Reprintedfrom
`
`Volume 15, Number 6
`
`June 1, 1997
`
`JOURNAL OF
`CLINICAL
`
`ONCOLOGY
`
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`Niltitmnl Cancer Institute lllCiInnmI Cllnlctll Trill: Crimp. Bruits! Cum’cr Sit: Grunp.
`
`ASCO_JCO
`
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`Ascga‘
`
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`[Vin/ring a world ol'tii/fln‘cnrc in cancer (arc
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`IPR2017-01122
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`

`

`Randomized Trial of Cyclophosphamide, Methotrexate,
`and Fluorouracil Chemotherapy Added to Tamoxifen as
`Adjuvant Therapy in Postmenopausal Women With
`Node-Positive Estrogen and/or Progesterone Receptor-
`Positive Breast Cancer: A Report of the National Cancer
`Institute of Canada Clinical Trials Group
`
`By Kathleen l. Pritcharcl, Alexander H.G. Paterson, Sheldon Fine, Nancy A. Paul, Benny Zee, Lois E. Shepherd,
`Hakam Abu-Zahra, Joseph Ragaz, Margaret Knowling, Mark N. Levine, Shall Verma, Daniele Perrault,
`P.L David Wolde, Vivien H.C. Bramwell, Mate Poljicolr, Norman Boyd, David Warr, Brian D. Norris, David Bowman,
`George R. Armitage, Harold Weizel, Robert A. Buckman, and the National Cancer Institute at Canada Clinical Trials
`Group Breast Cancer Site Group
`
`Pur ose and Methods: By the mid 1980s, tamoxifen
`alone was considered standard adiuvant therapy for
`postmenopausal women with node-positive, estrogen
`receptor (ER)- or progesterone receptor (ngl-positive
`breast cancer. From 1984 through 1990, 705 eligible
`postmenopausal women with node-positive, ER- or ng-
`positive breast cancer were randomized to a National
`Cancer Institute of Canada Clinical Trials Group (NCIC
`CTG) study that compared tamoxifen 30 mg by mouth
`daily for 2 years (TAM) versus TAM plus chemotherapy
`with all-intravenous cyclophosphamide 600 mg/m ,
`methotrexate 40 rug/m2, and fluorouracil 600 mglm2
`given every 21 days for eight cycles (CMF).
`Results: There were no significant differences in over-
`all survival, recurrence-free survival, locoregional recur-
`
`rence-free survival, or distant recurrence-free survival
`between the two treatment arms. However, there was
`significantly greater severe toxicity, which included ler
`koponia (P < .0001), nausea and vomiting [P < .0001),
`and thromboembolic events {P < .0001), as well as sig-
`nificantly more mild or greater toxicity, which included
`thrombocytopenia [P = .04), anemia (P = .02), infection
`(P = .0004), mucositis (P: .0001), diarrhea (P = .0001),
`and neurologic toxicity (P = .006], in women who re-
`ceived TAM plus CMF.
`Conclusion: The addition of CMF to TAM adds no ben-
`efit and considerable toxicity in this group of women.
`J Clin Oncol 15:2302-231 I. © 1 997 by American So-
`ciety of Clinical Oncology.
`
`Y THE MID 19808, chemotherapy had become stan-
`dard adjuvant therapy for node-positive premeno-
`pausal women,"3 while tamoxifen was the usual recom~
`mendation for many postmenopausal women with breast
`cancer.3""6 Tamoxifen‘s utility in women with tumors to-
`tally negative for estrogen receptor (ER) and progesterone
`receptor (PgR) remained (:ontrovei-sial,3""6 and its role in
`node-negative women was not established at that time.3
`However, it was, and still is by many today, considered
`
`the treatment of choice for node-positive postmenopausal
`women with ER- or PgR-positive breast cancer following
`primary therapy with surgery with or without breast irra-
`diation?7 The role of cytotoxic therapy in postmeno»
`pausal women was controversial in the mid 1980s and
`has remained so,“ despite more recent suggestions of its
`efficacy?“
`in
`Thus,
`in 1984, we began the trial reported here,
`which nodepositive, ER— or PgR—positive women follow“
`
`
`
`From the Torunto—Surmybrook Regional Cancer Centre, Ontario
`Cancer Treatment and Research Foundation (OCTRF), University
`of Toronto: Ontario Cancer Institute; Toronto Hospital, Toronto:
`Tom Baker Cancer Centre; University of Calgary, Calgary; Credit
`Valley Hospital, Mississauga; National Cancer Institute of Canada
`Clinical Trials Group Central Office, Queen ’3 University, Kingston;
`Windsor Regional Cancer Centre, OCTRF, Windsor; Britixh Calum-
`bia Cancer Agency and University of British Columbia, Vancouver;
`Hamilton Regional Cancer Centre, OCTRF; McMarter University,
`Hamilton; Ottawa Regional Cancer Centre, OCTRF.‘ University of
`Ottawa and Ottawa Civic Hospital, Ottawa: Plummer Memorial
`Hospital, Sault Ste Marie; London Regional Cancer Centre, OCTRF:
`University of Western Ontario, London; Hépital Notre»Dame, Uni—
`versity of Montréal. Montreal; British Columbia Cancer Agency;
`Frarer Valley Cancer Centre, Surrey: Health Sciences Centre, Uni—
`
`versity of Manitoba; Manitoba Cancer Foundation, Winnipeg; Sas-
`katoon Cancer Centre, Saskatchewan Cancer Foundation: Univer—
`sity of Saskatchewan, Saskatoon, Canada.
`Submitted July 11, 1996; accepted February 13, 1997.
`Supported by the National Cancer institute of Canada, To-
`ronto,
`the Medical Research Council of Canada, Ottawa, and
`Zeneca Pharma Inc (formerly ICI Pharma). Mississauga, Can-
`ado.
`Address repprini requests to Kathleen I. Pritchard, MD, Head,
`Medical Oncology/Haematology, Toronto—Sunnybrook Regional
`Cancer Centre and Sunnybrook Health Science Centre, University
`of Toronto, 2075 BayviewAve, Toronto, Ontario, Canarm M4N 3M5;
`Email kathyjritchardéioctrfomca.
`© 1997 by American Society of Clinical Oncology.
`0732-183X/97/I506-000633.00/0
`
`2302
`
`Journal of Clinical Oncology, Vol 15, No 6 (June), 1997: pp 2302-23l l
`
`
`
`

