By Eleni Diamandidou, Aman U. Buzdar, Terry L. Smith, Debra Frye, Maria Witiaksono, and Gabriel N. Hortobagyi

Transcription

1 Treatment-Related Leukemia in Breast Cancer Patients Treated With Flururacil-Dxrubicin- Cyclphsphamide Cmbinatin Adjuvant Chemtherapy: The University f Texas M.D. Andersn Cancer Center Experience By Eleni Diamandidu, Aman U. Buzdar, Terry L. Smith, Debra Frye, Maria Witiaksn, and Gabriel N. Hrtbagyi Purpse: Adjuvant chemtherapy fr breast cancer has been the rutine practice in the past decade. A number f studies have bserved an increased incidence f treatment-related leukemias fllwing chemtherapy with alkylating agents and/r tpismerase II inhibitrs. We evaluated the incidence f treatment-related leukemias in breast cancer patients treated in fur adjuvant and tw neadjuvant chemtherapy trials at The University f Texas M.D. Andersn Cancer Center. Patients and Methds: Between 1974 and 1989, 1,474 patients with stage II r III breast cancer were treated in six prspective trials f adjuvant (n=4) r neadjuvant (n=2) chemtherapy with flururacil, dxrubicin, and cyclphsphamide (CTX) (FAC) with r withut ther drugs. The median bservatin time was 97 mnths. In 1,107 patients, FAC chemtherapy was given pstperatively; 367 patients received inductin chemtherapy, as well as pstperative chemtherapy. Eight hundred ten patients had surgery fllwed by raditherapy and chemtherapy; 664 patients had surgery and chemtherapy nly. Patients in tw adjuvant and ne neadjuvant study received higher cumulative dses f CTX cmpared with thse in the ther studies. Results: Furteen cases f leukemia were bserved. Twelve f these patients had received raditherapy and chemtherapy, and tw had received chemtherapy nly. Six f the reprted patients with leukemia were treated with a cumulative CTX dse f greater than 6 g/ m 2. Five f these patients had received bth raditherapy and chemtherapy. The median latency perid in the 14 patients was 66 mnths (range, 22 t 113). Six f 10 patients with adequate cytgenetic analyses had abnrmalities that invlved chrmsmes 5 and/r 7. The rest f the patients had nnspecific cytgenetic abnrmalities r lacked cytgenetic infrmatin. The 10-year estimated leukemia rate was 1.5% (95% cnfidence interval [CI], 0.7% t 2.9%) fr all patients treated, 2.5% (95% CI, 1.0% t 5.1%) fr the raditherapy-plus-chemtherapy grup, and 0.5% (95% CI, 0.1% t 2.4%) fr the chemtherapy-nly grup; this difference was statistically significant (P =.01). The 10-year estimated leukemia risk fr the higher-dse (> 6 g/m 2 ) CTX grup was 2% (95% Cl, 0.5% t 5.0%) cmpared with 1.3% (95% CI, 0.4% t 3.0%) fr the lwer-dse grup, a difference that was nt statistically significant (P =.53) Cnclusin: These data illustrate that patients treated with adjuvant FAC chemtherapy plus raditherapy have a slightly increased risk f leukemia. This infrmatin needs t be cnsidered in the treatment plans fr patients with breast cancer. Hwever, fr mst patients, the benefits f adjuvant therapy exceed the risk f treatment-related leukemia. J Clin Oncl 14: by American Sciety f Clinical Onclgy. THE BENEFITS OF ADJUVANT chemtherapy in patients treated fr breast cancer are well established. 3 It is nevertheless f great imprtance t determine the ptential risks assciated with such therapy. The risk f leukemia in breast cancer patients treated in the past with alkylating agents-primarily melphalan-has been shwn t be high. 4`5 The published results frm recent studies addressing the issue f chemtherapy- Frm the Departments f Breast and Gyneclgic Medical Onclgy and Bimathematics, The University f Texas M.D. Andersn Cancer Center, Hustn, TX. Submitted September 26, 1995; accepted April 9, Address reprint requests t Aman U. Buzdar, MD, Department f Breast and