INITIAL - WebHost4Lifemauriciolema.webhost4life.com/rolmm/files/nsabpb15.pdfcomplied with NSABP prerequisites for quality control."' Patient accrual began on October 1, 1984, and was

Two Months of Doxorubicin-Cyclophosphamide With andWithout Interval Reinduction Therapy Compared With 6 Months

of Cyclophosphamide, Methotrexate, and Fluorouracil inPositive-Node Breast Cancer Patients With

Tamoxifen-Nonresponsive Tumors: Results From the NationalSurgical Adjuvant Breast and Bowel Project B-15

By Bernard Fisher, Ann M. Brown, Nikolay V. Dimitrov, Roger Poisson, Carol Redmond, Richard G. Margolese,David Bowman, Norman Wolmark, D. Lawrence Wickerham, Carl G. Kardinal, Henry Shibata, A.H.G. Paterson,

Carl M. Sutherland, Nicholas J. Robert, Phyllis Joyce Ager, Lawrence Levy, Janet Wolter, Timothy Wozniak,Edwin R. Fisher, and Melvin Deutsch

The National Surgical Adjuvant Breast and BowelProject (NSABP) implemented protocol B-15 to com-pare 2 months of Adriamycin (doxorubicin; AdriaLaboratories, Columbus, OH) and cyclophosphamide(AC) with 6 months of conventional cyclophospha-mide, methotrexate, and fluorouracil (CMF) in pa-tients with breast cancer nonresponsive to tamoxifen(TAM, T). A second aim was to determine whether ACfollowed in 6 months by intravenous (IV) CMF wasmore effective than AC without reinduction therapy.Through 3 years of follow-up, findings from 2,194patients indicate no significant difference in disease-free survival (DFS, P = .5), distant disease-free sur-vival (DDFS, P = .5) or survival (S, P = .8) among thethree groups. Since the outcome from AC and CMFwas almost identical, the issue arises concerningwhich regimen is more appropriate for the treatmentof breast cancer patients. AC seems preferable since,following total mastectomy, AC was completed on

INITIAL EVIDENCE to indicate that sys-temic adjuvant chemotherapy could alter the

natural history of patients with primary operablebreast cancer and no evidence of metastaticdisease came from the first randomized clinicaltrial (B-01) conducted by the National SurgicalAdjuvant Breast and Bowel Project (NSABP)."12That study, implemented in 1958, compared theoutcome of patients who received thiotepa on theday of operation and on each of the first 2postoperative days with the outcome of thosegiven placebo. The results indicated that disease-free survival (DFS) and survival (S) could bealtered by chemotherapy and that the response tochemotherapy was heterogeneous. However, thesefindings were, for the most part, ignored becausethey failed to meet physicians' expectations thatall patients would be cured by the therapy. Notuntil 1972 was another major randomized trial

day 63 versus day 154 for conventional CMF; patientsvisited health professionals three times as often forconventional CMF as for AC; women on AC receivedtherapy on each of 4 days versus on each of 84 daysfor conventional CMF; and nausea-control medicationwas given for about 84 days to conventional CMFpatients versus for about 12 days to patients on AC.The difference in the amount of alopecia between thetwo treatment groups was less than anticipated.While alopecia was almost universally observed follow-ing AC therapy, 71% of the CMF patients also hadhair loss and, in 41%, the loss was greater than 50%.This study and NSABP B-16, which evaluates theworth of AC therapy in TAM-responsive patients,indicate the merit of 2 months of AC therapy for allpositive-node breast cancer patients.J Clin Oncol 8:1483-1496. @ 1990 by American Soci-ety of Clinical Oncology.

begun to evaluate the worth of adjuvant chemo-therapy. That trial (B-05), also carried out by theNSABP, compared patients who received mel-phalan (L-PAM), on 5 consecutive days every 6weeks for 2 years with those who had been givenplacebo.3 As was demonstrated with thiotepa, thefindings showed a significant improvement in

From the National Surgical Adjuvant Breast and BowelProject Headquarters, Pittsburgh, PA.

Submitted October 30, 1989; accepted March 26, 1990.Supported by Public Health Service grants from the

National Cancer Institute (NCI-UlO-CA-12027, NCI-U10-CA-37377, and NCI-U10-CA-39086) and by a grant fromthe American Cancer Society (ACS-R-13).

Address reprint requests to the National Surgical Adju-vant Breast and Bowel Project Headquarters, Room 914,Scaife Hall, 3550 Terrace St, Pittsburgh, PA 15261.

@ 1990 by American Society of Clinical Oncology.0732-183X/90/0809-0010$3.00/0

Journal of Clinical Oncology, Vol 8, No 9 (September), 1990: pp 1483-1496 1483

Downloaded from jco.ascopubs.org by ALICIA HENAO URIBE on May 30, 2012 from 201.232.4.133Copyright © 1990 American Society of Clinical Oncology. All rights reserved.

FISHER ET AL

DFS and S among women s 49 years of age whohad been treated with L-PAM. Results of a trialsubsequently conducted in Milan, Italy, in whichwomen treated with a course of cyclophospha-mide, methotrexate, and fluorouracil (CMF)every month for 1 year were compared with anuntreated group of patients, also showed a benefitfrom the chemotherapy.4 A later study by thesame investigators indicated that CMF givenover a 6-month period produced a benefit at leastas good as that obtained from 12 months of thesame therapy.5 Consequently, CMF became themost frequently used adjuvant treatment forpatients with positive axillary nodes.

During the next decade, other major trialsconducted by the NSABP and other investiga-tors throughout the world established convinc-ingly the worth of a variety of multiagent chemo-therapeutic regimens for the treatment of primarybreast cancer. Among the findings obtained fromNSABP studies was evidence to indicate that theadvantage observed from administering tamox-ifen (TAM) with chemotherapy was associatedwith tumor estrogen (ER) and progesteronereceptor (PgR) content as well as patient age andnodal status.6 Consequently, patient populationscould be identified as being either TAM"nonresponsive" or TAM "responsive." Theformer group consisted of all patients aged < 49years and those 50 to 59 years with a tumor PgRless than 10 fmol, regardless of ER. All otherwomen constituted the TAM-responsive group.We have recently reported the worth of usingdoxorubicin (Adriamycin [A]; Adria Laborato-ries, Columbus, OH) in those patient cohorts. Inone NSABP study (B-11), TAM-nonresponsivepatients who received doxorubicin in addition toL-PAM and fluorouracil (PAF) were found tohave a significantly better DFS and S through 6years of follow-up than patients who received thetwo-drug combination without doxorubicin.7 Inanother study (B-16), the use of TAM and short-course Adriamycin-cyclophosphamide (AC) ther-apy (completed in 63 days) resulted in an out-come better than that achieved by TAM alone inpositive-node patients aged > 50 years withtumors responsive to TAM.8

Findings from NSABP studies, as well asthose of others, have generally indicated that if abenefit in DFS is to result from adjuvant chemo-therapy it is apt to become evident in the firstyear or so of follow-up, with the advantage likely

to result from the first few cycles of treatment.Administration of drug beyond that point is morelikely to produce greater toxicity without cer-tainty that a better outcome will result. If furtherbenefit is to be derived from the use of chemother-apy, effort must be directed toward improving onas well as sustaining the initial gain achieved.The present study was designed to determine thebenefit of short-course, intensive chemotherapyadministered after operation both with and with-out reinstituting a different chemotherapeuticregimen 6 months after completion of the initialtherapy.