`

`CMF ADDED TO POSTMENOPAUSAL ADJUVANT TAMOXIFEN
`
`2303
`
`ing primary surgery with or without breast irradiation
`were randomly allocated to receive tamoxifen 30 mg daily
`for 2 years (TAM) or TAM plus six cycles of chemother-
`apy with intravenous cyclophosphamide, methotrexate,
`and fluorouracil (CMF). a standard cytotoxic regimen of
`the time. We have previously published preliminary re~
`suits from this trial, including a report of an unexpectedly
`high level of thromboembolic events in the TAM plus
`CMF arm‘“5 and preliminary results of the major end
`points, disease-free and overall
`survival,
`in abstract
`form.”17 However, diis represents the first full report of
`the major outcomes of the trial, which completed accrual
`in December 1990.
`
`surgery. Approval of the trial protocol by a local human investiga-
`dons committee was performed in each center and in the data coordi-
`nating center.
`
`Treatment Regimens
`Tamoxifen was given in a dosage of 30 mg by mouth daily for
`2 years, while CMF was given concurrently with tamoxifen, all
`intravenously in doses of cyclophosphamide 600 mg/mz, methotrex-
`are 40 mg/m’, and fiuorouracil 600 mym2 bodysurface area every
`21 days for 8 cycles. CMF doses were reduced to 50% if the neutro~
`phi] count was less than 1,500/uL but a 1.000/nL, or the platelet
`count was less than 100,000/nL but 2 75,000/pL at the time that
`course was due. If the neutrophil count was less than LOOO or the
`platelet count less than 75,000, no chemotherapy was given until
`both counts reached acceptable levels.
`
`PATlENTS AND METHODS
`
`Statistical Methods
`
`Study Design
`This study is a randomized multicenter clinical trial designed and
`performed by the National Cancer Institute of Canada Clinical Trials
`Group (NCIC CTG) Breast Cancer Site Group (BCSG). The fourth
`in a series of trials in women with breast (mammary) cancer, it is
`therefore called MA.4. Randomization was performed by telephon-
`ing the NCIC CTG data coordinating center. Patients Were stratified
`according to ( 1) method of primary treatment (modified radical mas-
`tectomy (MRM]. partial mastectomy [PM], or PM plus breast radia-
`tion); (2) number of involved axillary nodes (one to three v 2 four);
`(3) time since menopause (< 5 years v 2 5 years); and (4) level of
`receptor assay (both between 10 and 30 fmollmg cytosol, either ER
`or PgR 2 30 {moi/mg). Patients were randomly alloeated with equal
`probability to one of the two treatment arms with TAM or TAM
`plus CMF using a blocked randomization procedure. A sample size
`of 500 patients was originally calculated to give an 80% power to
`detect a hazards ratio of 1.5 with respect to overall survival using
`a one-sided S%-level test, but this sample size was subsequently
`increased to 700 patients to detect a hazards ratio of 1.38 under the
`same conditions.
`
`Patient Eligibility
`Women were required to be postmenopausal (last menstrual period
`at least 6 months before surgery. both ovaries removed. or hysterec-
`tomy and age > 50 years) and to have had the following: (1) com-
`pletc removal of the primary tumor with histologically clear margins
`and at least a level 2 axillary node clearance (up to the axillary
`vein); (2) histologic examination of at least four axillary nodes; (3)
`at least one axillary node microscopically involved with breast can—
`cer; and (4) ER or PgR a 10 final/mg of tissue cytosol. Metastases
`were excluded by a panel of liver function tests, serum calcium and
`alkaline phosphatase levels, carcinoembryonic antigen (CEA) level,