Gyneclgic Medical Onclgy Bx 56, The University f Texas M.D. Andersn Cancer Center Hlcmbe Blvd. Hustn. TX 77030; amanbuzdar@isqm.mda.uth.tmc.edu. ( 1996 by American Sciety' f Clinical Onclgy X/96/ $3.00/0 primarily cyclphsphamide (CTX)-alne r in cmbinatin with raditherapy and the resulting leukemia risk are mre cntrversial. " Alkylating agent-related leukemias are characterized by a lng latency perid (3 t 5 years) and a smldering-- preleukemic-phase, and frequently invlve specific cytgenetic abnrmalities f chrmsme 5 and/r 7."4 Mre recently, the tpismerase-ii inhibitrs, including the anthracyclines (daunrubicin, dxrubicin, and epirubicin), have als been als implicated in the develpment f a clinically and cytgenetically defined frm f treatment-related leukemia (treatment-related myeldysplastic syndrme/treatment-related acute myelgenic leukemia (t-mds/t-aml) At The University f Texas M.D. Andersn Cancer Center, an adjuvant chemtherapy regimen f flururacil (5-FU), dxrubicin, and CTX (FAC) has been used with varius mdificatins in six clinical trials fr patients with early-stage breast cancer. The bjective f this retrspective review was t evaluate the 2722 Jurnal f Clinical Onclgy, Vl 14, N 10 (Octber), 1996: pp

2 LEUKEMIA IN BREAST CANCER PATIENTS TREATED WITH FAC 2723 Table 1. Chemtherapy Regimen by Study N. f Interval Between Median Observatin Duratin f Treatment study N. and Perid Therapy Planned Cycles Cycles (weeks) Time (mnths) (mnths) Adjuvant FAC + CMF + BCG FAC + CMF + BCG FACVP 7-10* ER+ r unknwn T r TMV 6 ER- MV VACP t ER+ TX1 yeart + IFN x 1 year Neadjuvant Preperative FACX3, befre 1980 pstperative FAC + CMF 9 9 after 1980" Preperative VACPX3, pstperative VACP r MVF Abbreviatins: ER, estrgen receptr; CMF, cyclphsphamide, methtrexate, and flururacil; BCG, bacillus Calmette-Gu6rin; FACVP, flururacil, dxrubicin, cyclphsphamide, vincristine, and prednisne; T, tamxifen; TMV, tamxifen, methtrexate, vinblastine; VACP, vincristine, dxrubicin, cyclphsphamide, and prednisne; IFN, interfern; MVF, methtrexate, vinblastine, and flururacil. 'Patients with T2NO f T3NO disease and 0 t 3 psitive lymph ndes received 300 mg/m 2 dxrubicin and had 7 cycles f chemtherapy; all ther patients received 400 mg/m 2 dxrubicin and had 10 cycles f chemtherapy. ter+ patients received tamxifen cncmitantly with chemtherapy fr 1 year. tduratin r treatment was up t 6 mnths (18 t 24 weeks) depending n recvery f the patient and abslute neutrphil cunt. Duratin f treatment was up t 9 mnths depending n patient recvery and the abslute neutrphil cunt. "Patients received 3 curses preperatively and 5 curses pstperatively fr a ttal f 8 curses. Observatin times were measured frm initiatin f adjuvant chemtherapy t death r last bservatin time. incidence f newly diagnsed treatment-related leukemias in breast cancer patients enrlled nt these FAC trials at ur institutin. Patients and Prtcls PATIENTS AND METHODS In six studies cnducted between 1974 and 1989, 1,474 patients were treated with adjuvant FAC chemtherapy with r withut ther drugs (Table 1). In study 1, between 1974 and 1977, 222 patients with stage II r III breast cancer were treated with FU, dxrubicin, and CTX, at dses f 400 mg/m 2, 40 mg/m 2, and 400 mg/m 2, respectively, until a cumulative dxrubicin dse f 300 mg/m 2 was reached and then cntinued n maintenance treatment with CTX (500 mg/m 2 ), 5-FU (500 mg/m2), and methtrexate (MTX; 30 mg/m 2 ) until cmpletin f chemtherapy at 24 mnths. The curses were repeated every 4 weeks. All patients received immuntherapy with bacillus Calmette- Guerin (BCG). One hundred ninety-eight patients received pstperative raditherapy befre chemtherapy; 24 patients did nt receive raditherapy. In study 2, a ttal f 238 patients were treated