapy. Acknwledgments We thank Misses Mmk Kitahara and Hirmi Orita fr secretarial assistance. References. Kakize T, Nakamura Y,Segami K, Yamaguchi N, Shiina M, Yamauchi M, et al. Cancer Statistics in Japan. Tky: Fundatin fr Prmtin f Cancer Research, ;-.. Dicksn RB, Lippman ME, Harris JR, Mrrw M, Nrtn L. Cancer f the breast. In DeVita VT, Hellman S, Rsenberg SA, editrs. Cancer - Principle and Practice f Onclgy, th ed. Philadelphia: Lippinctt, ;-.. Legha SS, Buzdar AU, Smith TL, Hrtbagyi GN, Swenertn KD, Blumenschein GR, et al. Cmplete remissins in metastatic breast cancer treated with cmbinatin drug therapy. Ann Intern Med ;:8-.. Rss MB, Buzdar AU, Smith TL, Eckles N, Hrtbagyi GN, Blumenschein GR, et al. Imprved survival f patients with metastatic breast cancer receiving cmbinatin chemtherapy. Cancer 8;:-.. Tdd M, Shag M, Cadman E. 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