NSABP clinical trial B-15 was conducted tocompare the worth of 2 months of AC with 6months of conventional CMF in breast cancerpatients considered to be nonresponsive to TAM.A second aim was to determine whether, in thesame patient population, AC therapy followed 6months later by reinduction chemotherapy withparenteral CMF (AC - intravenous [IV] CMF)would be more effective than AC without reinduc-tion therapy. This report provides the initialfindings from the B-15 study.

METHODSWomen with primary operable breast cancer and at least

one histologically verified positive axillary node were eligiblefor this study if they fulfilled specific criteria common to allNSABP clinical trials evaluating systemic therapy" and ifthey were considered to have TAM-nonresponsive tumors.Criteria for TAM-nonresponsiveness, defined in terms of ageand/or PgR status, were derived from a previous NSABPtrial (B-09) in which patients aged : 49 years and those 50 to59 years having tumors with a PgR level less than 10fmol/mg of cytosol protein, regardless of ER status,6 failed torespond any more favorably to a combination of L-PAM,5-FU and TAM (PFT) than to L-PAM and 5-FU (PF) alone.Women aged 50 to 59 years having tumors with a PgR level >10 fmol, regardless of ER, and all patients 60 to 70 yearsof age, regardless of ER or PgR, were defined as TAM-responsive and were assigned to another trial, B-16, theresults of which have been reported elsewhere.8

Tumor specimens were assayed for both ER and PgR levelsby the sucrose density gradient, dextran-coated charcoaltitration with Scatchard analysis, or dextran-coated charcoalwith a single saturating dose. A requirement of the study wasthat ER and PgR be performed in laboratories that hadcomplied with NSABP prerequisites for quality control."'

Patient accrual began on October 1, 1984, and wasterminated on October 14, 1988. Following assignment to thestudy, patients were stratified according to number of positivenodes (one to three, four to nine, 10 or more), quantitativePgR level (< 50 and > 50 fmol), and type of operation (totalmastectomy and axillary dissection, or lumpectomy, axillarydissection and breast radiation). Randomization was per-formed within strata, using a biased-coin approach to ensure

1484


SHORT, INTENSIVE AC IN POSITIVE-NODE BREAST CA

treatment balance within an institution. Patients were random-ized among three treatment arms. Therapy in all three groupswas initiated between 2 and 5 weeks after operation. Patientsin group I received AC therapy: Adriamycin 60 mg/m2 IV,and cyclophosphamide 600 mg/m2 IV, every 21 days for fourcycles. Women in group II received AC therapy in dosesidentical to those administered to women in group I. Sixmonths after the last course of AC chemotherapy, patients ingroup II received IV CMF: cyclophosphamide 750 mg/m2 IVevery 28 days for three cycles, methotrexate 40 mg/m2 IV ondays I and 8 every 28 days for three cycles, and 5-FU 600mg/m 2 IV on days 1 and 8 every 28 days for three cycles.Patients in group III received conventional CMF: cyclophos-phamide 100 mg/m2 by mouth on days 1 through 14 every 28days for six cycles, methotrexate 40 mg/m 2 IV on days 1 and8 every 28 days for six cycles, and 5-FU 600 mg/m2 IV ondays 1 and 8 every 28 days for six cycles.

No dose reduction of Adriamycin or cyclophosphamidewas allowed for patients receiving AC who developed hemato-logic or gastrointestinal toxicity. When hematologic toxicityoccurred, administration of AC was delayed until granulo-cyte counts were 2 1,000 and platelet counts were _ 100,000.When gastrointestinal toxicity was present, the administra-tion of AC was delayed until full dose could be tolerated. Ifpatients required hospitalization because of a septic episode(defined as fever > 38.5 0C and/or evidence of systemicinfection in the presence of a lowered granulocyte count), allsubsequent courses of Adriamycin and cyclophosphamidewere to be given at 75% of the original calculated dose.

For patients receiving parenteral CMF reinduction ther-apy, no dose reduction was permitted in the therapy adminis-tered on day 1. Administration of the three drugs was delayeduntil granulocyte and platelet counts permitted giving a fulldose. If on day 8 the granulocyte count was less than 1,000 orthe platelet count was less than 100,000, day-8 doses wereomitted. For patients who received conventional CMF, if theWBC count was less than 2,500 or the platelet count was lessthan 75,000 on day 1, therapy was delayed until the countsreturned to > 2,500 and > 75,000, respectively, at which time75% of the calculated dose was to be administered, or 100% ofthe dose if the WBC count was > 3,500 and the platelet countwas - 100,000. If on day 8 the WBC count was less than2,500 or the platelet count was less than 75,000, all day-8doses were omitted. Appropriate dose reductions were usedfor gastrointestinal toxicity.

Before January 1985, all patients had total mastectomyand axillary dissection. At that time, findings from NSABPB-06 indicated the efficacy of lumpectomy plus axillarydissection and breast radiation." As a result, patients whounderwent that operative procedure also became eligible for

this trial. (Details of lumpectomy plus axillary dissection andradiation therapy have been described elsewhere."2 ) In thosewomen who received AC (groups I and II), radiation therapywas begun after the fourth cycle of AC when there was noevidence of hematologic toxicity and no later than 4 weeksafter completion of chemotherapy. In patients randomized toconventional CMF (group III), radiation was begun aftercompletion of the first course of CMF when there was noevidence of hematologic toxicity. Administration of thesecond course of CMF was delayed until completion of the 5weeks of radiotherapy.

Data in this study were obtained from 2,194 eligiblepatients with follow-up information (Table 1). An additional124 eligible patients had been randomized but were notincluded in the analyses because they had not been in thestudy long enough to have a follow-up report submitted to theNSABP Biostatistical Center. Only 20 of the 2,338 patientsrandomized were considered ineligible for the protocol. Re-sults of analyses conducted with ineligible patients (seven inthe AC group, seven in the AC - CMF group, and six in theCMF group) included and excluded were essentially thesame; the results presented are with the 20 patients excluded.Reasons for patient ineligibility were multiple: four haddisease that was too far advanced, seven had problems withobtaining tumor ER or PgR analyses, four had too lengthy aperiod between pathologic diagnosis and randomization, twohad prior cancer, two had improper axillary dissection, andone had too long an interval between mastectomy andtreatment. The average time on study for each of the threetreatment groups was 26.2 months. Characteristics of theeligible patients with follow-up data as of December 31, 1988are shown in Table 2. As expected, the attributes used asstratification factors are well balanced across the treatmentgroups; the attributes not used in the stratification are alsowell balanced due to the randomization process.