between 1977 and Curses were repeated every 3 weeks; the ttal treatment time was 24 mnths. Patients were randmized t receive FAC alne r FAC plus BCG. A ttal f 163 patients received pstperative radiatin befre chemtherapy. Patients received CTX (400 mg/m2), 5- FU (400 mg/m 2 ), and dxrubicin (40 mg/m 2 ) until a cumulative dxrubicin dse f 300 mg/m 2 was reached and then cntinued n maintenance with MTX (30 mg/m2), CTX (500 mg/m2), and 5-FU (500 mg/m 2 ) until cmpletin f chemtherapy at 24 mnths. In study 3, a ttal f 336 patients were treated between 1980 and The ttal duratin f chemtherapy was decreased t 12 mnths, and the curses f chemtherapy were repeated every 3 weeks. The initial phase f chemtherapy cnsisted f 5-FU (400 mg/m 2 ), dxrubicin (40 mg/m2), CTX (400 mg/m 2 ) vincristine (1.4 mg/m2), and prednisne (40 mg rally fr 5 days) (FACVP). The ttal dse f dxrubicin was 300 mg/m 2 fr patients wh had zer t three psitive ndes and fr thse with T2NO r T3NO disease (n= 155). All ther patients (n= 179) received 400 mg/m 2 f dxrubicin. The ttal duratin f treatment fr patients wh received 300 mg/m 2 f dxrubicin was apprximately 5 mnths (seven curses f chemtherapy given every 3 weeks) and fr patients wh received 400 mg/m 2 f dxrubicin it was apprximately 7 mnths (10 curses given every 3 weeks). On cmpletin f FACVP, estrgen receptr (ER)-negative patients received maintenance chemtherapy with MTX (75 mg/m 2 ) every 2 weeks fr six dses fllwed by vinblastine (1.7 mg/m 2 ) daily fr 5 days every 3 weeks fr fur curses. The ttal duratin f maintenance therapy was 6 mnths in this study grup. If patients had ER-psitive disease r unknwn ER status, they were randmized t receive tamxifen r tamxifen and MTX/vinblastine (same schedule as earlier). The duratin f maintenance therapy in this grup was als 6 mnths. Seventy-tw patients received pstperative radiatin. In study 4, a ttal f 311 patients were treated between 1983 and All patients were treated with escalating dses f dxrubicin and CTX. Patients were given 1.5 mg/m 2 f vincristine, and dxrubicin was given at 60 mg/m 2 in curse 1, 70 mg/m 2 in curse 2, and 75 mg/m 2 in curses 3 t 6. CTX was given at 600 mg/m 2 in curse 1, 700 mg/m 2 in curse 2, and 750 mg/m 2 in curses 3 t 6. Prednisne (40 mg rally) was given n days 1 t 5. The duratin f treatment was decreased t 6 mnths, and the treatment was given every 3 weeks. All patients with ER-psitive r unknwn ER status als received tamxifen cncmitantly fr 1 year. After cmpletin

3 2724 f chemtherapy, patients were randmized t receive immuntherapy. This cnsisted f 3 x 106 U/d f human leukcyte interfern fr 8 weeks and then 3 x 106 U n Mnday, Wednesday, and Friday fr the remaining 44 weeks. Seventy-nine patients received pstperative radiatin befre chemtherapy. In study 5, 174 patients with stage IIIA r IIIB breast cancer were preperatively treated between 1974 and Initial chemtherapy cnsisted f 5-FU (500 mg/m2), dxrubicin (50 mg/m 2 ), and CTX (500 mg/m 2 ). In additin, BCG was given. After three curses f chemtherapy, all patients were reevaluated, and lcal treatment was recmmended. Twenty-nine patients were treated with radiatin nly, 103 had cmbined radiatin and surgery, 38 had surgery nly, and fur had n lcal treatment. A ttal f 132 patients had radiatin therapy. After initial lcreginal treatment, FAC-BCG was cntinued until a cumulative dxrubicin dse f 450 mg/m 2 was reached. Subsequently, MTX was substituted fr dxrubicin, and a CMFlike cmbinatin (CTX 500 mg/m 2 ; MTX 30 mg/m2; 5-FU 500 mg/ m 2 ) was cntinued until 24 mnths f treatment was cmpleted. After 1978, BCG was deleted frm the prgram. After 1980, it was recgnized that cmpliance with the 2-year treatment regimen was pr, and it was als believed that the maximum impact