`chest radiograph. and nuclear bone scan with radiographs of suspi—
`cious areas. Patients with clinical stages Tl-SNO-IMO were consid—
`ered eligible. Criteria of ineligibility included a serum creatinine
`level greater than 1.5 mg/lOO mL, and any previous malignancy
`excepting basal cell or squamous cell carcinoma of the skin, or
`carcinoma of the cervix, thyroid, uterus, or colon, treated and pre-
`sumed cured more than 5 years previously. N0 radiation was permit—
`ted except to the partially removed breast. Women were required to
`be in generally good health apart from the diagnosis of breast cancer
`and to be randomized and to begin therapy within 10 weeks of
`
`All eligible patients were included in this analysis. The data set
`for the final analysis was frozen on April 15, 1994. Recurrence-free
`survival. locoregional recurrence-free survival, distant recurrence-
`free survival, and overall survival were chosen as the major study
`end points. Recurrence’free survival was assessed using time of
`first recurrence as an end point. In assessing patterns of recurrence,
`recurrences within 30 days were considered simultaneous. An analy-
`sis of first breast recurrence was perfonned on the 247 patients who
`had received partial mastectomy with or without breast radiation.
`Sites of distant recurrence were further subdivided into first bone
`recurrence, first lung recurrence, and first liver recurrence. When
`two or more recurrences were determined simultaneously, the more
`prognostically serious site was taken to be the site of first recurrence.
`The order used was breast, chest wall/nodes, and distant (bone, lung,
`and liver). Dating of recurrence was based on the first date of onset
`of a sign, but never of a symptom. The date of first detection of a
`palpable lesion was acceptable only when the diagnosis of tumor
`involvement was subsequently established. The diagnosis of recur-
`rent disease by radiographs or scans was also dated from the first
`positive record, even if that was determined in retrospect.”
`Overall survival and recurrence—free survival rates were analyzed
`by the Kaplan»Meier method.” Log-rank statistics were used to test
`the difference between the two treatment ElnTlS. Multivariate analyses
`of prognostic factors for each of the major end points were performed
`and incorporated a variety of patient and tumor characteristics, which
`included the following: (1) center accrual size (5 25 v > 25 pa/
`tients); (2) age (continuous variable [cont])‘, (3) Kamofsky perfor—
`mance status (cont); (4) number of years since menopause (cont):
`(5) prior hormone replacement therapy (never v received > 6 months
`before study entry v received until < 6 months before study entry);
`(6) method of primary treatment (MRM v PM v PM plus breast
`radiation); (7) clinical stage (I v II v III); (8) pathologic stage (H v
`III); (9) receptor levels (both < 30 fmol/mg v one 2 30 fmol/mg);
`(10) nodal status (one to three v 2: four positive); (l 1) height (cont);
`(12) weight (com); and (13) auxomctn'c index, a clinical index of
`rate of growth of the tumor, which was based on an assessment of
`clinical progression over time (no breast change and duration > 12
`weeks v no breast change and duration 5 12 weeks v breast change
`and duration > 12 weeks v breast change and duration < 12
`weeks)?0 A Cox regression model was used to assess prognostic
`variables.21 Treatment effect after adjustment for important prognos-
`tic factors was estimated within the final Cox model. The propor-
`tional hazards assumption was validated by plots of cumulative haz-
`
`
`
`
`
`
`
`