The percentage of patients who were disease-free, distantdisease-free, or surviving through 36 months after surgerywas estimated by the actuarial life-table method.' 3 In analy-sis of DFS, an "event" is defined as the first documentedevidence of local, regional, or distant recurrence, recurrenceof tumor in the ipsilateral breast following lumpectomy,second primary cancer, or death without recurrence ofcancer. Events for analysis of distant DFS (DDFS) includedistant metastases as a first recurrence or following local orregional metastases, as well as second primary cancer. Foroverall S, death from any cause is the end point of interest.

The statistical significance of the difference between thelife-table distributions by treatment was determined by asummary X2 (log-rank) statistic,l4 with adjustment for thethree stratification variables. All P values relate to the entire

Table 1. Study Information

No. of Patients in Each Treatment Group

Group I Group II Group III Total No.Patient Status AC AC-IV CMF Conventional CMF of Patients

Randomized 781 781 776 2,338Eligible 774 774 770 2,318Eligible with follow-up 734 728 732 2,194

At 2 years 374 368 366 1,108At 3 years 196 201 179 576

Average time on study (months) 26.2 26.2 26.2 26.2

1485


1486

Table 2. Patient and Tumor Characteristics

Group I Group II Group IIIAC AC-IV CMF Conventional CMF

(N = 734) (N = 728) (N = 732)Characteristic* % % %

Age (years)S49 79 77 81

50-59 21 23 19No. of positive nodes

1-3 56 56 564-9 30 30 3010 + 14 15 14

OperationLumpectomy 27 28 27Total mastectomy 73 72 73

Tumor ER (fmol)0-9 46 44 49

10-49 33 35 3450-99 14 13 11100+ 7 8 6

Tumor PgR (fmol)0-9 53 53 55

10-49 17 16 1450-99 9 10 9100 + 21 21 22

Pathologic tumor size (cm)0-2.0 28 28 292.1-5.0 48 46 44> 5.1 8 7 8Unknown 16 19 19

NOTE. From eligible patients with follow-up as of December 31,1988.

*Values are percentage of patients in the treatment groups.

period of observation and are not truncated at 36 months.Two-sided P values below .05 are considered statisticallysignificant. There is adequate power to detect a 10% differ-ence in DFS and a 7% difference in S at 3 years aftermastectomy.

Adjusted curves for DFS, DDFS, and S were computedusing the summary relative odds method"5 with CMF desig-nated as the reference group for the adjusted curves. Thecurves were plotted on a logarithmic scale in which the slopeof the curve represents the rate of failure over time. Multivari-ate analysis using the Cox proportional hazards model' 6 wasundertaken to adjust for prognostic factors and to test forpossible treatment-covariate interactions. There were nosignificant interactions.

The percentage of patients who experienced selected toxic-ities is shown for all eligible or ineligible individuals withtoxicity information on file at the time of analysis. Patientswho experienced more than one grade of a side effect havebeen classified according to their greatest toxicity. Patientswho experienced less toxicity than the selected grades havebeen omitted. Since a different number of courses of therapywas administered to patients in each of the three groups, thenumber of courses associated with a specified toxicity is alsopresented to demonstrate the actual incidence.

The protocol-stipulated amount of each of the drugs to beadministered per patient, as well as the amount actuallyreceived, is expressed as milligrams per square meter. Theprotocol-stipulated dose intensity to be administered to each

FISHER ET AL

patient, as well as the dose intensity of the amount received, isexpressed as milligrams per square meter per month. Inlumpectomy-treated patients who received conventional CMF,analysis of dose intensity took into account the interruption ofchemotherapy to allow for administration of radiation ther-apy. Since no similar interruption occurred following totalmastectomy, data relative to total dose and dose intensity arepresented separately for the total mastectomy and lumpec-tomy patients. For CMF reinduction, the body-surface areaused to calculate total dose and dose intensity was thatdetermined at the time of the first course of reinductiontherapy rather than that determined at the time of randomiza-tion. These analyses were restricted to patients randomized inthe first 3 years of the protocol to allow adequate time forsubmission and processing of treatment information. Theresults are presented as both the median percentage of theprotocol-specified amount of drug received and as percentageof patients who received either > 80% or > 95% of theprotocol-specified dose and dose intensity.

Factors causing total dose to be less than the full amount asspecified by the protocol include treatment failure, discontinu-ance of therapy, protocol-specified omissions due to toxicity,and lack of adherence to protocol specifications. Whenconventional CMF was used, protocol-specified dose reduc-tions due to toxicity could affect total dosage. Such was notthe case, however, when AC or reinduction CMF therapy wasused since no dose reductions due to toxicity were permitted.

Factors affecting dose intensity include protocol-specifieddelays or omissions due to toxicity, lack of adherence toprotocol specifications, and, for conventional CMF, protocol-specified dose reductions due to toxicity. Neither treatmentfailure nor discontinuance of therapy affects dose intensitybecause the dose-intensity measure relates only to the periodof time during which a drug is actually received.

RESULTS

DFS, DDFS, and S

Simultaneous comparison of the three treat-ment groups using life-table analyses through 3years of follow-up indicated no significant differ-ence in DFS (P = .5), DDFS (P = .5), or S(P = .8) among the three groups (Fig 1). Theoutcome of patients who received four courses ofAC therapy given over 63 days was virtuallyidentical to the outcome of patients who receivedsix courses of conventional CMF given over 154days when patients were treated by total mastec-tomy and over 190 days when lumpectomy andbreast radiation was performed. At 3 years, theDFS was 62% for patients who received AC and63% for patients treated with CMF, the DDFSwas 68% for both groups, and the S 83% and82%, respectively. The group of patients whoreceived CMF reinduction therapy 6 monthsafter treatment with AC had a slightly, but notsignificantly, better 3-year DFS (68%) than afterAC alone (P = .5) or CMF (P = .2). No such


1487SHORT, INTENSIVE AC IN POSITIVE-NODE BREAST CA

AC COMPARED WITH AC-pi.v.CMF and Cony. CMF

100-

70-

60-

DISEASE-FREE SURVIVAL

0 AC• AC-i.v.CMF" Conv. CMF

MONTHS O 6 12 18 24 30 36# At Risk

O 734 pts, 167 events 96

8 728 pts, 154 events 115

A 732 pts. 171 events 84

DISTANT DISEASE-FREE SURVIVAL

0

O

A

6 12 18 24 30 36 0# At Risk

734 pts., 132 events 106

728 pts., 127 events 117

732 pts, 141 events 92

SURVIVAL

P=0.8

I II I I I

100

90

80

70

60

6 12 18 24 30 36# At Risk

O 734 pts, 69 deaths 135

* 728 pts, 71 deaths 134

A 732 pts., 73 deaths 113

50

Fig 1. Outcome of patients on AC with and without reinduction IV CMF compared with outcome of patients on conventionalCMF.

difference in DDFS or S was evident. When acomparison of DFS, DDFS, and S was madeamong patients in the three treatment groupstreated by total mastectomy, no significant differ-ence in any of the three outcomes was observed(P = .6, .6, and .9, respectively; Fig 2). Similarfindings were obtained when the comparisonswere made among patients in the three groups

treated by lumpectomy and breast radiation, acircumstance that required that the second andsubsequent courses of conventional CMF bedelayed until completion of the radiation.