f chemtherapy was achieved during the initial 6 mnths f chemtherapy. Therefre, CMF maintenance treatment was discntinued, and the ttal duratin f treatment was reduced frm 24 mnths t apprximately 9 mnths. In study 6, 193 patients with stage IIB, IIIA, r IIIB breast cancer were enrlled between 1985 and All patients were given preperative chemtherapy that cnsisted f vincristine (1.5 mg/m2), dxrubicin (curse 1, 60 mg/m2; curse 2, 70 mg/m2; curse 3, 75 mg/m2), CTX ( curse 1, 600 mg/m2; curse 2, 700 mg/m 2 ; curse 3, 750 mg/m 2 ), and prednisne (40 mg rally n days 1 t 5), (VACP). The duratin f chemtherapy was 6 mnths, and the curses were repeated every 3 weeks. After three curses f preperative chemtherapy, the status f the tumr was reevaluated. Patients with evidence f prgressive disease r n change in tumr status had preperative radiatin. Patients whse residual tumr at the time f mastectmy measured less than 1 x I cm cntinued with the same chemtherapy (VACP) after surgery until a cumulative dxrubicin dse f 500 mg/m 2 was reached. Patients whse residual tumr was larger than 1 x 1 cm were randmized t receive vincristine, dxrubicin, CTX, and prednisne r MTX (120 mg/m 2 ), 5-FU (1,000 mg/m2, with leucvrin rescue), and vinblastine (1.5 mg/ m 2 ) (VMF). This chemtherapy was given every 3 weeks fr five pstperative curses. Tw patients had radiatin nly (n surgery), eight had preperative radiatin, five had pstperative radiatin, 151 had radiatin after chemtherapy, and 27 did nt have radiatin therapy. Patients treated in the fur adjuvant and tw neadjuvant studies received raditherapy as fllws. Raditherapy was given with a cbalt-60 machine with a tumr dse f 5,000 rad delivered in 5 t 6 weeks t the chest wall (r breast). T cver the draining lymphatics, a 5,000-rad dse was delivered t the axilla, internal mammary, and supraclavicular ndes. A bst f 1,200 rad was given t the mastectmy scar. In patients wh had breast preservatin, a 3,000- rad tumr dse in 2 weeks was delivered t the breast t reduce tangential fields. In patients treated in the neadjuvant studies, the area f residual tumr was given an additinal 1,500- t 2,000-rad bst. In patients with bulky disease after initial chemtherapy, if raditherapy alne was used, fractinatin was used. Radiatin was given twice daily t a ttal dse f 5,500 rad t the breast ver 5 weeks with a bst t the area f residual disease. Data Cllectin DIAMANDIDOU ET AL The medical recrds f all patients in these six trials wh develped leukemias were further reviewed t determine the type f leukemia, latency perid between breast cancer treatment and develpment f leukemia, cytgenetics, and time between diagnsis f leukemia and death. Cytgenetic analysis was perfrmed in 10 f 14 patients with a diagnsis f leukemia. Actual cumulative dses f CTX were calculated fr all patients in study 5 because f wide range f pssible CTX dses. In studies 1 and 2 with high planned dses f CTX, infrmatin was available regarding which patients did nt cmplete therapy as planned. We calculated dse-intensity (DI) fr each study grup; the dse density was defined as the amunt f drug administered per unit time. The delivered DI was calculated frm the dsage administered during the first six curses (cycles) f chemtherapy (DI). Duratin f treatment was defined as the interval (in weeks) between day 1 f the first cycle f chemtherapy and day 21 r 28 f the sixth curse. In the calculatin f DI6 fr patients wh received fewer than six curses f chemtherapy, the duratin f therapy was calculated based n the prjected interval fr six curses, ie, 18 weeks. The median bservatin time fr the ttal grup was 97 mnths; 564 patients were mnitred fr mre than 10 years. Statistical Analyses The Kaplan-Meier methd was used t estimate risk f