`

`2304
`
`PRITCHARD ET AL
`
`Table 1. Pollen? Characteristics
`Treatment Arm
`TAM [n = 352)
`TAM + QAF (n = 3531
`Both (n = 705)
`No
`%
`No
`%
`Factor
`No
`%
`
`
`224
`32
`96
`
`166
`186
`
`73
`101
`1 40
`32
`6
`
`207
`1 18
`27
`
`1 2
`142
`198
`
`11
`92
`238
`1
`1
`
`14
`299
`39
`
`63 6
`9 1
`27 3
`
`47 2
`52 8
`
`20 7
`28 7
`39 8
`9 1
`1 7
`
`58 8
`33 5
`7 7
`
`3 4
`40 3
`56 3
`
`3 1
`26 2
`67.6
`3 1
`
`4 0
`84 9
`11 1
`
`234
`32
`87
`
`174
`179
`
`76
`91
`151
`31
`4
`
`214
`106
`33
`
`15
`162
`176
`
`7
`99
`224
`23
`
`8
`316
`29
`
`66 3
`91
`246
`
`493
`50 7
`
`21.5
`25 8
`42 8
`8 8
`1
`1
`
`60 6
`300
`94
`
`4 2
`45 9
`49 9
`
`20
`28 0
`63 5
`65
`
`2 3
`89 5
`B 2
`
`Primary surgery'
`MRM
`PM
`PM + rodlohon
`Receptor slotus'
`ER and PgR < 30 FmOI/mg
`ER or PgR z 30 fmol/mg
`Years postmenopausal‘
`:5 5
`5'1 0
`1 0-20
`20-30
`2 31
`No of positive nodes'
`1-3
`4'9
`2 10
`No 01 nodes examined
`4
`5'9
`2 10
`Clinical stage
`Unknown
`l
`11
`111
`Pathologlc stage
`Unknown
`11
`111
`Auxamelnc clossahcohon
`10 1
`71
`77
`27
`12 5
`44
`No change > 12 weeks
`50 8
`358
`52 1
`184
`A9 4
`174
`No change 5 12 weeks
`20 1
`142
`19 8
`70
`20 5
`72
`Change > 12 weeks
`
`
`
`2O 4 13472 19 0
`Change < 12 weeks
`62
`17 6
`'Strohfied before randomization
`
`458
`64
`183
`
`340
`365
`
`149
`192
`291
`63
`10
`
`421
`224
`60
`
`27
`304
`374
`
`18
`191
`462
`3A
`
`22
`615
`68
`
`65 0
`9 1
`25 9
`
`48 3
`51 7
`
`21.1
`27 2
`41 3
`8 9
`1 4
`
`59 7
`31 8
`8 5
`
`3 8
`43 I
`53 1
`
`2 6
`27 1
`65 5
`A 8
`
`3 l
`87 2
`9 1
`
`ards functions Treatment covariate interactions were also tested
`under the Cox model
`Toxtcxty data were collected usrng the Eastern Cooperative Group
`(ECOG) toxtcny cntena and analyzed usmg x2 tests
`
`RESULTS
`
`Randomization and Eligibility
`
`Seven hundred thirty—31x women were randomized to
`one of the two treatment arms between January 1984 and
`December 1990. Of these 736 women, 31 (4.2%) were
`ineligible for reasons that included incomplete surgery (n
`= 11), metastatic disease (11 = 4),
`inadequate staging
`information (n = 3), involved margins (n = 3), receptor
`status unknown or negative (n = 3), clinical stage T4 (n
`= 2). premenopausal status (n = 2), abnormal renal func-
`
`tion (n = 1), randomized more than 10 weeks after sur-
`gery (n = l), and other serious illness (11 = 1). Of the
`remaining 705 eligible women, 352 were randomized to
`TAM alone and 353 to TAM plus CMF.
`Patient Characteristics
`
`The two treatment arms were comparable according
`to their baseline characteristics (Table 1). Patients were
`stratified according to numbers of years postmenopausal,
`primary surgery, receptor status, and number of positive
`nodes before randomization, and so the distribution of
`these factors was well balanced between the two treat-
`ment arms. Other potential prognostic factors, for which
`there was no stratification before randomization, are also
`well balanced between the two treatment arms (Table 1).
`
`
`
`
`
`
`
`