Sites of Treatment FailureThe distribution of first sites of treatment

failure in the various treatment groups is pre-

AC COMPARED WITH AC-ei.v.CMF and Conv. CMF

DISEASE FREE SURVIVAL

0 6 12 18

0 535 pts., 128 events* 526 pts., 120 eventA 538 pts., 134 event

TOTAL MASTECTOMY PATIENTS

DISTANT DISEASE-FREE SURVIVAL

24 30 36 0 6 12 18 24 30 36# At Risk # At Risk

8 70 0 535 pts., 102 events 79

s 86 C 526 pts., 101 events 87a 61 A 538 pts., 113 events 65

LUMPECTOMY PLUS RADIATION PATIENTS

o AC* AC-i.v.CMF P=0.8A Conv. CMF

I I I I I IMONTHS 0 6 12 18 24 30 36

# At RiskO 199 pts., 39 events 26C 202 pts., 34 events 29A 194 pts., 37 events 23

0 6 12 18

O 199 pts., 30 events• 202 pts., 26 eventsA 194 pts., 28 events

24 30 36# At Risk

2730

s 27

SURVIVAL

P=0.9

i 6 12 18 24 30 36# At Risk

O 535 pts., 59 deaths 99• 526 pts., 56 deaths 102A 538 pts., 61 deaths 81

6 12 18 24 30 36# At Risk

O 199 pts., 10 deaths 36* 202 pts., 15 deaths 32A 194 pts., 12 deaths 32

100

90

80

70

60

50

10090

80

70

60

50

Fig 2. Outcome of patients according to operative therapy received: total mastectomy or lumpectomy plus breast radiation.

rnr

P=0.5

I I - I II-

1(

%

MONTHS (

100-

90-

80-

70-

60.

E .

P=0.8

i i i i

P=0.5

.

LUMPECTOMY PLUS RADI ION PATIENTS1 *


FISHER ET AL

sented in Table 3. The findings fail to indicate atthis time that one regimen is more effective thananother in reducing the incidence of first treat-ment failure at a particular site.

ToxicityInformation regarding severity of toxicity, ie,

the maximum toxicity per patient, is summarizedin Table 4. For the 1,492 patients treated withAC, the average number of courses received atthe time of compilation of the data was 3.8 of apossible four. For the 509 patients treated withCMF reinduction therapy, the average numberof courses of IV CMF was 2.8 of three. For the739 women treated with conventional CMF, theaverage number of courses received was 5.5 ofthe protocol-required six courses. Myelosuppres-sion was slightly less serious after AC therapythan after CMF, as were nausea without vomit-ing, diarrhea, hemorrhagic cystitis, and weightgain. On the other hand, patients who receivedAC therapy were more likely to experiencevomiting (76%) than were their counterparts onconventional CMF (39%). Vomiting was alsolikely to be more severe in the AC-treatedpatients. Alopecia was more severe following ACthan after conventional CMF. Whereas 92% ofAC-treated patients had hair loss, 71% of those

Table 3. Location of First Site of Treatment Failure

Group IIIGroup I Group II Conventional

AC AC- IV CMF CMF(N = 734) (N = 728) (N = 732)

Site of Recurrence No. No. No.

Local-regional 64 54 61Ipsilateral breast* 6 11 5Chest wall 25 13 14Scar 5 6 6Axilla 7 8 10Supraclavicular node 10 9 12More than one 11 7 14

Distant 92 94 103Opposite breastt 5 10 12Skeletal 40 37 31Respiratory 19 12 20Other 28 35 40

Combinations 7 2 4Local and distant 4 1 2Regional and distant 1 0 2Unknown 2 1 0

Second primary 2 2 2Dead without breast cancer 2 2 1Alive, event-free 567 574 561

"*In patients treated by lumpectomy."tlncludes second cancers.*Except opposite breast

treated with conventional CMF were reported tohave lost some hair. The loss was at least 50% in89% of the patients who received AC and 41% inthose receiving conventional CMF. Only 14% ofthe patients who received reinduction CMF suf-fered that extent of alopecia. No deaths occurredwhile patients were receiving protocol therapy.Three cases of blood dyscrasia were reported, onein each of the three protocol groups (AC alone,AC with CMF reinduction, and conventionalCMF).

Information on the incidence of selected toxic-ities for each treatment regimen, specifically thenumber of courses in which each type of toxicitywas reported per 100 patients receiving thatregimen, is presented in Table 5. Gastric distressduring AC therapy was observed in 290 coursesper 100 patients, in 175 courses per 100 patientsafter CMF reinduction therapy, and in 294courses per 100 patients in those who receivedconventional CMF. Patients experienced nauseawithout attendant vomiting more frequently inthe six-course conventional CMF than in thefour-course AC or three-course CMF reinduc-tion regimens. Vomiting was reported more oftenin the AC regimen. Diarrhea was a more com-mon complaint when conventional CMF wasadministered. Although patients who receive con-ventional CMF are somewhat more likely toexperience neurologic toxicity (eight courses per100 patients v four courses per 100 patients), thedifference is accounted for by grade 1 toxicity(transient incoordination). There is little differ-ence between AC and conventional CMF for theother toxicities shown in Table 5.

Information on courses of therapy delayedbecause of hematologic or gastrointestinal toxic-ity according to the drug combination used issummarized in Table 6. These data relate todelayed courses, regardless of the number ofdelays per course. However, very few courseswere delayed more than 1 week, and delays weremost often the result of hematologic rather thangastrointestinal toxicity. The percentage of-courses delayed and the percentage of patientshaving delayed courses were greatest followingconventional CMF; the fewest delays occurredfollowing CMF reinduction therapy.