leukemia; bservatins were dated frm the start f FAC chemtherapy. Patients wh died were cunted as censred at date f death, assuming that such patients were at the same risk f develping leukemia as thse wh survived. Cnfidence intervals (CIs) fr 10-year estimates f leukemia risk were adjusted fr effective sample size. 25 Leukemia rates were cmpared using a likelihd rati methd, assuming a Pissn distributin fr develpment f leukemia. Observatin times were measured frm initiatin f adjuvant chemtherapy t death r last bservatin date. RESULTS Of 1,474 patients treated, 1,107 (75%) had received adjuvant chemtherapy and 367 (25%) had received neadjuvant chemtherapy. Furteen patients were diagnsed with leukemia at times that ranged frm 22 t 113 mnths (median, 66) fllwing initiatin f chemtherapy. The median survival time fllwing the diagnsis f leukemia was 7 mnths. Table 2 presents the actual cumulative CTX dse, duratin f treatment, type f leukemia, mrphlgy, cytgenetic abnrmalities, and survival fr the 14 patients. We bserved specific cytgenetic abnrmalities that invlved chrmsmes 5 and/r 7 in six f 10 patients with adequate cytgenetic analysis (Table 2). Cytgenetic infrmatin was nt available fr fur patients. Eleven f the patients wh develped leukemia had n evidence f breast cancer at the time f the leukemia diagnsis. Patient n. 3 was fund t have bne marrw invlvement by adencarcinma early 1982, and 2 t 3 mnths later (53 mnths fllwing treatment fr breast cancer), she presented with a lw WBC cunt (1.5 X 103/ IL), with 31% blasts in the bne marrw, and lw platelet

4 LEUKEMIA IN BREAST CANCER PATIENTS TREATED WITH FAC 2725 Table 2. Leukemia Cases Accrding t Raditherapy Status, Actual Cumulative CTX Dse, Duratin f Treatment, Type f Leukemia, Cytgenetic Abnrmalities, and Survival Actual Duratin f Cumulative Chemtherapy Patient N./ CTX Dse (mnths)/ Type f Latency Study N. Raditherapy (g/m 2 ) N. f Cycles Leukemia Perid' Mrphlgy Cytgenetic Abnrmalities Survival 1/1 Yes /24 AML 90 WBC =73.1; PBB = 34 %; 56XX,(+6,+8,+8,+11,+12,+13, 5 PL = 23; Hb = 9.3; +14,+19,+20,+21) BMB = 20% 2/2 N /23 MDS (RAEB) 113 WBC = 6.7; PBB = 22%; 44XX,(-5,-7,-8,-21,+M,+M) 11 PL= 22; Hb= 10; BMB = 16% 3/2 Yes /17 AML 53 WBC = 1.5; PL = 21; 45X,+(xp;7q), Hb = 5.9; BMB = 31% 4/2 Yes /20 AML 29 WBC = 12.3; PBB = 19%; Diplid female karytype,46xx 29 PL = 15; Hb = 9.6; BMB = 30% 5/2 Yes /31 APL 27 WBC = 0.6; PL = 68K; t(15;17) 61 Hb = 12; BMB = 60% 6t/2 Yes /10 MDS 104 N/A N/A N/A 7/2 Yes /16 MDS 59 N/A N/A N/A 8/3 Yes 3.2 8/8 MDS (RAEB) 78 WBC = 0.9; PBB = 8%; -7 4 PL= 111;Hb= 12.3; BMB = 15% 9/4 N 4.3 7/6 CML 72 WBC = 73.5; PBB = 1%; Ph+clne 46XX,+(9q+;22q-) 23 PL= 1.438; Hb = 12; BMB = 2.8% 10t/5 Yes 3.5 7/6 MDS 81 WBC = 4.0; PBB = 6%; 2p+,-5,-7, 14+,-18,19p+,-20, 3 PL = 311; Hb = 4.6; 21p+,+mar BMB = 25% 11/5 Yes /9 AML 22 WBC = 56.4; PBB = 98%; N/A < 1 PL= 44; Hb = 10 12/6 Yes 1.8 7/8 MDS 111 WBC= 0.6; PL= 34; del(5)(q22q35)+idic(8)(p2),+9, 2 Hb = 7.8; BMB = 7.8% +11,del(12)(q22q24) +der(l 3;15)(q10;q10),+19, +20, +21,+r,+mars 13/6 Yes 4.5 6/8 MDS (RAEBT) 58 WBC = 5.5; PBB = 6%; 5q+,- 7 2 PL = 31; Hb = 8.5; BMB = 24% 14/6 Yes 5.3 7/8 MDS 52 N/A N/A 8 Abbreviatins: AML, acute myelgeneus leukemia; MDS, myeldysplastic syndrme; APL, acute prmyelcytic leukemia; CML, chrnic myelgenus leukemia; N/A, nt available; WBC, WBC cunt (x 10 3 /ML); PBB, peripheral-bld blasts (%); PL, platelet cunt (x 10 3 //L) Hb, hemglbin (g/dl); BMB, bne marrw blasts; MDS (RAEB), refractry anemia with excessive blasts; MDS(RAEBT), refractry anemia with excessive blasts in transfrmatin. *Time between breast cancer treatment and develpment f leukemia (mnths). tsurvival after diagnsis with leukemia (mnths). tpatients n. 6 and 10 had t discntinue the chemtherapy early because