`

`CMF ADDED TO POSTMENOPAUSAL ADJUVANT TAMOXIFEN
`
`2305
`
`Table 2. Toxicilies by Treatment Arm
`Treatment Arm
`
`TAM + CMF
`TAM (n ’- 352)
`(n — 353]
`
`Toxicity/Grade
`No.
`96
`No.
`9":
`Leukopenia'
`l
`2
`3
`4
`Thrombocylopeniu‘l’
`1
`2
`3
`Anemia?
`l
`2
`3
`Hemorrhage§
`l
`2
`Infection?
`1
`2
`3
`4
`Vascular”
`l
`2
`3
`4
`5
`Nausea & vomiting"
`1
`2
`3
`Mucositisfi
`l
`2
`3
`
`19
`0
`0
`O
`
`l
`0
`l
`
`0
`O
`0
`
`0
`0
`
`l
`4
`l
`0
`
`0
`A
`l
`4
`0
`
`24
`6
`O
`
`0
`0
`0
`
`5.4
`O
`0
`0
`
`0.3
`O
`0.3
`
`0
`O
`0
`
`O
`0
`
`0.3
`l .l
`0.3
`0
`
`0
`l .l
`0.3
`l .l
`0
`
`6.8
`l .7
`O
`
`0
`0
`O
`
`43
`80
`91
`79
`
`24
`7
`l
`
`40
`6
`l
`
`4
`l
`
`20
`l 7
`3
`4
`
`2
`l 2
`24
`7
`3
`
`811
`135
`39
`
`39
`22
`4
`
`l 2.2
`22.7
`25.8
`22.4
`
`6.8
`2.0
`0.3
`
`l l .3
`l .7
`0.3
`
`l .l
`0.3
`
`5.7
`4.8
`0.9
`l . l 3
`
`0.6
`3.4
`6.8
`2.0
`0.8
`
`23.8
`38.2
`l l . l
`
`l l . l
`6.2
`l .l
`
`Treatment Compliance
`
`The majority (84%) of women discontinued tamoxifen
`either at the end of 2 years (69.5%) or at disease recur-
`rence (14.7%), as directed by the protocol. Only 4% dis-
`continued tamoxifen because of toxicity: 5.6% in the
`TAM plus CMF arm and 2.3% in the TAM-alone arm.
`Forty-nine (7.0%) were still receiving tamoxifen, in viola-
`tion of the protocol, at the time of this analysis. Of these,
`19 were in the TAM plus CMF arm (5.6%) and 30 were
`in the TAM—alone arm (8.7%) (P = .138).
`Two hundred ninety-six women (84%) completed eight
`cycles of therapy. Ninety—three percent of patients had
`received at least 85% of the correct dose, taking into
`consideration the dose modifications described in the pro-
`tocol (predicted dose). However, compliance with chemo-
`therapy was inferior in the early part of the study. The
`proportions of patients who received less than 85% of
`the total predicted dose for eight cycles in 1984, 1985,
`and 1986 were 19%, 11%, and 10%, respectively, com-
`pared with less than 5% from 1987 to 1990. However,
`overall survival and recurrence-free survival rates for pa-
`tients entered between 1984 and 1986 versus those en-
`tered between 1987 and 1990 were not significantly dif-
`ferent (P = .54; P = .58). A Cox regression model on
`the rank of the date of entry for patients was used to
`assess the effect of early noncompliance problems. They
`were not significant with respect to overall and/or recur-
`rence-free survival (P = .51; P = .60).
`
`Toxicity
`
`Table 2 lists worst toxicities by treatment arms. Patients
`in the TAM plus CMF arm had a significantly higher
`incidence of severe or worse (grade 2 3) toxicities, which
`included leukopenia (48% v 0%; P < .0001), nausea and
`vomiting (11% v 0%; P < .0001), and vascular events
`(10% v 1%; P < .0001). Significantly higher incidences
`of more than mild (grade 2 2) thrombocytopenia (P =
`.04), anemia (P = .02), infection (P = .0004), mucositis
`(P = .0001), diarrhea (P = .0001). and neurologic toxicity
`(P = .006) were also found in the TAM plus CMF arm.
`There was also significantly more hemorrhage (P = .06)
`and renal damage (P = .03) of any grade in the TAM
`plus CMF arm. Deaths due to toxicity alone included one
`from pulmonary embolism and one from a cerebrovascu—
`lar accident (CVA). Both occurred in patients randomized
`to TAM plus CMF, although one patient never actually
`received CMF, while one received only one course of
`CMF and did not develop the CVA until 14 months later.
`Both were still receiving tamoxifen at or within days of
`the time of the adverse event. Deaths related to toxicity
`and to breast cancer involved the occurrence of a deep-
`
`‘P< .0001 (0-1 v 2+ or 0-2 v 3+).
`TP = .04 (0-1 v 2+).
`tP = .02 (0-1 v 2+),- P= .0001 (o v 1-3).
`§P= .06 (o vl+).
`1w = .0004 (0-1 v 2+),- P = .069 (0-2 v 3+).
`”P <.0001(0»)v 2+ or 072’ v3+).
`"P < .0001 (0-1 v2+ or 0-2 v3+].
`‘H’P < .000] (0‘1 v2+).
`
`vein thrombosis followed by a gastrointestinal hemor~
`rhage in one patient and a CVA in another. Both patients
`were randomized to the TAM plus CMF arm, but both
`had completed CMF a 1 year before the adverse event
`occurred. The patient who developed a CVA was still
`receiving tamoxifen at the time of the adverse event,
`while the other had discontinued tamoxifen a few months
`
`earlier. Twenty—eight second malignancies were reported
`
`
`
`
`
`