Amount of Drug ReceivedThe total protocol dose (milligrams per square

meter) and dose intensity (milligrams per square

1488


SHORT, INTENSIVE AC IN POSITIVE-NODE BREAST CA 1489

Table 4. Severity of Toxicity: Greatest Toxicity per Patient

Group II Group IIIGroup I Reinduction Conventional

AC IV CMF CMF(N = 1492) (N = 509) (N = 739)

% % %

WBCGrade 3 (1,000-1,999) 3.4 5.1 9.4Grade 4 (< 1,000) 0.3 0 0.3

PlateletsGrade 3 (25,000-49,999) 0 0.2 0.3Grade 4 (< 25,000) 0.1 0 0

Nausea and vomitingNausea only 15.5 20.2 42.8Vomiting s 12 hours 34.4 38.9 25.2Vomiting > 12 hours 36.8 16.9 12.0Intractable 4.7 1.0 1.6

Diarrhea> 4 stools/day 2.6 2.6 4.5Hemorrhage with dehydration 0.3 0 0.3Death 0 0 0

AlopeciaThinning < 50% 3.0 23.0 30.8Incomplete > 50% 19.9 8.3 25.5Complete 69.5 5.9 15.1

Cardiovascular-functionalAsymptomatic 0.2 0 0.1Transient 0.1 0.2 0Symptomatic 0.1 0 0Nontreatment responsive 0 0 0Death 0 0 0

PhlebitisSuperficial 0.5 0.2 1.1Deep 0.1 0 0.3Embolism 0.1 0 0.3Death 0 0 0

InfectionSystemic 0.9 0.4 0.3Shock, sepsis 1.5 1.2 0.9Death 0 0 0

Hemorrhagic cystitisMild 0.3 0.4 1.6Severe 0 0 0.1

Weight gain5%-10% 10.6 24.8 27.910%-20% 2.1 12.2 12.0> 20% 1.7 2.0 2.3

Weight loss5%-10% 6.2 5.3 5.710%-20% 1.4 1.8 2.3> 20% 1.0 0.6 0.5

FeverModerate (380C-40"C) 5.1 2.2 3.2Severe (> 40C) 0.4 0.4 0.3

Total no. courses 5,676 1,416 4,068Average no. per patient 3.8 2.8 5.5


FISHER ET AL

Table 5. Incidence of Toxicity


Toxicity AC IV CMF CMF

Nausea without vomiting 84* 64 211Vomiting 206 111 83Diarrhea 39 25 65Stomatitis 54 41 51Neurologic toxicity 4 3 8Skin reaction 10 5 11Fever 10 4 7Infection 16 11 16No. of courses 5,676 1,416 4,068No. of patients 1,492 509 739Courses/patient 3.8 2.8 5.5Courses/regimen 4.0 3.0 6.0

*Number of courses with specified toxicity per 100 patients.

meter per month) of each drug and the medianpercentages received are shown in Table 7. Themedian dose of AC received by the AC-treatedpatients in groups I and II was almost 100% ofthe full protocol-defined dose. In those womentreated by conventional CMF (group III), themedian amount of drug received was about 90%of the full protocol amount, and in those given IVCMF reinduction therapy (group II), the medianamount of drug received was about 98% for eachof the three drugs in the combination. For alldrugs in each of the combinations administered,the median percentage of the protocol dose inten-sity received was approximately the same as thecorresponding median percentage of the totalprotocol dose received. There was little difference

Table 6. Delay in Therapy Administration Because ofHematologic or Gastrointestinal Toxicity


Attribute AC IV CMF CMF

No. of patients withcourse information 1,492* 509 739

No. of courses 5,676 1,416 4,068Delayed courses

No. 342 63 408% 6.0 4.4 10.0

Patients with delayed coursesNo. 233 50 234% 15.6 9.8 31.7

*AC only plus AC portion of AC -- CMF.

in the median percentage of the total dose or doseintensity of the drugs received in the conven-tional CMF combination following either totalmastectomy or lumpectomy plus breast irradia-tion.

More patients on AC therapy received at least80% of the protocol-prescribed amount than didthe patients on CMF reinduction or conventionalCMF therapy (Table 8). There was little differ-ence between CMF reinduction and conventionalCMF at the 80% level. For each drug in eachcombination, the percentage of patients whoreceived > 80% of the protocol-specified doseintensity was approximately the same as thepercentage of patients who received at least 80%of the protocol-specified dose. Patients assignedto AC therapy were less likely to receive 95% ofthe specified dose intensity than 95% of the total

Table 7. Total Protocol Dose and Dose Intensity and Median Percentage ReceivedGroup III

Group I Group II Conventional CMFAC AC - IV CMF TM L + XRT

(N = 558) (N = 556) (N = 413) (N = 142)

Protocol Median % Protocol Median % Protocol Median % Protocol Median %Measurement Amount Received Amount Received Amount Received Amount Received

AC Adria mg/m 2* 240 99.8 240 99.8 - - -mg/m

2/mo: 87 98.9 87 98.3 - - -

AC cyclo mg/m 2 2,400 99.7 2,400 99.6 - -mg/m

2/mo 867 98.9 867 98.7 - - -

CMF cyclo mg/m2 - - 2,250 98.0 8,400 87.6 8,400 88.3mg/m 2/mo - - 813 97.9 1,517 87.0 1,174 89.1

CMF MTX mg/m2 - - 240 99.6 480 91.7 480 92.1mg/m 2/mo - - 87 95.5 87 90.5 67 91.7

CMF 5-FU mg/m 2 - - 3,600 98.4 7,200 90.9 7,200 91.7mg/m 2/mo - - 1,300 93.7 1,300 88.5 1,007 90.8

Abbreviations: Adria, Adriamycin; cyclo, cyclophosphamide; MTX, methotrexate; TM, total mastectomy; L + XRT, lumpectomy plus breastirradiation.

*mg/m 2 = total dose.fmg/m 2/mo = intensity.

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Table 8. Percentage of Patients Receiving Specified Amount of Full Protocol Dose and Full Dose Intensity

Group IIIGroup I Group II Conventional CMF

AC AC - IV CMF TM L + XRTAmount of Drug (N = 558) (N = 556) (N = 413) (N = 142)

Received Drug mg/m 2 mg/m 2/mo mg/m' mg/m 2/mo mg/m' mg/m2/mo mg/m 2 mg/m 2/mo

> 80% AC Adria 89 93 85 89 - - - -AC cyclo 89 92 84 90 - - - -CMF cyclo - - 71 75 64 66 70 70CMF MTX - - 69 70 74 73 77 83CMF 5-FU - - 69 69 71 71 75 76

95% AC Adria 84 66 78 64 - - - -AC cyclo 84 66 77 64 - - - -CMF cyclo - - 65 58 29 27 30 34CMF MTX - - 54 51 41 38 44 44CMF 5-FU - - 55 51 38 32 39 42

NOTE. mg/m 2 = total dose; mg/m 2/mo = intensity.

dose, since the protocol mandated treatmentdelays for toxicity but not dose reductions. Thedifference between dose and dose intensity at the95% level was less pronounced with CMF reinduc-tion and did not occur with conventional CMFfor which dose reductions rather than delayswere specified for moderate toxicity. Despite thedisparity between dose and dose intensity, pa-tients on AC were more likely to receive _ 95% ofboth dose and dose intensity than were patientson either conventional CMF or CMF reinduc-tion. The percentage of patients receiving _ 95%of the protocol dose intensity was somewhathigher for those on conventional CMF treatedwith lumpectomy and breast radiation than withtotal mastectomy.