f txicity (acute hepatitis and heart failure, respectively). cunt (21 x 103 /L). Cytgenetic analysis shwed an abnrmality invlving chrmsme 7. Patient n. 5 presented at 27 mnths with a lw WBC cunt (0.6 x 103/ pal), lw platelet cunt (68 x 10 3 /pl), and bne marrw initially shwing insufficient metaphases (repeated bne marrw sampling als shwed insufficient metaphases). With cytarabine treatment, the patient achieved remissin f her leukemia fr 2.5 years; subsequently, she had a relapse, and this time the cytgenetic findings were cnsistent with a t(15; 17) chrmsmal abnrmality. The patient was diagnsed with acute prmyelcytic leukemia. The bne marrw als shwed infiltratin with adencarcinma cells. Patient n. 12 was diagnsed with pulmnary metastases 3 years befre the diagnsis f leukemia, was placed n tamxifen, and had stable disease at the time f leukemia diagnsis. Neither f these cases has been treated with chemtherapy fr the metastatic breast carcinma. Patient n. 9 presented at 72 mnths with a high WBC cunt (73.5 x 10 3 /ktl), high platelet cunt (1,438 x 103 /gl), and cytgenetic abnrmalities cnsistent with the Philadelphia chrmsme (Ph+) clne. This

5 2726 DIAMANDIDOU ET AL Table 3. Patient Characteristics Cumulative CTX Dse FAC FAC + XRT 6 g/m 2 > 6 g/m 2 Characteristic N. % N. % N. % N. % Stage II III IV Age, years < > Abbreviatin: XRT, raditherapy. leukemia was presumably unrelated t treatment fr breast cancer. Twelve patients with leukemia received bth radiatin therapy and chemtherapy, and tw received chemtherapy nly. Of the ttal study ppulatin, 810 patients (55%) had bth raditherapy and chemtherapy; 664 patients (45%) received chemtherapy nly. Table 3 lists the stage and age fr the raditherapy and nnraditherapy grups. There were mre stage III patients in the raditherapy grup, but the age distributin was similar in the tw grups. Treatment with chemtherapy and raditherapy was linked t a significantly increased risk f leukemia (Table 4). The additin f raditherapy t chemtherapy, regardless f the cumulative CTX dse, resulted in higher numbers f leukemia cases, as shwn in Table 5. Figure 1 graphically shws the estimated rates f leukemia fr patients wh received FAC chemtherapy alne versus FAC and raditherapy. We als examined leukemia incidence by cumulative CTX dse (Table 6). The majrity f patients (1,194, 81%) received the planned cumulative CTX dse and planned cumulative dxrubicin dse (Table 6). Mst Table 4. Rate f Leukemia by Chemtherapy Dse and Raditherapy Status N. f Cumulative Estimate Ttal N. Leukemia (%) f Leukemia at Grup f Patients Cases 10 Years 95% CI Ttal 1, Cyclphsphamide dse Lw* 1, Hight Raditherapy N Yes *Grup f patients wh received cumulative CTX dse 6 g/m 2. tgrup f patients wh received cumulative CTX dse > 6 g/m 2. Table 5. Cases f Leukemia by Chemtherapy Dse and Raditherapy Status N Raditherapy Cases Leukemia/Ttal Patients Raditherapy Chemtherapy Dse N. % N. % Lw. 1/ / Hight 1/ / *Cumulative CTX dse 6 g/m 2. tcumulative CTX dse > 6 g/m 2. patients (1,020, 69%) received a cumulative CTX dse f - 6 g/m 2. This dse was selected as the cutpint t cnsider leukemia incidence by dse, because it crrespnds t a cumulative CTX dse f 10 g, at the median bdy-surface area f 1.7 mg/m 2 (the median in ur patient ppulatin). Fur hundred fifty-fur patients (31%) received a cumulative CTX dse f greater than 6 g/m 2. Patients treated in studies 1 and 2 and a subgrup f patients treated in study 5 (thse treated fr 24 mnths) were included in the higher CTX dse grup. Patients wh discntinued chemtherapy early (and received - 6 g/m 2 cumulative CTX dse) because f txicity were included in the lwer cumulative CTX dse grup. Six f 14 patients wh develped leukemia were in the higher CTX dse grup. The ther eight