`

`2306
`
`PRITCHARD ET AL
`
`Table 3. Second Malignancies
`Treatment ArmWW
`TAM
`TAM + CMF
`Tomi
`
`%
`No.
`%
`Site
`No.
`%
`N0.
`
`92
`None
`325
`92
`326
`651
`92
`3
`Breast
`l 2‘
`4
`TO
`22'
`3
`0.9
`Skin
`5
`l .4
`3
`8
`l . 1
`0.5
`Lung
`2
`0.5
`2
`4
`0.5
`0.2
`Colorectol
`3
`0.5
`l
`4
`0,5
`0.9
`Ovary
`0
`O
`3
`3
`0.4
`0.5
`Bladder
`0
`o
`2
`2
`0.3
`0.5
`Endometriol
`l '
`0.3
`2
`3'
`0.3
`0.5
`Biliary Tree
`0
`0
`2
`2
`0.3
`0.5
`Other
`5
`l .4
`2
`7
`0.9
`Total
`
`353352 705
`
`'One patient first developed a second breast carcinoma and then an endometrial carcinoma.
`
`in the TAM and 27 in the TAM plus CMF arms. Of these,
`12 and 10 were second breast primary tumors, while 16
`and 17 were other new primary tumors in the TAM and
`TAM plus CMF arms, respectively. Further details of
`these second primary tumors are listed in Table 3.
`
`Recurrence—Free Survival
`
`There were 143 (41%) and 142 (40%) recurrences in
`the TAM plus CMF and TAM~alone arms, respectively.
`The patterns of sites of first recurrence, classified as pre—
`viously described (Methods), are listed in Table 4. They
`are not different between treatment arms. The relative
`risk of recurrence for the TAM plus CMF compared with
`the TAM~alone arm was 0.97 (95% confidence interval
`[CI], 0.77 to 1.23). The 5-year recurrence—free survival
`rates for the TAM plus CMF and TAM—alone arms were
`64% and 61% (3% difference; 95% CI, ‘5% to 11%).
`Kaplan-Meier curves for recurrence-free survival are
`shown in Fig 1. There is no significant difference between
`the two arms (P 2 0.80).
`Cox proportional hazards model showed that younger
`patients (P = .0096), patients with four or more involved
`nodes (P = .0001), patients with both receptor levels
`between 10 and 30 fmol/mg (P = .0001). and patients
`
`Table 4. First Recurrence: by Treatment Arm
` Treatment
`TAM
`TAM + CMF
`
`in = 352’ [n -K 353]Site PM
`
`
`l l
`5
`Breast
`.31
`Locoregionoi
`45
`43
`.92
`Distant
`86
`94
`.73
`
`who did not receive PM plus radiation (ie, those who
`received either mastectomy or PM without radiation) had
`an inferior recurrence—free survival (P = .0085). Auxome—
`trio index was significant in univariate analysis, but not
`in the Cox regression model. Treatment effect of TAM
`plus CMF versus TAM alone was not significant after
`adjusting for these prognostic factors (P = .59). The tests
`for interaction between treatment and other prognostic
`factors were not significant.
`
`Breast and Locoregional Recurrence-Free Survival
`
`The patterns of recurrence listed in Table 4 demonstrate
`no statistically significant difference in numbers of breast
`recurrences or of locoregional recurrences between treat-
`ment arms. First breast recurrences, of course, can only
`be seen in the patients who received either PM or PM
`plus breast radiation as primary therapy. There were 11
`and 17 first breast recurrences and 53 and 59 first locore-
`gional recurrences in the TAM plus CMF and TAM—
`alone arms, respectively, if we include those determined
`simultaneously with other types of recurrence. After cor-
`recting for simultaneous recurrence in a competing—risk
`model as outlined earlier (see Methods), the TAM plus
`CMF and TAM-alone arms had six and 11 first breast
`recurrences and 43 and 45 first locoregional recurrences,
`respectively. The Kaplan—Meier curves that compared
`first breast recurrence (P = .309) and those that compared
`first locoregional recurrence (P = .72) were not signifi—
`cantly different. The relative risk of first breast recurrence
`for TAM plus CMF versus TAM alone was 0.60 (95%
`CI, 0.22 to 1.62). The relative risk of first locoregional
`recurrence was 0.93 (95% CI, 0.61 to 1.41) for TAM plus
`CMF versus TAM alone.
`A Cox proportional hazards model showed that patients
`
`
`
`142 143Total .80M
`
`
`
`
`
`