Compliance With Reinduction TherapyInformation regarding acceptance of reinduc-

tion therapy was obtained from patients whowere randomized to AC -- CMF as of December31, 1987 (Table 9). Patients entered on studyduring 1988 have been omitted because of eitherinsufficient time to allow for completion of ACtherapy and the 6-month rest period or becauseof inadequate time to obtain treatment informa-tion. Of the 610 randomized patients, 87 (14%)were not eligible for reinduction therapy forreasons summarized in Table 9. Over half (7.9%)of these were ineligible because of a prior eventsuch as a treatment failure, second cancer, ordeath from causes other than cancer. Only 5% ofthose who were eligible for IV CMF therapyfailed to start treatment.

DISCUSSION

This report indicates that the DFS, DDFS, S,and first sites of treatment failure of patientstreated with AC are nearly identical to thoseobtained following administration of conven-tional CMF. Thus, the issue arises as to which ofthe two regimens might be more appropriate foruse as the control group in a new clinical trial orfor the treatment of patients unable to partici-pate in clinical trials. Since CMF is currently themost commonly used regimen for treatment ofstage II breast cancer and is, consequently, theone with which physicians are most familiar, thefindings are likely to be viewed as providingsupport for the continued use of conventionalCMF. On the other hand, information from thisstudy (B-15), as well as findings from otherNSABP clinical trials using Adriamycin, providejustification for seriously considering replace-

Table 9. Compliance With Reinduction TherapyPatient Information No. of Patients % of Patients

Randomized through 12/31/87 610 100Ineligible for reinduction therapy,

IV CMF (at 9 months) 87 14Prior event 48 (7.9)Discontinued AC 18 (3.0)Never started AC 9 (1.5)Protocol ineligible 6 (1.0)Consent withdrawal 2 (0.3)Other reasons 4 (0.7)

Eligible for reinduction therapy,IV CMF (at 9 months) 523 86

Started reinduction 495 81Failed to start 28 5

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ment of CMF with AC. The fact that ACadministration is completed on day 63 of ther-apy, whereas the last dose of CMF is not givenuntil the 154th day of treatment when totalmastectomy has been performed and even later(about 190 days) following lumpectomy andbreast irradiation, is a strong recommendationfor the use of the AC regimen. A further reasonfor using AC is that patients who receive thatdrug combination usually see a physician orother health care professional only four times toreceive drugs, whereas patients on CMF are seen12 times for that purpose. In addition, a womanon AC therapy has a personal responsibility forseeing that she takes chemotherapy on each ofonly 4 days, whereas, if she is the recipient ofCMF, she is obligated to be certain that shereceives some or all of the drugs on each of 84days. In addition to these quality-of-life consider-ations, it has been found that the toxicity result-ing from the 2 months of AC therapy comparesfavorably with the side effects associated with the6 months of conventional CMF.

Despite the fact that CMF has been widelyused for more than a decade, a meticulouslydocumented, detailed account of the toxicityresulting from the regimen is lacking, particu-larly one that characterizes the experience of alarge group of physicians who have used thetherapy as originally described. This report pro-vides such information, including not only themaximum toxicity per patient (severity) for bothCMF and AC but also the number of courses ineach type of toxicity experienced (incidence) inboth regimens. While the incidence of gastricdistress was remarkably similar in both the ACand conventional CMF regimens (290 coursesper 100 patients in the former and 294 coursesper 100 patients in the latter), the nature of thedistress differed.

Nurses who participated in the currently re-ported study have estimated that almost allCMF-treated women required medication to con-trol nausea and other side effects throughouteach 14-day course of therapy, ie, for about 84days. In contrast, such medication is adminis-tered to patients on AC for only 12 days, ie, forabout 3 days after each course. While vomitingwas more common after AC therapy, myelosup-pression, diarrhea, hemorrhagic cystitis, andweight gain occurred more often following the

administration of conventional CMF. There waslittle difference between the two groups in thefrequency of other toxicities except for alopecia,which has always been considered to be a tempo-rarily vexing side effect of Adriamycin therapy.It has not been as well appreciated that hair lossfollowing CMF occurs with the frequency inwhich it was observed in this study: 71% ofpatients had some alopecia, and, in 41%, hair lossof greater than 50% occurred. Because of therelatively short follow-up, this report cannotaddress the equivalence of the two regimensrelative to long-term toxicities, eg, cardiac ormyeloproliferative disorders.

Information obtained from two additionalanalyses provides support for use of the ACregimen. Both of these analyses indicate thattoxicity makes compliance with CMF administra-tion more difficult. The first analysis showed thatdelays and dose reductions occurred more fre-quently when CMF was used than when AC wasused. Both the percentage of treatment coursesdelayed and the percentage of patients havingdelayed courses because of hematologic or gas-trointestinal toxicity were greater following treat-ment with conventional CMF than with AC. Inthe second analysis, when the median amount ofdrug received was examined either according tothe amount per square meter of body surface oraccording to the amount per square meter ofbody-surface area per month (intensity), it wasfound that the median percentage of total drugdose received was lower in patients receivingCMF than in those on AC. Moreover, it wasfound that a greater percentage of patients onAC therapy received a larger percentage of thetotal protocol-defined amount of drug, eithermilligrams per square meter or milligrams persquare meter per month, than did patients onCMF.

When this study was designed, there wasconcern regarding the appropriateness of admin-istering breast radiation to lumpectomy patientssimultaneously with chemotherapy.1 7-20 Severalinvestigators had recommended either giving oneor two courses of chemotherapy before the radia-tion therapy and then completing the chemother-apy subsequent to the irradiation, or modifyingthe CMF given during radiation by deleting themethotrexate and then restoring that drug to thecombination in the courses given after irradia-tion. Concern with cosmesis, hematologic toxic-

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ity, and the ability to deliver protocol-stipulateddoses of drugs prompted such modifications.Thus, in this study, all lumpectomy patientsrandomized to conventional CMF received radia-tion therapy after completion of the first courseof CMF; the five additional courses were givensubsequent to completion of radiation. In pa-tients treated by total mastectomy, the six coursesof CMF were given without interruption. Noevidence was obtained to indicate that the inter-ruption of conventional CMF therapy by radia-tion therapy affected the outcome of patientsreceiving that regimen. Regardless of whetherlumpectomy plus breast radiation or total mastec-tomy was performed, the median percentage ofthe total protocol-prescribed dose (milligramsper square meter) or the total protocol-pre-scribed intensity (milligrams per square meterper month) of each of the drugs received bypatients treated by the conventional CMF combi-nation was similar.