patients with leukemia received a lwer cumulative CTX dse. We included in the lwer CTX grup ne patient (n. 6) frm study 2 wh had t discntinue chemtherapy early because f txicity and had nt received the higher CTX dse. Of six patients with leukemia bserved in the higher cumulative CTX dse grup, five were in study 2 and ne in study 1. The cases f leukemia bserved in study 5 were amng the subgrup with the lwer CTX dse. Cmparing study 2 with study 1, we bserved a difference in bth the cumulative CTX dse (16.3 g/m 2 in study 2 v 12.3 g/m 2 in study 1) and the DI6 ( mg/m 2 /wk in study 2 v 100 mg/m 2 /wk in study 1) (Table 6). Hwever, the number f leukemia cases is nt large enugh t draw statistically significant cnclusins regarding the crrelatin between cumulative dse, DI, and duratin f treatment in these tw studies. Stage distributins were similar in the higher and the lwer cumulative CTX dse grups, but a slightly higher prprtin f lder patients received lwer CTX dse (Table 3). The incidence f leukemia was slightly higher in the higher-dse grup, but this difference did nt reach statistical significance (Table 4 and Fig 2). DISCUSSION We evaluated the incidence f treatment-related leukemias in 1,474 patients treated with adjuvant r neadju-

6 LEUKEMIA IN BREAST CANCER PATIENTS TREATED WITH FAC 2727 E c -0 FAC = 0.5% (95% CI, %) FAC+XRT = 2.5% (95% Cl, %) p = = FiCR$9=4~ 810 Fig 1. Estimated rates f leukemia fr patients wh received FAC chemtherapy alne v FAC chemtherapy and raditherapy (P =.011 D 0 6 q ~-~-~-~-~-~-~- ' Mnths frm Start f FAC 120 vant FAC chemtherapy with r withut raditherapy in six different trials frm 1974 t The verall leukemia rate at 10 years fr all patient treated was 1.5% (95% CI, 0.7% t 2.9%). Wmen treated with chemtherapy and raditherapy had a higher cumulative leukemia rate, 2.5% (95% CI, 1.0% t 5.1%), cmpared with thse treated nly with chemtherapy, 0.5% ( 95% CI, 0.1% t 2.4%); this difference is statistically significant (P =.01). Patients treated with a cumulative CTX dse f greater than 10,000 mg (> 6 g/m 2 ) had a slightly higher risk f leukemia, 2.0% (95% CI, 0.5% t 5.0%) cmpared with thse wh did nt, 1.3% (95% CI, 0.4% t 3.0%), a difference that is nt statistically significant (P =.53). Cytgenetic abnrmalities that invlved chrmsmes 5 and/r 7 were bserved in six f 10 leukemia patients with adequate cytgenetic analysis. The presence f this chrmsmal abnrmality is characteristic f treatmentrelated leukemias in patients treated with alkylating Table 6. Cumulative CTX Dse and DI, Cumulative Dxrubicin Dse, Radiatin Status, and Leukemia Incidence per Study N. f Patients Planned Cumulative Receiving N. f Study N. f Dse f Dxrubicin Planned Cumulative Planned CTX DI, Planned Dse Radiatn Stats Leukemia N. Patients (mg/m 2) Dse f CTX (g/m 2 ) (mg/m 2 /wk) N. % Yes N Cases ' 2.8-4t t 'Patients with T2NO r T3NO disease and 0 t 3 psitive lymph ndes (n = 1551 received 300 mg/m 2 dxrubicin; all thers (n = 179) received 400 mg/m 2 dxrubicin. Tw patients with unknwn lymph nde status were nt assessable. ta ttal f 138 f 155 patients received, as planned, a cumulative dse f CTX f 2.8 g/m 2 ; 152 f 179 patients received, as planned, a cumulative dse f CTX f 4 g/m 2. tsixty-five patients treated befre 1980 had chemtherapy fr 24 mnths, with planned cumulative CTX dses f 17 g/m 2 ; 21 patients received CTX as planned; 109 patients treated after 1980 had chemtherapy fr 9 mnths, with planned cumulative CTX dses f 4.5 g/m 2 ; 95 received cumulative CTX as planned. Fifty-ne patients cntinued after surgery with the same preperative regimen and received the planned cumulative CTX dse f 5.8 g/m 2 ; 135 patients received CTX nly in the preperative regimen and received a cumulative CTX dse f 2.05 g/m 2.