`

`CMF ADDED TO POSTMENOPAUSAL ADJUVANT TAMOXIFEN
`
`2307
`
`Fig I. Kuplan-Meier curves
`recurrence-free survival by
`of
`treatment arm {P = .30) (TAM,
`...; TAM plus CMF, ~).
`
`
`
`PercentageAlive
`
`
`
`0.0
`353
`352
`
`1.0
`351
`350
`
`2.0 3-0 4.0 5-0 6.0 7.0 8.0 9.0 10.0
`340
`315
`242
`178
`112
`Ti
`36
`6
`O
`333
`312
`236
`185
`118
`77
`4‘!
`7
`0
`
`Time (Years)
`# A: Rlsk (Arm CT)
`1" At filsk (Arm 1')
`
`who received breast radiation had a lower risk of first breast
`recurrence than those who were treated with PM alone (P =
`.032). The treatment effect of TAM plus CMF versus TAM
`alone on first breast recunence was not significant after ad-
`justment for other confounding factors (P = .22). A Cox
`proportional hazards model for first locoregional recurrence
`showed that younger age (P = .02), four or more involved
`axillary nodes (P = .0001), both receptor levels between 10
`and 30 finollmg (P = .03), and pathologic stage IE1 tumors
`(P = .003) were each associated with a higher risk of locore—
`gional recurrence. Patients who had PM plus breast radiation
`were also significantly less likely to develop loooregional
`recurrence (P = .02). Treatment effect of TAM plus CMF
`versus TAM alone was not significant for locoregional recur—
`rence after adjusting for significant prognostic factors within
`the final Cox model (P = .83). The tests for interaction
`between treatment and other prognostic factors were not sig-
`nificant.
`
`Distant Recurrence-Free Survival
`
`Distant recurrence-free survival was not significantly
`different between the two treatment arms. The relative
`risk of distant recurrence for TAM plus CMF versus TAM
`alone was 1.05 (95% CI, 0.79 to 1.41). A Cox regression
`model showed that four or more involved axillary nodes
`(P = .0001) and low receptor levels (P = .0001) were
`significantly associated with a higher risk of distant recur-
`rence. Patients with PM plus breast radiation had a sig-
`
`nificantly lower risk of developing a distant recurrence
`(P = .023). Systemic treatment effect was not significant
`after adjusting for significant prognostic factors (P = .93).
`There were a total of 146 bone recurrences, 60 lung
`recurrences, and 71 liver recurrences, if we include all
`recurrences even if they occurred simultaneously at multi-
`ple sites. Correcting for simultaneous recurrences in the
`competing—risks model, as outlined earlier (see Methods).
`the numbers of first bone, first lung. and first liver metas-
`tases become 106, 28, and 28, respectively. A Cox propor-
`tional hazards model for first bone recurrence showed
`that four or more involved axillary nodes (P = .0001),
`low (both between 10 and 30 fmol/mg) receptor levels
`(P = .02), and greater patient height (P = .007) were
`significantly associated with a higher risk of first bone
`recurrence. Four or more positive nodes and low receptor
`levels were each significantly associated with a higher
`risk of developing either first lung or first liver recur-
`rences. Treatment effects of TAM plus CMF versus TAM
`alone were not significant for first bone, lung, or liver
`recurrence after adjusting for significant prognostic fac-
`tors (P = .758, P = .84, and P = .34, respectively). The
`tests for interaction between treatment and other prognos—
`tic factors were not significant.
`
`Overall Survival
`
`There were 172 (24%) deaths, 86 in each treatment
`arm, at the time of this analysis. There was no significant
`
`
`
`