The advantage we recently reported resultingfrom the addition of Adriamycin to L-PAM and5-FU (PAF) in the NSABP study B-11 withoutconsequential side effects attributable to thatdrug further attests to the safety and effective-ness of Adriamycin.7 In that study, not only wasthere a highly significant benefit in DFS follow-ing use of the drug in 344 patients who weresimilar to those in the B-15 study, ie, patientswho were TAM-nonresponsive, but the Adriamy-cin added little hematologic toxicity, cardiactoxicity, or other side effect of consequence,either during or subsequent to completion of thetherapy. We have also recently observed inNSABP B-16 that the addition of AC, as used inB-15, to TAM in women with TAM-responsivestage II breast cancer resulted in a significantlybetter DFS than that which occurred followingthe use of TAM alone.7 The side effects resultingfrom the use of AC in that trial were similar tothose reported in B-15.

The demonstrated efficacy of AC in bothTAM-responsive and TAM-nonresponsive pa-tients indicates that there is justification for theuse of AC therapy in all pre- or postmenopausalbreast cancer patients with positive axillary nodes,as well as in all breast cancer patients withtumors that are either ER-negative or ER-positive. As a consequence of these findings, ACis currently being used in NSABP protocolsevaluating the worth of preoperative chemother-

apy (B-18) and in a stage II study (B-22)evaluating the efficacy of (1) intensifying thedose of cyclophosphamide (keeping the total doseof the drug similar to that currently used, ie,2,400 mg/m2, but administering it over twocourses [1,200 mg/m 2 each] instead of four); and(2) not only intensifying the dose but also increas-ing the total cumulative dose by administering1,200 mg/m 2 at each of four courses, for a totalof 4,800 mg/m2. Findings from B-22 will besignificant in determining whether administeringincreasing amounts of a drug for even shorterperiods of time than is currently being done maybe more efficacious.

In order to test the value of reinduction ther-apy in this study, a rest period rather thanimmediate sequencing of regimens was used.Since there was no information available regard-ing tumor cell growth kinetics-either directly orfrom modeling-which could aid us in determin-ing the time interval to be used for administeringa putatively noncross-resistant regimen (paren-teral CMF), we resorted to information obtainedby our examination of hazard functions obtainedfrom a previous generation of NSABP protocols.These data led us to use the 6-month intervalbetween the completion of the AC therapy andthe onset of the parenteral CMF.

There was concern that patients who hadundergone previous treatment with adjuvant ther-apy (AC) would be reluctant to receive addi-tional therapy, particularly after their hair hadgrown back and they were completely asymptom-atic. That concern was not realized, in that 95%of patients eligible for the reinduction therapycomplied by initiating it. These patients werereadily managed, and it was generally agreedthat fewer undesirable effects resulted from IVCMF therapy than were observed from the use ofconventional CMF. Of particular interest in thatregard was the observation that less hair lossoccurred following parenteral CMF than follow-ing conventional CMF or AC therapy. As withconventional CMF, weight gain relative to weightat randomization was reported to have occurredin about 40% of patients. Sufficient follow-uptime has not yet elapsed to allow for the presenta-tion of findings to indicate the worth of thereinduction chemotherapy as used in this study.

ACKNOWLEDGMENTWe acknowledge the contribution of Tanya Spewock in the

preparation of this manuscript.

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APPENDIXInstitutions Contributing Ten or More Patients to This Study

Principal Investigator Institution

Robert W. Sponzo, MDAjit Desai, MDDavid Prager, MDKarl K. Boatman, MDWilliam S. Blakemore, MDWilliam Reed, MD, and Charles F. White, MDJesse Spector, MDDavid B. Myers, MDMaureen T. Kavanah, MDJohn Michael Sterchi, MDReginald Pugh, MD

Carl G. Kardinal, MD

Jerry T. Guy, MDJames S. Ungerleider, MDJames R. Borst, MDH. James Wallace, Jr, MD

James L. Hoehn, MDJulian B. Hill, MDPhyllis Joyce Ager, MDSteven Jubelirer, MDJose Terz, MDA. H. G. Paterson, MDSpencer O. Raab, MDJames Evans, MDRichard Welling, MDDavid State, MDPeter Deckers, MDAndri Robidoux, MDYosef H. Pilch, MDRichard G. Margolese, MDAndrew G. Glass, MDMarvin Nicola, MDMartin Potvin, MDIsidore Cohn, Jr, MDLee Smith, MDJohn Gullo, MDDavid Bowman, MDPeter D. Eisenberg, MDTimothy Wozniak, MDWalter Lawrence, MDDavid Plaotkin, MDRichard Desser, MDNikolay V. Dimitrov, MDRichard G. Rosen, MDMichael Thirlwell, MDRichard Bornstein, MD and Lawrence Levy, MDFrederick J. Meyers, MD

Leo Stolbach, MDAlan J. Lippman, MDDaniele J. Perrault, MDHarvey J. Lerner, MDCharles J. Lusch, MDHenry Shibata, MD

Albany Regional Cancer Center, Albany, NYAlbert Einstein Medical Center, Philadelphia, PAAllentown Hospital, Allentown, PABaptist Medical Center, Oklahoma City, OKBaptist Medical Centers, Birmingham, ALBaystate Medical Center, Springfield, MABerkshire Medical Center, Pittsfield, MABillings Interhospital Oncology Project, Billings, MTBoston University, Boston, MABowman Gray School of Medicine, Winston-Salem, NCCommunity Clinical Oncology Program, Allegheny-Singer Research Corp,

Pittsburgh, PACommunity Clinical Oncology Program, Alton Ochsner Medical Foundation,

New Orleans, LACommunity Clinical Oncology Program, Columbus, OHCommunity Clinical Oncology Program, Dayton, OHCommunity Clinical Oncology Program, Grand Rapids, MICommunity Clinical Oncology Program, Green Mountain Oncology Group,

Green Mountain, VTCommunity Clinical Oncology Program, Marshfield Clinic, Marshfield, WICommunity Clinical Oncology Program, North Mississippi, Tupelo, MSCommunity Clinical Oncology Program, San Joaquin Valley, Fresno, CACommunity Clinical Oncology Program, West Virginia, Charleston, WVCity of Hope Medical Center, Duarte, CACross Cancer Institute, Edmonton, CanadaEast Carolina University, Greenville, NCGeisinger Medical Center, Danville, PAGood Samaritan Hospital, Cincinnati, OHHarbor General Hospital, Torrance, CAHartford Hospital, Hartford, CTHotel-Dieu, Montreal, CanadaIllinois Masonic Medical Center, Chicago, ILJewish General Hospital, Montreal, CanadaKaiser Permanente, Portland, ORKaiser Permanente, San Diego, CAL'Hopital Laval, Quebec City, CanadaLouisiana State University, New Orleans, LAMid-Atlantic Oncology Program, Hematology Oncology Associates, Alexandria, VAMid-Atlantic Oncology Program, Hematology Oncology Associates, Syracuse, NYManitoba Cancer Foundation, Winnipeg, CanadaMarin General Hospital, Greenbrae, CAMedical Center of Delaware, Inc, Newark, DEMedical College of Virginia, Richmond, VAMemorial Cancer Research Foundation, Los Angeles, CAMichael Reese Hospital, Chicago, ILMichigan State University, E Lansing, MIMontefiore Hospital and Medical Center, Bronx, NYMontreal General Hospital, Montreal, CanadaMount Sinai Medical Center, Cleveland, OHNorthern California Cancer Center/Northern California Oncology Group,