7 2728 DIAMANDIDOU ET AL E a) C 3 CTX higher dse = 2% (95% CI, %) CTX lwer dse = 1.3% (95% CI, %) p = 0.53 l = _ ht~geqpse N=1020 lg er se =. 0 0 Fig 2. Estimated rates f leukemia fr patients in the higher and lwer CTX dse grups (P =.53). C a- q c 0. d _~ _~~~~~. _._.., -... I 1 I Mnths frm Start f FAC 120 agents. Alkylating agent-related leukemic cnditins represent a separate entity in the spectrum f acute leukemias. 26 They cnstitute apprximately 10% f acute myelgenus leukemias (AMLs) and have distinct characteristics.. l -4 Apprximately half f the patients present with MDS, and 55% f MDS cases subsequently transfrm int AML.' 2 " 9 The clinical picture includes a smldering r preleukemic phase. There is strng assciatin with chrmsme 5 and/r 7 abnrmalities, and the respnse t chemtherapy is pr. 1 ' 14 An increase in the ccurrence f treatment-related leukemias has been recgnized in patients with early breast cancer wh received alkylating agents as adjuvant chemtherapy ' Chemtherapy regimens that include melphalan have been assciated with a higher risk f leukemia than thse that include CTX. 4 ' 5 ' 32 The leukemgenic ptential f the alkylating agents is influenced by the cumulative dse f the alkylating agent, the DI, and the duratin f treatment. 4 5 ' 21 ' 33 Recently, Curtis et a1 5 reprted that the relative risks (RRs) fr leukemia in patients wh received a cumulative CTX dse f 20,000 t 29,999 mg and 30,000 mg were 4.7 and 9.4, respectively; these are statistically significantly higher than the RRs f 1.5 and 2.5 fr patients wh received less than 10,000 mg and 10,000 t 19,999 mg, respectively. The same investigatrs pinted ut that the RR f leukemia was significantly increased in relatin t the duratin f treatment: 1.2 fr less than 12 mnths versus 7.1 fr 18 mnths. Hwever, the cumulative CTX dse was the strngest independent determinant f leukemia risk in that study. These bservatins agree with ur results regarding the rle f cumulative CTX dse in leukemia risk. CTX has largely replaced melphalan in adjuvant chemtherapy fr breast cancer tday, and it is given at lwer dses and fr shrter perids than in the past. This likely reflects the results f recent reprts 781 ' that did nt shw a significant leukemia risk frm adjuvant CTX-based chemtherapy. 6 l0 Patients with breast cancer wh were treated with cmbinatin raditherapy and chemtherapy have been fund t have a significantly higher risk f leukemia in sme, 5 ' but nt all studies. 7 Curtis et al 5 reprted a twfld increase in the risk f leukemia after reginal raditherapy, with a sevenfld increase in risk with average bne marrw dses f greater than 9 Gy. These results are cnsistent with ur reprted risk f leukemia in patients treated with cmbined mdality chemtherapy and raditherapy, 2.5 versus 0.5 fr chemtherapy alne. Several recent studies 8 ' 5-24 have reprted an increased incidence f AML fllwing chemtherapy with tpismerase-ii inhibitrs, including anthracyclines. These patients d nt have trilineage dysplasia in the bne marrw, the latency perid is usually shrt (typically 1 t 3 years), there is a shrt r undetected preleukemic phase, and the patients usually present with vert acute leukemia, mst ften with an M4 r M5 French-American-British (FAB)

8 LEUKEMIA IN BREAST CANCER PATIENTS TREATED WITH FAC 2729 subtype and typically with cytgenetic abnrmalities that invlve chrmsme llq23. The leukemgenic activity f tpismerase-ii inhibitrs may be enhanced by cncurrent treatment with alkylating agents and cisplatin,' 53 6 and the greatest risk f treatment-related leukemia may ccur in patients wh receive higher dses f bth alkylating agents and tpismerase-ii inhibitrs. 37 Hwever, in ur study ppulatin treated with dxrubicin- and CTXbased chemtherapy, nne f the patients had an llq23 chrmsmal abnrmality. The use f standard adjuvant chemtherapy fr breast cancer has been shwn in a number f randmized trials t increase survival. Thus, fr many wmen, the benefit f these treatments in prlnging life exceeds the risk f leukemia demnstrated in this and ther published studies. Alkylating agents, given alne r in cmbinatin with tpismerase-ii inhibitrs, cisplatin, and/r raditherapy, have been shwn in several studies t be leukemgenic. 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