`

`
`
`PercentageRecurrence—Free
`
`0')0
`
`.9.O
`
`
`NO
`
`2308
`
`100
`
`PRITCHARD ET AL
`
`80
`
`Fig 2. Kaplon-Meier curves
`of overall survival by treatment
`arm (P = .94,
`(TAM, ---,' TAM
`plus CMF, —).
`
`0.0
`353
`352
`
`1.0
`330
`319
`
`2.0 3.0 4.0 5.0
`306
`264
`200
`132
`288
`254
`192
`120
`
`6.0
`so
`34
`
`7.0 8.0 9.0 10.0
`53
`26
`4
`o
`56
`so
`5
`0
`
`Time (Years)
`vi At Rlsk (Ann CT)
`# At Fllsk (Arm T)
`
`difference between treatment in the proportion of deaths
`from disease. from complications of disease and treat-
`ment, from second malignancies, or from other causes.
`Kaplan-Meier survival curves (Fig 2) are not significantly
`different between the two arms (P = .94). The relative
`risk of death for women in the TAM plus CMF arm
`versus those who received TAM alone was 1.01 (95%
`CI, 0.75 to 1.36). The 5-year survival rates for TAM plus
`CMF versus TAM alone were 82% and 80%, respectively
`(2% difference; 95% CI, —4% to 8%). Cox proportional
`hazards model showed that women with four or more
`nodes involved (P = .0001) and low (between 10 and 30
`fmol/mg) receptor levels (P = .0001) had a significantly
`inferior overall survival rate. Auxometric index was sig—
`nificant in univariate analysis (P = .011), but not in Cox
`model after controlling for other confounding factors (P
`= .088). The tests for interacu'on between treatment and
`other prognostic factors were not significant.
`In summary, the addition of CMF to TAM was not
`significantly beneficial in terms of recurrence-free sur-
`vival, overall survival, or any subset of recurrence-free
`survival (breast. locoregional, or distant recurrence—free
`survival). In the Cox model, four or more nodes and low
`receptor levels were predictive of recurrence;
`locore-
`gional recurrence; distant recurrence;
`liver,
`lung, and
`bone recurrence; and of overall survival. Young age was
`predictive of recurrence and of locoregional recurrence,
`but not of distant recurrence or survival. Pathologic stage
`
`III was predictive of locoregional recurrence, but not of
`overall survival, distant recurrence, or recurrence in gen-
`eral. Patients who had PM plus breast radiation were less
`likely than those who had PM or MRM to develop any
`recurrence (P = .009), locoregional recurrence (P = .02),
`or distant recurrence (P = .02), particularly bone recur—
`rence, but this factor was not predictive for lung or liver
`recurrence or for overall survival. Breast recurrence was
`affected only by the use of breast radiation (P = .032).
`
`DISCUSSION
`
`An early analysis of data from this trial suggested a
`borderline improvement in recurrence-free survival, par-
`ticularly locoregional recurrence-free survival, with the
`addition of CMF to tamoxifen in this group of women.16
`However, with more mature follow-up data, even this
`advantage was no longer seen}7 In this,
`the first full
`analysis of the results of this study, we find no advantage
`in overall survival, progression—free survival, or locore~
`gional or distant progression-free survival.
`Many studies now support the utility of tamoxifen as
`adjuvant therapy in this subset of womenf'g'w'l "22‘2“ as they
`did when we began this trial in 1984.” However, the role
`of chemotherapy in this setting has remained controversial.
`Used alone, it appears to have some benefit, as summarized
`in the results of the Early Breast Cancer Trialists’ over-
`view,‘°'” In that analysis, prolonged chemotherapy produced
`a 13% reduction in the annual odds of death (nonsignificant)
`
`
`
`

`

`CMF ADDED TO POSTMENOPAUSAI. ADJUVANT TAMOXIFEN
`
`2309
`
`and a 24% reduction in the annual odds of recurrence (sig-
`nificant) in women 2 50 years of age. In the same age
`group, tamoxifen produced a reduction of 20% in the annual
`odds of death and of 27% in the annual odds of recurrence
`(both significant). Both of these tamoxifen effects increased
`with increasing ER positivity.”
`Trials of chemohormonal therapy in postmenopausal
`women have had three possible designs. Some, such as
`our own, compared tamoxifen versus tamoxifen plus che—
`motherapy,9"2'13 sometimes with the addition of a no—
`treatment control arm.” Some compared chemotherapy
`versus the same chemotherapy plus tamoxifen,”34 while
`others compared tamoxifen alone versus chemotherapy
`alone versus tamoxifen plus the same chemotherapy,”38
`with”35 or without”38 a no-treatment control arm.
`Trials of tamoxifen added to chemotherapy versus che—
`motherapy alone in the postmenOpausal, node-positive,
`ER—positive group, generally demonstrate, as does the
`overview,'°"' a statistically significant improvement in
`disease-free and overall survival with the addition of ta-
`moxifen.”38 However. trials of chemotherapy added to
`tamoxifen versus tamoxifen alone show much less effect.
`Since the overview analysis of these trials describes a
`signifith 27% reduction in the annual odds of recur-
`rence, but no significant overall survival advantage,‘ ’ it
`is not surprising that the individual trials, most of which
`are summarized in the overview data, show a similar but
`more variable picture. Several, like our own, show no
`recurrence—free or overall survival atdvantage,35'37'38 others
`demonstrate a significant improvement in recurrence-free
`but not overall survival,”36 while some show a significant
`advantage for both.9-‘2"3
`The first of the trials that demonstrated an advantage in
`b