University of California, Davis, CANew England Deaconess Hospital, Boston, MANewark Beth Israel Medical Center, Newark, NJOttawa Regional Cancer Centre, Ottawa, CanadaPennsylvania Hospital, Philadelphia, PAReading Hospital and Medical Center, West Reading, PARoyal Victoria Hospital, Montreal, Canada

(continued on following page)

FISHER ET AL



APPENDIXInstitutions Contributing Ten or More Patients to This Study (Cont'd)

Principal Investigator Institution

Janet Wolter, MDRoger Poisson, MDAlan N. Morrison, MDJohn R. Keyserlingk, MDLeo Mahoney, MDJean Couture, MDNicholas LiCalzi, MDA. Robert Thiessen, MDBrian Pruitt, MDNicholas Robert, MDCarl M. Sutherland, MDNeil Abramson, MDRobert Oishi, MDPeter Jochimsen, MDEdward H. Romond, MDJoseph C. Allegro, MDE. George Elias, MD, PhDAlfred S. Ketcham, MDBernard Fisher, MDAnatolio B. Cruz, Jr, MDRoger S. Foster, Jr, MD

Rush Presbyterian-St Luke's Medical Center, Chicago, ILSt Luc Hospital, Montreal, CanadaSt Luke's Hospital, Bethlehem, PASt Mary's Hospital Center, Montreal, CanadaSt Michael's Hospital, Toronto, CanadaSt Sacrement Hospital, Quebec City, CanadaSouth Nassau Communities Hospital, Long Island, NYTacoma General Hospital, Tacoma, WATexas Tech Medical School, Amarillo, TXTufts University, New England Medical Center, Boston, MATulane University, New Orleans, LAUniversity of Florida, Blood and Cancer Center, Jacksonville, FLUniversity of Hawaii, Honolulu, HIUniversity of Iowa, Iowa City, IAUniversity of Kentucky, Lexington, KYUniversity of Louisville, Louisville, KYUniversity of Maryland, Baltimore, MDUniversity of Miami, Miami, FLUniversity of Pittsburgh, Pittsburgh, PAUniversity of Texas, San Antonio, TXUniversity of Vermont, Burlington, VT

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adjuvant chemotherapy in cancer of the breast: Results of adecade of cooperative investigation. Ann Surg 168:337-356,1968

2. Fisher B, Slack N, Katrych D, et al: Ten-year follow-upresults of patients with carcinoma of the breast in a coopera-tive clinical trial evaluating surgical adjuvant chemotherapy.Surg Gynecol Obstet 140:528-534, 1975

3. Fisher B, Carbone P, Economou SG, et al: L-phenylala-nine mustard (L-PAM) in the management of primary breastcancer: A report of early findings. N Engl J Med 292:117-122, 1975

4. Bonadonna G, Brusamolino E, Valagussa P, et al:Combination chemotherapy as an adjuvant treatment inoperable breast cancer. N Engl J Med 294:405-410, 1976

5. Tancini G, Bonadonna G, Valagussa P, et al: AdjuvantCMF in breast cancer: Comparative 5-year results of 12versus 6 cycles. J Clin Oncol 1:2-10, 1983

6. Fisher B, Redmond C, Brown A, et al: Influence oftumor estrogen and progesterone receptor levels on theresponse to tamoxifen and chemotherapy in primary breastcancer. J Clin Oncol 1:227-241, 1983

7. Fisher B, Redmond C, Wickerham DL, et al: Doxorubi-cin-containing regimens for the treatment of Stage II breastcancer: The NSABP experience. J Clin Oncol 7:572-582,1989

8. Fisher B, Redmond C, Legault-Poisson S, et al: Postop-erative chemotherapy and tamoxifen compared with tamox-ifen alone in the treatment of positive-node breast cancerpatients aged 50 years and older with tumors responsive totamoxifen: Results from the National Surgical AdjuvantBreast and Bowel Project B-16. J Clin Oncol 8:1005-1018,1990

9. Fisher B, Glass A, Redmond C, et al: L-phenylalanine

mustard (L-PAM) in the management of primary breastcancer: An update of earlier findings and a comparison withthose utilizing L-PAM plus 5-fluorouracil (5-FU). Cancer39:2883-2903, 1977

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11. Fisher B, Bauer M, Margolese R, et al: Five-yearresults of a randomized clinical trial comparing total mastec-tomy and segmental mastectomy with or without radiation intreatment of breast cancer. N Engl J Med 312:665-673, 1985

12. Fisher B, Wolmark N, Fisher ER, et al: Lumpectomyand axillary dissection for breast cancer: Surgical, pathologi-cal and radiation considerations. World J Surg 9:692-698,1985

13. Cutler SJ, Ederer F: Maximum utilization of thelife-table method in analyzing survival. J Chronic Dis 8:699-712, 1958

14. Mantel N: Evaluation of survival data and two newrank order statistics arising in its consideration. CancerChemother Rep 50:163-170, 1966

15. Hankey BF, Myers MH: Evaluating differences insurvival between two groups of patients. J Chronic Dis24:523-531, 1971

16. Cox DR: Regression models and life-tables. JR StatSoc (B) 34:187-220, 1972

17. Botnick LE, Lange R, Come S, et al: Primary breastirradiation and concomitant adjuvant chemotherapy, in Har-ris JR, Hellman S, Silen W (eds): Conservative Managementof Breast Cancer, New Surgical and Radiotherapeutic Tech-niques. Philadelphia, PA, Lippincott, 1982, pp 321-328

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18. Glick JH, Weiler C, Danoff BF, et al: Adjuvantchemotherapy in patients undergoing definitive irradiationfor primary breast cancer-The University of Pennsylvaniaexperience, in Harris JR, Hellman S, Silen W (eds): Conser-vative Management of Breast Cancer, New Surgical andRadiotherapeutic Techniques. Philadelphia, PA, Lippincott,1982, pp 311-320

19. Lichter AS, d'Angelo TM, Lippman ME, et al:Adjuvant chemotherapy in patients treated primarily with

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irradiation for localized breast cancer, in Harris JR, HellmanS, Silen W (eds): Conservative Management of BreastCancer, New Surgical and Radiotherapeutic Techniques.Philadelphia, PA, Lippincott, 1982, pp 299-310

20. Danoff BF, Goodman RL, Glick JH, et al: The effectof adjuvant chemotherapy on cosmesis and complications inpatients with breast cancer treated by definitive irradiation.Int J Rad One Biol Phys 9:1625-1630, 1983


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INITIAL - WebHost4Lifemauriciolema.webhost4life.com/rolmm/files/nsabpb15.pdfcomplied with NSABP prerequisites for quality control."' Patient accrual began on October 1, 1984, and was